Synthesis of non-nucleoside anti-viral cyclopropylcarboxacyl hydrazones and initial anti-HSV-1 structure-activity relationship studies.
Abstract The synthesis of a lead anti-viral cyclopropyl carboxy acyl hydrazone 4F17 (5) and three sequential arrays of structural analogues along with the initial assessment and optimization of the antiviral pharmacophore against the herpes simplex virus type 1 (HSV-1) are reported. PMID: 32961320 [PubMed - as supplied by publisher] (Source: Bioorganic and Medicinal Chemistry Letters)
Source: Bioorganic and Medicinal Chemistry Letters - September 19, 2020 Category: Chemistry Authors: McNulty J, Babu Dokuburra C, D'Aiuto L, Demers M, McClain L, Piazza P, Williamson K, Zheng W, Nimgaonkar VL Tags: Bioorg Med Chem Lett Source Type: research

Sulfamic acid catalyzed synthesis of new 3,5-[(sub)phenyl]-1H-pyrazolebearing N1-isonicotinoyl: and their pharmacological activity evaluation.
Abstract A sustainable synthesis of new 3,5-[(sub)phenyl]-1H-pyrazole bearing N1-isonicotinoyl derivatives from substituted chalcones and isoniazid by using sulfamic acid and their pharmacological activity evaluationis reported. An anti-oxidant study is performed by using DPPH assay. In vitro anti-mycobacterial activity of compounds bearing R/R'=4-CH3/4-F and 3-OCH3/4-Cl showed complete inhibition (99%) at the MIC of 31 and 34 μM respectively. Antibacterial screening of compounds bearing R/R'= 4-CH3/4-F; 4-OCH3/4-Br; and 4-OCH3/4-Cl) has shown noticeable inhibition (27 mm) against Staphylococcus aureus. The ant...
Source: Bioorganic and Medicinal Chemistry Letters - September 19, 2020 Category: Chemistry Authors: Bhirud JD, Patil RD, Narkhede HP Tags: Bioorg Med Chem Lett Source Type: research

Benzylidene thiazolidinediones: Synthesis, in vitro investigations of antiproliferative mechanisms and in vivo efficacy determination in combination with Imatinib.
Abstract Thiazolidinedione (TZD) has been an interesting scaffold due to its proven antidiabetic activity and encouraging findings in anticancer drug discovery. We synthesised benzylidene thiazolidinedione derivatives which exhibited excellent antiproliferative effects in chronic myeloid leukemic cells K562 and the most active compounds 3t and 3x had GI50 value of 0.9 and 0.23 µM respectively. Both the compound was found to arrest the growth of K562 cells in G0/G1 phase in a time and dose dependent manner. Further, western blot analysis revealed that 3t and 3x could also inhibit the expression of cell prolif...
Source: Bioorganic and Medicinal Chemistry Letters - September 19, 2020 Category: Chemistry Authors: Joshi H, Patil V, Tilekar K, Upadhyay N, Gota V, Ramaa CS Tags: Bioorg Med Chem Lett Source Type: research

Discovery of a Series of Ester-substituted NLRP3 Inflammasome Inhibitors.
AP Abstract The NLRP3 inflammasome is a component of the innate immune system involved in the production of proinflammatory cytokines. Aberrant activation by a wide range of exogenous and endogenous signals can lead to chronic, low-grade inflammation. It has attracted a great deal of interest as a drug target due to the association with diseases of large unmet medical need such as Alzheimer's disease, Parkinson's disease, arthritis, and cancer. To date, no drugs specifically targeting inhibition of the NLRP3 inflammasome have been approved. In this work, we used the known NLRP3 inflammasome inhibitor CP-456,773 (a...
Source: Bioorganic and Medicinal Chemistry Letters - September 18, 2020 Category: Chemistry Authors: Harrison D, Boutard N, Brzozka K, Bugaj M, Chmielewski S, Cierpich A, Doedens JR, R Y Fabritius CH, Gabel CA, Galezowski M, Kowalczyk P, Levenets O, Mroczkowska M, Palica K, Porter RA, Schultz D, Sowinska M, Topolnicki G, Urbanski P, Woyciechowski J, Watt Tags: Bioorg Med Chem Lett Source Type: research

Rhopaladins' analogue (E)-2-aroyl-4-(4-fluorobenzylidene)- 5-oxopyrrolidines inhibit proliferation, promote apoptosis and down-regulation of E6/E7 mRNA in cervical cancer.
Abstract The occurrence and development of cervical cancer threaten women's life and health, HPV-induced cervical cancer is a major health issue among women. We synthesized three Rhopaladins' analogue (E)-2-aroyl-4-(4-fluorobenzylidene)-5-oxopyrrolidines via a tandem Ugi 4CC/SN cyclization with pyrrolidone as a core structure. In addition, the cytotoxicity of these new compounds in the cervical cancer cell line CaSki was studied by MTT assay. And then we chose one to research the apoptosis and the expression of E6/E7 mRNA in CaSki cells. The results indicated that the new compound can not only inhibited the prolif...
Source: Bioorganic and Medicinal Chemistry Letters - September 17, 2020 Category: Chemistry Authors: Zhu XL, Tian XQ, Xu HH, Wang HM, Chen QH, Zeng XH Tags: Bioorg Med Chem Lett Source Type: research

Design, synthesis and biological evaluation of novel heptamethine cyanine dye-erlotinib conjugates as antitumor agents.
In this study, in order to improve the tumor cell targeting ability of EGFR-TKI, EGFR-TKI erlotinib was conjugated with the cancer cell-targeting heptamethine cyanine dyes to form seventeen novel erlotinib-dye conjugates. The efficiency of tumor targeting properties of conjugates against cancer cell growth and EGFR-TK inhibition was evaluated in vitro. The result revealed that most erlotinib-dye conjugates exhibited stronger inhibitory effect on A549, H460, H1299 and MDA-MB-231 cell lines than the parent drug erlotinib. Meanwhile, representative compounds exhibited weak cytotoxicity on human normal mammary epithelial MCF-1...
Source: Bioorganic and Medicinal Chemistry Letters - September 16, 2020 Category: Chemistry Authors: Yang X, Hou Z, Wang D, Mou Y, Guo C Tags: Bioorg Med Chem Lett Source Type: research

