Identification and structural analysis of a selective tropomyosin receptor kinase C (TRKC) inhibitor
Eur J Med Chem. 2022 Jul 19;241:114601. doi: 10.1016/j.ejmech.2022.114601. Online ahead of print.ABSTRACTTropomyosin receptor kinases (TRKs) are a family of TRKA, TRKB and TRKC isoforms. It has been widely reported that TRKs are implicated in a variety of tumors with several Pan-TRK inhibitors currently being used or evaluated in clinical treatment. However, off-target adverse events frequently occur in the clinical use of Pan-TRK inhibitors, which result in poor patient compliance, even drug discontinuation. Although a subtype-selectivity TRK inhibitor may avert the potential off-target adverse events and can act as a mor...
Source: European Journal of Medicinal Chemistry - July 25, 2022 Category: Chemistry Authors: Zhijie Wang Jiwei Ren Kun Jia Yuming Zhao Li Liang Zitian Cheng Fei Huang Xiaofei Zhao Jie Cheng Shiyu Song Tiancheng Sheng Weiqi Wan Qingqing Shu Donglin Wu Junhao Zhang Tao Lu Yadong Chen Ting Ran Shuai Lu Source Type: research

Synthesis of antiplasmodial 2-aminothieno[3,2-d]pyrimidin-4(3H)-one analogues using the scaffold hopping strategy
Eur J Med Chem. 2022 Jul 20;241:114619. doi: 10.1016/j.ejmech.2022.114619. Online ahead of print.ABSTRACTGamhepathiopine (also known as M1), is a multi-stage acting antiplasmodial 2-tert-butylaminothieno[3,2-d]pyrimidin-4(3H)-one hydrochloride that was first described in 2015. The development of this compound is limited by poor microsomal stability, insufficient aqueous solubility and low intestinal permeability. In order to obtain new optimized derivatives, we conducted a scaffold hopping strategy from compound M1, resulting in the synthesis of 20 new compounds belonging to six chemical series. All the compounds were test...
Source: European Journal of Medicinal Chemistry - July 25, 2022 Category: Chemistry Authors: Romain Musti ère Prisca Lagard ère S ébastien Hutter Viviana Dell'Orco Nadia Amanzougaghene Shahin Tajeri Jean-Fran çois Franetich Sophie Corvaisier Marc Since Aur élie Malzert-Fréon Nicolas Masurier Vincent Lisowski Pierre Verhaeghe Dominique Mazie Source Type: research

Design, synthesis and activity evaluation of isopropylsulfonyl-substituted 2,4- diarylaminopyrimidine derivatives as FAK inhibitors for the potential treatment of pancreatic cancer
Eur J Med Chem. 2022 Jul 19;241:114607. doi: 10.1016/j.ejmech.2022.114607. Online ahead of print.ABSTRACTA series of isopropylsulfonyl-substituted 2,4-diarylaminopyrimidine derivatives were designed and synthesized as FAK inhibitors to evaluate their biological activity against pancreatic cancer. One of the most promising compound, 9h, effectively interfered with FAK-mediated phosphorylation and suppressed the proliferation of human pancreatic cancer AsPC-1 cells with half maximal inhibitory concentration (IC50) values of 0.1165 nM and 0.1596 μM, respectively. In addition, 9h also exhibited relatively low toxicity against...
Source: European Journal of Medicinal Chemistry - July 25, 2022 Category: Chemistry Authors: Xu Zheng Xing Li Liangliang Tian Bin Wu Jiawen Yu Changyuan Wang Xiuli Sun Xiaodong Ma Lixue Chen Yanxia Li Source Type: research

Discovery of potent ebola entry inhibitors with (3S,4aS,8aS)-2-(3-amino-2-hydroxypropyl) decahydroisoquinoline-3-carboxamide scaffold
In this study, we discovered a series of potent Ebola entry inhibitors with the (3S,4aS,8aS)-2-(3-amino-2-hydroxypropyl)decahydroisoquinoline-3-carboxamide scaffold from high-throughput screening in reported pseudotyped virus system. Further optimization resulted a most potent compound 28 (IC50= 0.05 μM, SI = 98), which displayed 3-fold potency compared to the known inhibitor Toremifene (IC50= 0.17 μM, SI = 55). Moreover, compound 28 exhibited the remarkable selectivity between EBOV-GP and VSV-G (Spec. Index = 58), thus could exclude nonspecific effects. Structure-activity relationship and molecular docking analysis of t...
Source: European Journal of Medicinal Chemistry - July 25, 2022 Category: Chemistry Authors: Sheng Han Heng Li Weixiong Chen Li Yang Xiankun Tong Jianping Zuo Youhong Hu Source Type: research

Identification and structural analysis of a selective tropomyosin receptor kinase C (TRKC) inhibitor
Eur J Med Chem. 2022 Jul 19;241:114601. doi: 10.1016/j.ejmech.2022.114601. Online ahead of print.ABSTRACTTropomyosin receptor kinases (TRKs) are a family of TRKA, TRKB and TRKC isoforms. It has been widely reported that TRKs are implicated in a variety of tumors with several Pan-TRK inhibitors currently being used or evaluated in clinical treatment. However, off-target adverse events frequently occur in the clinical use of Pan-TRK inhibitors, which result in poor patient compliance, even drug discontinuation. Although a subtype-selectivity TRK inhibitor may avert the potential off-target adverse events and can act as a mor...
Source: European Journal of Medicinal Chemistry - July 25, 2022 Category: Chemistry Authors: Zhijie Wang Jiwei Ren Kun Jia Yuming Zhao Li Liang Zitian Cheng Fei Huang Xiaofei Zhao Jie Cheng Shiyu Song Tiancheng Sheng Weiqi Wan Qingqing Shu Donglin Wu Junhao Zhang Tao Lu Yadong Chen Ting Ran Shuai Lu Source Type: research

Synthesis of antiplasmodial 2-aminothieno[3,2-d]pyrimidin-4(3H)-one analogues using the scaffold hopping strategy
Eur J Med Chem. 2022 Jul 20;241:114619. doi: 10.1016/j.ejmech.2022.114619. Online ahead of print.ABSTRACTGamhepathiopine (also known as M1), is a multi-stage acting antiplasmodial 2-tert-butylaminothieno[3,2-d]pyrimidin-4(3H)-one hydrochloride that was first described in 2015. The development of this compound is limited by poor microsomal stability, insufficient aqueous solubility and low intestinal permeability. In order to obtain new optimized derivatives, we conducted a scaffold hopping strategy from compound M1, resulting in the synthesis of 20 new compounds belonging to six chemical series. All the compounds were