Design of a dual ERK5 kinase activation and autophosphorylation inhibitor to block cancer stem cell activity.
Abstract The importance of ERK5 kinase signaling in tumorigenicity, metastasis, and drug resistance of cancer stem cells (CSCs) has been recognized recently, and we report a unique dual inhibitor that blocks binding of the ERK5 activator and ERK5 autophosphorylation simultaneously. The conventional ATP-binding site inhibitors have not yet yielded expected level of anti-cancer effects, due to complexities in converting ERK5 activation into CSC biological effects. We designed the first ERK5-targeted anti-CSC dual active hetero-bivalent inhibitor that blocks the regulatory peptide interaction involved in ERK5 kinase ...
Source: Bioorganic and Medicinal Chemistry Letters - September 15, 2020 Category: Chemistry Authors: Kedika SR, Shukla SP, Gomika Udugamasooriya D Tags: Bioorg Med Chem Lett Source Type: research

The synthesis and anti-tumour properties of novel 4-substituted phthalazinones as Aurora B kinase inhibitors.
Abstract A series of novel 4-substituted phthalazinones as Aurora B kinase inhibitors was synthesized and evaluated the anti-proliferative activities against A549, HCT116, MCF-7 and HepG2 cells. 1-(4-(2-((4-Oxo-3,4-dihydrophthalazin-1-yl)amino)ethyl) phenyl)-3-(3-(trifluoromethyl)phenyl)urea (17b) exhibited the most potent anti-proliferative activity against HCT116 cells with IC50 value of 4.35±1.21 μM, as well as the moderate Aurora B inhibitory activity with the IC50 value of 142 nM. Furthermore, 17b inhibited the phosphorylation of Aurora B on Thr232, leading to cell cycle arrest in the G2/M phase by ...
Source: Bioorganic and Medicinal Chemistry Letters - September 14, 2020 Category: Chemistry Authors: Zhang XJ, Xu Y, Mou HX, Wang S, Hao SY, Chen SW Tags: Bioorg Med Chem Lett Source Type: research

3-(Cyclopropylmethyl)-7-((4-(4-[11C]methoxyphenyl)piperidin-1-yl)methyl)-8-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine: Synthesis and Preliminary Evaluation for PET Imaging of Metabotropic Glutamate Receptor Subtype 2.
Abstract Selective metabotropic glutamate receptor 2 (mGluR2) inhibitors have been demonstrated to show therapeutic effects by improving alleviating symptoms of schizophrenic patients in clinical studies. Herein we report the synthesis and preliminary evaluation of a 11C-labeled positron emission tomography (PET) tracer originating from a mGluR2 inhibitor, 3-(cyclopropylmethyl)-7-((4-(4-methoxyphenyl)piperidin-1-yl)methyl)-8-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine (CMTP, 1a). [11C]CMTP ([11C]1a) was synthesized by O-[11C]methylation of desmethyl precursor 1b with [11C]methyl iodide in 19.7 ± 8.9 % ...
Source: Bioorganic and Medicinal Chemistry Letters - September 14, 2020 Category: Chemistry Authors: Kumata K, Zhang Y, Ogawa M, Kurihara Y, Mori W, Hu K, Fujinaga M, Nengaki N, Zhang MR Tags: Bioorg Med Chem Lett Source Type: research

Discovery of 1-(1H-Indazol-4-yl)-3-((1-Phenyl-1H-Pyrazol-5-yl)methyl) Ureas as Potent and Thermoneutral TRPV1 Antagonists.
Abstract A series of 1-indazol-3-(1-phenylpyrazol-5-yl)methyl ureas were investigated as hTRPV1 antagonists. The structure-activity relationship study was conducted systematically for both the indazole A-region and the 3-trifluoromethyl/t-butyl pyrazole C-region to optimize the antagonism toward the activation by capsaicin. Among them, the antagonists 26, 50 and 51 displayed highly potent antagonism with Ki(CAP) = 0.4-0.5 nM. Further, in vivo studies in mice indicated that these derivatives both antagonized capsaicin induced hypothermia, consistent with their in vitro activity, and themselves did not induce hypert...
Source: Bioorganic and Medicinal Chemistry Letters - September 12, 2020 Category: Chemistry Authors: Mi Kang J, Ok Kwon S, Ann J, Blumberg PM, Ha H, Dong Yoo Y, Frank-Foltyn R, Lesch B, Bahrenberg G, Stockhausen H, Christoph T, Lee J Tags: Bioorg Med Chem Lett Source Type: research

Structural basis for producing selective MAP2K7 inhibitors.
We report a crystal structure of MAP2K7 complexed with a potent covalent inhibitor bearing an acrylamide moiety as an electrophile, which discloses a structural basis for producing selective and potent MAP2K7 inhibitors. PMID: 32931911 [PubMed - as supplied by publisher] (Source: Bioorganic and Medicinal Chemistry Letters)
Source: Bioorganic and Medicinal Chemistry Letters - September 12, 2020 Category: Chemistry Authors: Murakawa Y, Valter S, Barr H, London N, Kinoshita T Tags: Bioorg Med Chem Lett Source Type: research

Mycophenolic anilides as broad specificity inosine-5'-monophosphate dehydrogenase (IMPDH) inhibitors.
Abstract Inosine-5'-monophosphate dehydrogenase (IMPDH) is a potential target for microorganisms. However, identifying inhibitor design determinants for IMPDH orthologs continues to evolve. Herein, a series of mycophenolic anilide inhibitors of Cryptosporidium parvum and human IMPDHs are reported. Furthermore, molecular docking of 12 (e.g. SH-19; CpIMPDH Ki,app = 0.042 ± 0.015 µM, HsIMPDH2 Ki,app = 0.13 ± 0.05 µM) supports different binding modes with the two enzymes. For CpIMPDH the inhibitor extends into a pocket in an adjacent subunit. In contrast, the inhibitor interacts with Ser276 i...
Source: Bioorganic and Medicinal Chemistry Letters - September 12, 2020 Category: Chemistry Authors: Lee S, Ku A, Rao Vippila M, Wang Y, Zhang M, Wang X, Hedstrom L, Cuny GD Tags: Bioorg Med Chem Lett Source Type: research

Antifungal Polybrominated Proxyphylline Derivative Induces Candida albicans Calcineurin Stress Response in Galleria mellonella.
Abstract Candida albicans CNB1 plays a role in the response in vitro and in vivo to stress generated by PB-WUT-01, namely 1,3-dimethyl-7-(2-((1-(3-(perbromo-2H-benzo[d][1,2,3]triazol-2-yl)propyl)-1H-1,2,3-triazol-4-yl)methoxy)propyl)-1H-purine-2,6(3H,7H)-dione. The antifungal mechanism involved the calcineurin pathway-regulated genes SAP9-10. Galleria mellonella treated with PB-WUT-01 (at 0.64 µg/mg) showed limited candidiasis and remained within the highest survival rates. The molecular mode of action of PB-WUT-01 was rationalized by in silico docking studies toward both human and C. albicans calcineurin A ...
Source: Bioorganic and Medicinal Chemistry Letters - September 12, 2020 Category: Chemistry Authors: Gizińska M, Staniszewska A, Kazek M, Koronkiewicz M, Kuryk Ł, Milner-Krawczyk M, Baran J, Borowiecki P, Staniszewska M Tags: Bioorg Med Chem Lett Source Type: research

Synthesis and Biofilm Inhibition Studies of 2-(2-amino-6-arylpyrimidin-4-yl)quinazolin-4(3H)-ones.
Abstract Synthesis of novel 4(3H)-quinazolinonyl aminopyrimidine derivatives has been achieved via quinazolin only enones which in turn were obtained from 2-acyl-4(3H)-quinazolinone. They have been assayed for biofilm inhibition against Gram-positive (methicillin-resistant Staphylococcus aureus (MRSA) and Gram-negative bacteria (Acinetobacter baumannii). The analogues with 2,4,6-trimethoxy phenyl, 4-methylthio phenyl, and 3-bromo phenyl substituents (5h, 5j &5k) have been shown to inhibit biofilm formation efficiently in MRSA with IC50 values of 20.7-22.4 μM). The analogues 5h and 5j have demonstrated low t...
Source: Bioorganic and Medicinal Chemistry Letters - September 11, 2020 Category: Chemistry Authors: Rasapalli S, Murphy ZF, Reddy Sammeta V, Golen JA, Weig AW, Melander RJ, Melander C, Macha P, Vasudev MC Tags: Bioorg Med Chem Lett Source Type: research

Biochemical, Cellular and Structural Characterization of Novel and Selective ERK3 Inhibitors.
r C Abstract Triazolo[4,5-d]pyrimidin-5-amines were identified from kinase selectivity screening as novel ERK3 inhibitors with sub-100 nanomolar potencies in a biochemical assay using MK5 as substrate and with an attractive kinase selectivity profile. ERK3 crystal structures clarified the inhibitor binding mode in the ATP pocket with impact on A-loop, GC- loop and αC -helix conformations suggesting a potential structural link towards MK5 interaction via the FHIEDE motif. The inhibitors also showed sub-100 nM potencies in a cellular ERK3 NanoBRET assay and with excellent correlation to the biochemical IC50s. ...
Source: Bioorganic and Medicinal Chemistry Letters - September 11, 2020 Category: Chemistry Authors: Grädler U, Busch M, Leuthner B, Raba M, Burgdorf L, Lehmann M, Linde N, Esdar C Tags: Bioorg Med Chem Lett Source Type: research

Synthesis of metronidazole based thiazolidinone analogs as promising antiamoebic agents.
Abstract Metronidazole and its derivatives are widely used for the treatment of amoebiasis. However, metronidazole is considered as the standard drug but it has many side effects. The present study describes the synthesis of a series of metronidazole based thiazolidinone analogs via Knoevenagel condensation of 4-[2-(2-methyl-5-nitro-1H-imidazole-1-yl)ethoxy]benzaldehyde 1 with various thiazolidinone derivatives 2-14 to get the new scaffold (15-27) having better activity and lesser toxicity. Six compounds have shown better efficacy and lesser cytotoxicity than the standard drug metronidazole towards HM1: IMSS strai...
Source: Bioorganic and Medicinal Chemistry Letters - September 11, 2020 Category: Chemistry Authors: Ansari MF, Inam A, Ahmad K, Fatima S, Agarwal SM, Azam A Tags: Bioorg Med Chem Lett Source Type: research

Dihydrodibenzothiepine: Promising Hydrophobic Pharmacophore in the Influenza Cap-dependent Endonuclease Inhibitor.
Abstract This work describes a set of discovery research studies of an influenza cap-dependent endonuclease (CEN) inhibitor with a carbamoyl pyridone bicycle (CAB) scaffold. Using influenza CEN inhibitory activity, antiviral activity and pharmacokinetic (PK) parameters as indices, structure activity relationships (SAR) studies were performed at the N-1 and N-3 positions on the CAB scaffold, which is a unique template to bind two metals. The hydrophobic substituent at the N-1 position is extremely important for CEN inhibitory activity and antiviral activity, and dihydrodibenzothiepine is the most promising pharmaco...
Source: Bioorganic and Medicinal Chemistry Letters - September 11, 2020 Category: Chemistry Authors: Taoda Y, Miyagawa M, Akiyama T, Tomita K, Hasegawa Y, Yoshida R, Noshi T, Shishido T, Kawai M Tags: Bioorg Med Chem Lett Source Type: research

Exploring efficacy of Natural-derived Acetylphenol Scaffold Inhibitors for α-Glucosidase: synthesis, in vitro and in vivo biochemical studies.
Exploring efficacy of Natural-derived Acetylphenol Scaffold Inhibitors for α-Glucosidase: synthesis, in vitro and in vivo biochemical studies. Bioorg Med Chem Lett. 2020 Sep 10;:127528 Authors: Yu X, Zhang F, Liu T, Liu Z, Dong Q, Li D Abstract The discovery of novel α-glucosidase inhibitors and anti-diabetic candidates from natural or natural-derived products represents an attractive therapeutic option. Here, a collection of acetylphenol analogues derived from paeonol and acetophenone were synthesized and evaluated for their α-glucosidase inhibitory activity. Most of derivatives, su...
Source: Bioorganic and Medicinal Chemistry Letters - September 10, 2020 Category: Chemistry Authors: Yu X, Zhang F, Liu T, Liu Z, Dong Q, Li D Tags: Bioorg Med Chem Lett Source Type: research

Structure-activity relationships of GPX4 inhibitor warheads.
Abstract Direct inhibition of GPX4 requires covalent modification of the active-site selenocysteine. While phenotypic screening has revealed that activated alkyl chlorides and masked nitrile oxides can inhibit GPX4 covalently, a systematic assessment of potential electrophilic warheads with the capacity to inhibit cellular GPX4 has been lacking. Here, we survey more than 25 electrophilic warheads across several distinct GPX4-targeting scaffolds. We find that electrophiles with attenuated reactivity compared to chloroacetamides are unable to inhibit GPX4 despite the expected nucleophilicity of the selenocysteine re...
Source: Bioorganic and Medicinal Chemistry Letters - September 10, 2020 Category: Chemistry Authors: Eaton JK, Furst L, Cai LL, Viswanathan VS, Schreiber SL Tags: Bioorg Med Chem Lett Source Type: research

Synthesis of indole-tethered [1,3,4]thiadiazolo and [1,3,4]oxadiazolo[3,2-a]pyrimidin-5-one hybrids as anti-pancreatic cancer agents.
Abstract New indole-tethered [1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one (8a-j) and [1,3,4]oxadiazolo[3,2-a]pyrimidin-5-one hybrids (9a-e) were synthesized using [4+2] cycloaddition reactions of functionalized 1,3-diazabuta-1,3-dienes with indole-ketenes. All molecular hybrids were structurally characterized by spectroscopic techniques (IR, NMR, and HRMS) and screened for their anti-pancreatic cancer activity in vitro. The [1,3,4]oxadiazolo[3,2-a]pyrimidin-5-one hybrids (9a-e) showed stronger anti-pancreatic cancer activity than the [1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one hybrids (8a-j) against the PANC-1 cell line....
Source: Bioorganic and Medicinal Chemistry Letters - September 10, 2020 Category: Chemistry Authors: Gummidi L, Kerru N, Awolade P, Raza A, Sharma AK, Singh P Tags: Bioorg Med Chem Lett Source Type: research

Structure-based optimisation of orally active & reversible MetAP-2 inhibitors maintaining a tight 'molecular budget'.
Structure-based optimisation of orally active & reversible MetAP-2 inhibitors maintaining a tight 'molecular budget'. Bioorg Med Chem Lett. 2020 Sep 09;:127533 Authors: Hirst DJ, Brandt M, Bruton G, Christodoulou E, Cutler L, Deeks N, Goodacre JD, Jack T, Lindon M, Miah A, Page K, Parr N, Shukla L, Sims M, Thomas P, Thorpe J, Holmes DS Abstract Structure-based led optimisation of orally active reversible Methionine Aminopeptidase-2 (MetAP-2) inhibitors utilising a 'molecular budget' medicinal chemistry strategy is described. The key physicochemical parameters of target molecules (cLogP, molecular ...
Source: Bioorganic and Medicinal Chemistry Letters - September 9, 2020 Category: Chemistry Authors: Hirst DJ, Brandt M, Bruton G, Christodoulou E, Cutler L, Deeks N, Goodacre JD, Jack T, Lindon M, Miah A, Page K, Parr N, Shukla L, Sims M, Thomas P, Thorpe J, Holmes DS Tags: Bioorg Med Chem Lett Source Type: research

Synthesis and Biological Evaluation of 5'-C-Methyl Nucleotide Prodrugs for Treating HCV Infections.
Abstract Nucleotide prodrugs are of great clinical interest for treating a variety of viral infections due to their ability to target tissues selectively and to deliver relatively high concentrations of the active nucleotide metabolite intracellularly. However, their clinical successes have been limited, oftentimes due to unwanted in vivo metabolic processes that reduce the quantities of nucleoside triphosphate that reach the site of action. In an attempt to circumvent this, we designed novel nucleosides that incorporate a sterically bulky group at the 5'-carbon of the phosphoester prodrug, which we reasoned would...
Source: Bioorganic and Medicinal Chemistry Letters - September 9, 2020 Category: Chemistry Authors: Dasari M, Ma P, Pelly SC, Sharma SK, Liotta DC Tags: Bioorg Med Chem Lett Source Type: research

Design, Synthesis and Evaluation of Novel Indirubin-based N-Hydroxybenzamides, N-Hydroxypropenamides and N-Hydroxyheptanamides as Histone Deacetylase Inhibitors and Antitumor Agents.
Abstract Several novel indirubin-based N-hydroxybenzamides, N-hydropropenamides and N-hydroxyheptanamides (4a-h, 7a-h, 10a-h) were designed using a fragment-based approach with structural features extracted from several previously reported HDAC inhibitors, such as SAHA (vorinostat), MGCD0103 (mocetinostat), nexturastat A and PXD-101 (belinostat). The biological results reveal that our compounds showed excellent cytotoxicity toward three common human cancer cell lines (SW620, PC-3 and NCI-H23) with IC50 values ranging from 0.09 to 0.007 µM. The cytotoxicity of the compounds was equipotent or even up to 10-tim...
Source: Bioorganic and Medicinal Chemistry Letters - September 8, 2020 Category: Chemistry Authors: Anh DT, Hai PT, Dung DTM, Dung PTP, Huong LT, Park EJ, Jun HW, Kang JS, Kwon JH, Tung TT, Han SB, Nam NH Tags: Bioorg Med Chem Lett Source Type: research

Characterization of SPK 98, a Torin2 analog, as ATR and mTOR dual kinase inhibitor.
Abstract A series of Torin2, a second-generation ATP-competitive inhibitor, analogues were biologically characterized to identify their potential for ATR and mTOR kinase inhibition. Compound SPK 98 was observed to inhibit ATR/mTOR kinase selectively over ATM kinase in HCT116 cell line. In addition to that, SPK 98 on 30 min incubation with human, mice and rat liver microsomes showed improved properties with an increased half-life (a maximum T ½ of 157 min) and internal clearance in mouse as compared to Torin2. Further, SPK 98 was also noticed to indulge in inducing premature chromatin condensation as a resul...
Source: Bioorganic and Medicinal Chemistry Letters - September 7, 2020 Category: Chemistry Authors: Bhakuni R, Shaik A, Priya B, Kirubakaran S Tags: Bioorg Med Chem Lett Source Type: research

Synthesis, Biological Activities, and SAR Studies of Novel 1-(2-chloro-4,5-difluorophenyl)-1H-pyrazole Derivatives.
Abstract In order to search for the new ryanodine receptor (RyR) regulator, a series of 35 novel fluoro-substituted compounds introduced 1-(2-chloro-4,5-difluorophenyl)-1H-pyrazole moiety containing modified pyrazole heterocycle were designed and synthesized. Then, they were tested for the insecticidal activities against Mythimna separata and Plutella xylostella in our greenhouse. After a systematic biological screening, it was found out that IVc showed 50% larvicidal activities against Mythimna separata at 0.1 mg L-1, equivalent to that of chlorantraniliprole (36%, 0.1 mg L-1). The activity of IVc against Plutell...
Source: Bioorganic and Medicinal Chemistry Letters - September 5, 2020 Category: Chemistry Authors: Zhao Y, Li H, Sun P, Gao L, Liu J, Zhou S, Xiong L, Yang N, Li Y, Li Z Tags: Bioorg Med Chem Lett Source Type: research

Fragment-Based Lead Discovery of a Novel Class of Small Molecule Inhibitors of Neuropeptide B/W Receptor Subtype 1 (GPR7).
Abstract Here, we report the discovery of a new class of NPBWR1 antagonists identified from a fragment-based screen. Compound 1 (cAMP IC50 = 250 µM; LE = 0.29) emerged as an initial hit. Further optimization of 1 by SAR-by-catalogue and chemical modification produced 21a (cAMP IC50 = 30 nM; LE = 0.39) with a 6,700-fold increase in potency from fragment 1. Somewhat surprisingly, Schild analysis of compound 21a suggested that in vitro inhibition of NPW-mediated effects on upon cAMP accumulation were saturable, and that compound 21a dose-dependently increased [125I]-hNPW23 dissociation rate constants from NPBWR...
Source: Bioorganic and Medicinal Chemistry Letters - September 5, 2020 Category: Chemistry Authors: Moningka R, Anthony Romero F, Hastings NB, Guo Z, Wang M, Di Salvo J, Li Y, Trusca D, Deng Q, Tong V, Terebetski JL, Ball RG, Ujjainwalla F Tags: Bioorg Med Chem Lett Source Type: research

Inhibitory Effect of 5-FU loaded ultrasound microbubbles on Tumor Growth and Angiogenesis.
Abstract The anti-neovascularization treatment is one of the effective strategies for tumor molecular target therapy. At present, the target and effect of the anti-neovascularization treatment is limited, and it is urgent to establish a new vascular targeting strategy to effectively treat tumors. In this work, we used high intensity focused ultrasound (HIFU) combined with targeted microbubbles to establish a molecular targeted ultrasound response microbubble for neovascular cells. Furthermore, the effects of drug loaded microbubbles on neovascularization and tumor cells were studied. The tumor vascular targeted an...
Source: Bioorganic and Medicinal Chemistry Letters - September 5, 2020 Category: Chemistry Authors: He Y, Zhang Y, Qin HY, Gu DY, Lu X, Hu JX, Ye WL, He GB Tags: Bioorg Med Chem Lett Source Type: research

Discovery of ONO-8590580: a novel, potent and selective GABAA α5 negative allosteric modulator for the treatment of cognitive disorders.
Discovery of ONO-8590580: a novel, potent and selective GABAA α5 negative allosteric modulator for the treatment of cognitive disorders. Bioorg Med Chem Lett. 2020 Sep 05;:127536 Authors: Lewis A, Beresford A, Chambers MS, Clark G, Hartley DC, Hirst KL, Higashino M, Kawahadara S, Nakanishi M, Saito T, Imagawa A, Habashita H, Maidment S, Macleod AM, Owens AP, Rae A, Rouse C, Wishart G Abstract The identification and SAR development of a series of negative allosteric modulators of the GABAA α5 receptor is described. This novel series of compounds was optimised to provide analogues with high ...
Source: Bioorganic and Medicinal Chemistry Letters - September 5, 2020 Category: Chemistry Authors: Lewis A, Beresford A, Chambers MS, Clark G, Hartley DC, Hirst KL, Higashino M, Kawahadara S, Nakanishi M, Saito T, Imagawa A, Habashita H, Maidment S, Macleod AM, Owens AP, Rae A, Rouse C, Wishart G Tags: Bioorg Med Chem Lett Source Type: research

Probing the B- & C-rings of the antimalarial tetrahydro- β-carboline MMV008138 for steric and conformational constraints.
Probing the B- & C-rings of the antimalarial tetrahydro-β-carboline MMV008138 for steric and conformational constraints. Bioorg Med Chem Lett. 2020 Sep 05;:127520 Authors: Ding S, Ghavami M, Butler JH, Merino EF, Slebodnick C, Cassera MB, Carlier PR Abstract The antimalarial candidate MMV008138 (1a) is of particular interest because its target enzyme (IspD) is absent in human. To achieve higher potency, and to probe for steric demand, a series of analogs of 1a were prepared that featured methyl-substitution of the B- and C-rings, as well as ring-chain transformations. X-ray crystallography, N...
Source: Bioorganic and Medicinal Chemistry Letters - September 5, 2020 Category: Chemistry Authors: Ding S, Ghavami M, Butler JH, Merino EF, Slebodnick C, Cassera MB, Carlier PR Tags: Bioorg Med Chem Lett Source Type: research

Synthesis and biological evaluation of diaryl urea derivatives as FLT3 inhibitors.
Abstract As a class III receptor tyrosine kinase (RTK), FMS-like tyrosine kinase 3 (FLT3) is always overexpressed in many cases of acute leukemia. This paper studies the structure-based synthesis and biological evaluation of diaryl urea derivatives as FLT3 inhibitors. Encouragingly, compounds 15b, 16b, 24a, and 24c showed excellent biological activities in a low nanomolar range. In particular, compound 16b demonstrated significant inhibitory potency against FLT3-ITD (IC50 = 5.60 nM) and better antiproliferative activity than quizartinib against MV4-11 cell line (IC50 = 0.176 nM). It is indicated that compound 16b ...
Source: Bioorganic and Medicinal Chemistry Letters - September 5, 2020 Category: Chemistry Authors: Zhang Q, Zhao K, Zhang L, Jiao X, Zhang Y, Tang C Tags: Bioorg Med Chem Lett Source Type: research

Discovery of Small Molecule FLT3 Inhibitors That Are Able to Overcome Drug-Resistant Mutations.
Abstract Herein we report the discovery of 1-(5-(tert-butyl)isoxazol-3-yl)-3- (3-fluorophenyl)urea derivatives as new FLT3 inhibitors that are able to overcome the drug resistance mutations: the secondary D835Y and F691L mutations on the basis of the internal tandem duplications (ITD) mutation of FLT3 (FLT3-ITD/D835Y and FLT3-ITD/F691L, respectively). The most potent compound corresponds to 1-(5-(tert-butyl)isoxazol-3-yl)-3-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3- fluorophenyl)urea (4d), which showed IC50s (half maximal inhibitory concentrations) of 0.072 nM, 5.86 nM and 3.48 nM against FLT3-ITD, FLT3-ITD/F691L and...
Source: Bioorganic and Medicinal Chemistry Letters - September 3, 2020 Category: Chemistry Authors: Zhang G, Zhang W, Shen C, Nan J, Chen M, Lai S, Zhong J, Li B, Wang T, Wang Y, Yang S, Li L Tags: Bioorg Med Chem Lett Source Type: research

Cryo-EM as a powerful tool for drug discovery.
Abstract The recent revolution in cryo-EM has produced an explosion of structures at near-atomic or better resolution. This has allowed cryo-EM structures to provide visualization of bound small-molecule ligands in the macromolecules, and these new structures have provided unprecedented insights into the molecular mechanisms of complex biochemical processes. They have also had a profound impact on drug discovery, defining the binding modes and mechanisms of action of well-known drugs as well as driving the design and development of new compounds. This review will summarize and highlight some of these structures. M...
Source: Bioorganic and Medicinal Chemistry Letters - September 2, 2020 Category: Chemistry Authors: Van Drie JH, Tong L Tags: Bioorg Med Chem Lett Source Type: research

Synthesis and in vitro antitumour activity of carboplatin analogues containing functional handles compatible for conjugation to drug delivery systems.
We describe herein the synthesis of a series of carboplatin derivatives with different functional groups at position 3 of the cyclobutane ring. This pharmacomodulation approach aims at facilitating the vectorisation of these analogues, via their subsequent conjugation to a drug delivery system. Five different derivatives bearing a hydroxy, keto, iodo, azido or amino function at position 3 were synthesised. One of these compounds was coupled to a bifunctional maleimide-containing linker. All compounds were tested in vitro for their cytotoxicity on four different cell lines including two platinum-resistant colorectal cancer ...
Source: Bioorganic and Medicinal Chemistry Letters - September 2, 2020 Category: Chemistry Authors: Rečnik LM, Cantelli C, Fersing C, Gongora C, Pouget JP, Lisowski V Tags: Bioorg Med Chem Lett Source Type: research

Structure-based amelioration of PXR transactivation in a novel series of macrocyclic allosteric inhibitors of HIV-1 integrase.
Abstract Previous studies have identified a series of imidazo[1,2-a]pyridine (IZP) derivatives as potent allosteric inhibitors of HIV-1 integrase (ALLINIs) and virus infection in cell culture. However, IZPs were also found to be relatively potent activators of the pregnane-X receptor (PXR), raising the specter of induction of CYP-mediated drug disposition pathways. In an attempt to modify PXR activity without affecting anti-HIV-1 activity, rational structure-based design and modeling approaches were used. An X-ray cocrystal structure of (S,S)-1 in the PXR ligand binding domain (LBD) allowed an examination of the p...
Source: Bioorganic and Medicinal Chemistry Letters - September 2, 2020 Category: Chemistry Authors: Sivaprakasam P, Wang Z, Meanwell NA, Khan JA, Langley DR, Johnson SR, Li G, Pendri A, Connolly TP, Gao M, Camac DM, Klakouski C, Zvyaga T, Cianci C, McAuliffe B, Ding B, Discotto L, Krystal MR, Jenkins S, Peese KM, Narasimhulu Naidu B Tags: Bioorg Med Chem Lett Source Type: research

Synthesis and SAR of a series of mGlu7 NAMs based on an ethyl-8-methoxy-4-(4-phenylpiperazin-1-yl)quinoline carboxylate core.
Abstract A High-Throughput Screening (HTS) campaign identified a fundamentally new mGlu7 NAM chemotype, based on an ethyl-8-methoxy-4-(4-phenylpiperazin-1-yl)quinolone carboxylate core. The initial hit, VU0226390, was a potent mGlu7 NAM (IC50 = 647 nM, 6% L-AP4 min) with selectivity versus the other group III mGlu receptors (>30 μM vs. mGlu4 and mGlu8). A multi-dimensional optimization effort surveyed all regions of this new chemotype, and found very steep SAR, reminiscent of allosteric modulators, and unexpected piperazine mimetics (whereas classical bioisosteres failed). While mGlu7 NAM potency could be im...
Source: Bioorganic and Medicinal Chemistry Letters - September 2, 2020 Category: Chemistry Authors: Kalbfleisch JJ, Reed CW, Park C, Spearing PK, Quitalig MC, Jenkins MT, Rodriguez AL, Blobaum AL, Jeffrey Conn P, Niswender CM, Lindsley CW Tags: Bioorg Med Chem Lett Source Type: research

Synthesis of Functionalized Derivatives of the Gamma-Secretase Modulator BMS-932481 and Identification of its Major Metabolite.
Abstract In an effort to improve physical properties by introducing polar functionality into the bicyclic pyrimidine gamma-secretase modulator (GSM) clinical candidate BMS-932481, we prepared several oxidative products of BMS-932481. Among the analogs that were prepared, the C-5 alcohol 3 was identified as the predominant metabolite of BMS-932481 found in rat and human liver microsomes. Alcohol 3 was determined to be chemically unstable, leading to the hypothesis that 3 may lead to the production of reactive species both in vitro and in vivo. PMID: 32890687 [PubMed - as supplied by publisher] (Source: Bioorga...
Source: Bioorganic and Medicinal Chemistry Letters - September 2, 2020 Category: Chemistry Authors: Zhang Y, Boy KM, Wu YJ, Ramirez A, Toyn JH, Ahlijanian MK, Albright CF, Zhuo X, Johnson BM, Denton RR, Olson RE, Thompson LA, Macor JE Tags: Bioorg Med Chem Lett Source Type: research

Synthesis and evaluations of selective COX-2 inhibitory effects: Benzo[d]thiazol analogs.
Abstract A series of benzo[d]thiazole analogs were synthesized and evaluated for their anti-inflammatory and analgesic effects. Using an ear edema model, except for compounds 2k, 2m-2q and 3a, other compounds showed the anti-inflammatory effects. Among them, compounds 2c, 2d, and 2g showed the best anti-inflammatory activity (inhibition rate: 86.8%, 90.7% and 82.9%, respectively). By the acetic acid-induced abdominal writhing test, except for compounds 2e, 2l, 2m, 2o, 2p and 3a, other compounds showed the analgesic effects with inhibition rate values of 51.9-100% (2a-2r) and 68.6-100% (3a-3g). Next, compounds 2c, ...
Source: Bioorganic and Medicinal Chemistry Letters - August 4, 2020 Category: Chemistry Authors: He LY, Zhang SS, Peng DX, Guan LP, Wang SH Tags: Bioorg Med Chem Lett Source Type: research

A highly selective and sensitive boronic acid-based sensor for detecting Pd2+ ion under mild conditions.
Abstract Herein, a boronic acid-based sensor was reported selectively to recognize Pd2+ ion. The fluorescence intensity increased 36-fold after sensor binding with 2.47 × 10-5 M of Pd2+ ion. It was carried out in the 99% aqueous solution for binding tests, indicating sensor having good water solubility. In addition, it is discernible that Pd2+ ion turned on the blue fluorescence of sensor under a UV-lamp (365 nm), while other ions (Ag+, Al3+, Ba2+, Ca2+, Cr2+, Cd2+, Co2+, Cs2+, Cu2+, Fe2+, Fe3+, K+, Li+, Mg2+, Mn2+, Na+, Ni2+ and Zn2+) did not show the similar change. Furthermore, sensor has a...
Source: Bioorganic and Medicinal Chemistry Letters - August 4, 2020 Category: Chemistry Authors: Fang G, Zhan D, Wang R, Bian Z, Zhang G, Wu Z, Yao Q Tags: Bioorg Med Chem Lett Source Type: research

Improved cytosolic delivery of macromolecules through dimerization of attenuated lytic peptides.
In this study, we prepared dimers of L17E and its analog L17E/Q21E. Dimerization of L17E increased cytotoxicity leading to reduced intracellular delivery compared with L17E. On the other hand, the dimers of the L17E analog, L17E/Q21E, especially when tethered at the N-termini, yielded a comparable level of intracellular delivery with L17E at decreased amounts of delivery peptides and cargoes. PMID: 32738963 [PubMed - in process] (Source: Bioorganic and Medicinal Chemistry Letters)
Source: Bioorganic and Medicinal Chemistry Letters - August 4, 2020 Category: Chemistry Authors: Nomura Y, Sakamoto K, Akishiba M, Iwata T, Hirose H, Futaki S Tags: Bioorg Med Chem Lett Source Type: research

Synthesis of 18F-labeled streptozotocin derivatives and an in-vivo kinetics study using positron emission tomography.
In this study, novel Fluorine-18-labeled streptozotocin (STZ) derivatives were synthesized to serve as glycoside analogs for in-vivo GLUT2 imaging. Fluorine was introduced to hexyl groups at the 3'-positions of the compounds, and we aimed to synthesize compounds that were more stable than STZ. The nitroso derivatives exhibited relatively good stability during purification and purity analysis after radiosynthesis. We then evaluated the compounds in PET imaging and ex-vivo biodistribution studies. We observed high levels of radioactivity in the liver and kidney, which indicated accumulation in these organs within 5 min ...
Source: Bioorganic and Medicinal Chemistry Letters - August 4, 2020 Category: Chemistry Authors: Arimitsu K, Yagi Y, Koshino K, Nishito Y, Higuchi T, Yasui H, Kimura H Tags: Bioorg Med Chem Lett Source Type: research

Optimizing the aryl-triazole of cjoc42 for enhanced gankyrin binding and anti-cancer activity.
Abstract Gankyrin is an oncoprotein overexpressed in numerous cancer types and appears to play a key role in regulating cell proliferation, cell growth, and cell migration. These roles are largely due to gankyrin's protein-protein interaction with the 26S proteasome. We previously published a study exploring the aryl sulfonate ester of cjoc42 in an effort to enhance gankyrin binding and inhibit cancer cell proliferation. In order to further improve the gankyrin binding ability of the cjoc42 scaffold, an extensive SAR for the aryl-triazole moiety of cjoc42 was developed. Our cjoc42 derivatives exhibited enhanced ga...
Source: Bioorganic and Medicinal Chemistry Letters - August 4, 2020 Category: Chemistry Authors: Kanabar D, Farrales P, Kabir A, Juang D, Gnanmony M, Almasri J, Torrents N, Shukla S, Gupta V, Dukhande VV, D'Souza A, Muth A Tags: Bioorg Med Chem Lett Source Type: research

Discovery of (3S,4S)-3-methyl-3-(4-fluorophenyl)-4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxyprop-2-yl)phenyl)pyrrolidines as novel ROR γt inverse agonists.
Discovery of (3S,4S)-3-methyl-3-(4-fluorophenyl)-4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxyprop-2-yl)phenyl)pyrrolidines as novel RORγt inverse agonists. Bioorg Med Chem Lett. 2020 Sep 01;30(17):127392 Authors: Jiang B, Duan JJ, Stachura S, Karmakar A, Hemagiri H, Raut DK, Gupta AK, Weigelt CA, Khan J, Sack JS, Wu DR, Yarde M, Shen DR, Galella MA, Mathur A, Zhao Q, Salter-Cid LM, Carter PH, Dhar TGM Abstract A novel series of cis-3,4-diphenylpyrrolidines were designed as RORγt inverse agonists based on the binding conformation of previously reported bicyclic sulfonamide 1. Preliminary synthesi...
Source: Bioorganic and Medicinal Chemistry Letters - August 4, 2020 Category: Chemistry Authors: Jiang B, Duan JJ, Stachura S, Karmakar A, Hemagiri H, Raut DK, Gupta AK, Weigelt CA, Khan J, Sack JS, Wu DR, Yarde M, Shen DR, Galella MA, Mathur A, Zhao Q, Salter-Cid LM, Carter PH, Dhar TGM Tags: Bioorg Med Chem Lett Source Type: research

Discovery of a novel selective water-soluble SMAD3 inhibitor as an antitumor agent.
This study not only provided a preferable lead compound, 16d, for further drug discovery or a potential tool to study SMAD3 biology, but also proved the effectiveness of our strategy for water-solubility driven optimization. PMID: 32738967 [PubMed - in process] (Source: Bioorganic and Medicinal Chemistry Letters)
Source: Bioorganic and Medicinal Chemistry Letters - August 4, 2020 Category: Chemistry Authors: Wu N, Lian G, Sheng J, Wu D, Yu X, Lan H, Hu W, Yang Z Tags: Bioorg Med Chem Lett Source Type: research

Evaluation of the effect of synthetic compounds derived from azidothymidine on MDA-MB-231 type breast cancer cells.
s F Abstract The present study aimed to investigate the effect of AZT derivates containing tellurium (Te) on human breast cancer cell lines and the mechanisms underlying cell death. The inhibitory effect of AZT and its derivatives (7m and 7r) was determined by the MTT assay (6.25, 12.5, 25, 50 and 100 μM in 24 and 48 h time points), meanwhile the induction of apoptosis and the cell cycle phases was investigated by flow cytometry. The MTT assay showed that AZT derivatives decreased the rate of cell proliferation at concentrations of 12.5 μM, while commercial AZT showed low antitumor potential. ...
Source: Bioorganic and Medicinal Chemistry Letters - August 4, 2020 Category: Chemistry Authors: Oliveira Rocha AM, Severo Sabedra Sousa F, Mascarenhas Borba V, S Munchen T, Guerin Leal J, Dorneles Rodrigues OE, G Fronza M, Savegnago L, Collares T, Kömmling Seixas F Tags: Bioorg Med Chem Lett Source Type: research

Structure-activity relationship analysis of dammarane-type natural products as muscle-type creatine kinase activators.
In this study, twelve dammarane-type compounds were used for structure-activity relationship analysis in terms of enzyme activity, intermolecular interaction, and molecular docking. Enzyme activity analysis showed that 20(S)-PPD, 20(R)-PPD, 20(S)-protopanaxatriol [20(S)-PPT], 25-OH-PPD, 24-COOH-PPD, panaxadiol (PD), and ginsenoside Rh2 significantly increased CK-MM activity. Panaxatriol (PT), ocotillol, ginsenoside Rg1, and ginsenoside Rd had no significant influence on CK-MM activity, while jujubogenin inhibited its activity. Biolayer Interferometry (BLI) assay produced the same results as those on enzyme activity. The in...
Source: Bioorganic and Medicinal Chemistry Letters - August 4, 2020 Category: Chemistry Authors: Cheng Y, Li R, Lin Z, Chen F, Dai J, Zhu Z, Chen L, Zhao Y Tags: Bioorg Med Chem Lett Source Type: research

Topical 'dual-soft' glucocorticoid receptor agonist for dermatology.
Abstract Steroidal glucocorticoids (GR agonists) have been widely used for the topical treatment of skin disorders, including atopic dermatitis. They are a very effective therapy, but they are associated with both unwanted local effects in the skin (skin thinning/atrophy) and systemic side effects. These effects can limit the long-term utility of potent steroids. Here we report on a topically delivered non-steroidal GR agonist, that has the potential to deliver high efficacy in the skin, but due to rapid metabolism in the blood & liver ("dual-soft") it should have greater systemic safety than existin...
Source: Bioorganic and Medicinal Chemistry Letters - August 4, 2020 Category: Chemistry Authors: Dack KN, Johnson PS, Henriksson K, Eirefelt S, Carnerup MA, Stahlhut M, Ollerstam AK Tags: Bioorg Med Chem Lett Source Type: research

MK-5204: An orally active β-1,3-glucan synthesis inhibitor.
MK-5204: An orally active β-1,3-glucan synthesis inhibitor. Bioorg Med Chem Lett. 2020 Sep 01;30(17):127357 Authors: Apgar JM, Wilkening RR, Parker DL, Meng D, Wildonger KJ, Sperbeck D, Greenlee ML, Balkovec JM, Flattery AM, Abruzzo GK, Galgoci AM, Giacobbe RA, Gill CJ, Hsu MJ, Liberator P, Misura AS, Motyl M, Kahn JN, Powles M, Racine F, Dragovic J, Fan W, Kirwan R, Lee S, Liu H, Mamai A, Nelson K, Peel M Abstract Our previously reported efforts to produce an orally active β-1,3-glucan synthesis inhibitor through the semi-synthetic modification of enfumafungin focused on replacing the C2 ac...
Source: Bioorganic and Medicinal Chemistry Letters - August 4, 2020 Category: Chemistry Authors: Apgar JM, Wilkening RR, Parker DL, Meng D, Wildonger KJ, Sperbeck D, Greenlee ML, Balkovec JM, Flattery AM, Abruzzo GK, Galgoci AM, Giacobbe RA, Gill CJ, Hsu MJ, Liberator P, Misura AS, Motyl M, Kahn JN, Powles M, Racine F, Dragovic J, Fan W, Kirwan R, Le Tags: Bioorg Med Chem Lett Source Type: research

Identification of potent inhibitors of the sortilin-progranulin interaction.
B, Klein DJ, Soisson SM, Zerbinatti C, Coleman PJ Abstract High-throughput screening methods have been used to identify two novel series of inhibitors that disrupt progranulin binding to sortilin. Exploration of structure-activity relationships (SAR) resulted in compounds with sufficient potency and physicochemical properties to enable co-crystallization with sortilin. These co-crystal structures supported observed SAR trends and provided guidance for additional avenues for designing compounds with additional interactions within the binding site. PMID: 32738972 [PubMed - in process] (Source: Bioorganic and M...
Source: Bioorganic and Medicinal Chemistry Letters - August 4, 2020 Category: Chemistry Authors: Stachel SJ, Ginnetti AT, Johnson SA, Cramer P, Wang Y, Bukhtiyarova M, Krosky D, Stump C, Hurzy DM, Schlegel KA, Cooke AJ, Allen S, O'Donnell G, Ziebell M, Parthasarathy G, Getty KL, Ho T, Ou Y, Jovanovska A, Carroll SS, Pausch M, Lumb K, Mosser SD, Volet Tags: Bioorg Med Chem Lett Source Type: research

Potent, non-covalent reversible BTK inhibitors with 8-amino-imidazo[1,5-a]pyrazine core featuring 3-position bicyclic ring substitutes.
E, Zhang-Hoover J, Knemeyer I, Garlisi CG, Stivers P, Brandish PE, Hicks A, Kim R, Kozlowski JA Abstract Bruton's tyrosine kinase (BTK) is a Tec family kinase with a well-defined role in the B cell receptor (BCR) pathway. It has become an attractive kinase target for selective B cell inhibition, and for the treatment of B cell related diseases. Many BTK inhibitors have been discovered for the treatment of cancer and rheumatoid arthritis, including a series of BTK inhibitors based on 8-amino-imidazo[1,5-a]pyrazine we recently reported. The X-ray crystal structures of BTK with inhibitors were also published, which p...
Source: Bioorganic and Medicinal Chemistry Letters - August 4, 2020 Category: Chemistry Authors: Liu J, Guiadeen D, Krikorian A, Gao X, Wang J, Babu Boga S, Alhassan AB, Yu W, Selyutin O, Yu Y, Anand R, Xu J, Kelly J, Duffy JL, Liu S, Yang C, Wu H, Cai J, Bennett C, Maloney KM, Tyagarajan S, Gao YD, Fischmann TO, Presland J, Mansueto M, Xu Z, Leccese Tags: Bioorg Med Chem Lett Source Type: research

Orally bioavailable HCV NS5A inhibitors of unsymmetrical structural class.
Abstract A novel unsymmetrical structural class of orally bioavailable hepatitis C virus (HCV) nonstructural 5A protein (NS5A) inhibitors has been generated by improving both the solubility and membrane permeability of the lead compound found in our previous work. The representative compound 14, with a 5-hydroxymethylpyrazine group and a 3-t-butylpropargyl group on each side of the molecule, exhibited the best oral bioavailability in this study, inhibiting not only the HCV genotype 1a, 1b, 2a, and 3a replicons with EC50 values in the picomolar range, but also inhibited 1a Q30 mutants induced by launched symmetrica...
Source: Bioorganic and Medicinal Chemistry Letters - August 4, 2020 Category: Chemistry Authors: Nakamura H, Fujioka S, Terui T, Okuda S, Kondo K, Tamatani Y, Akagi Y, Komoda Y, Kinoshita W, Ito S, Maeda K, Ukaji Y, Inaba T Tags: Bioorg Med Chem Lett Source Type: research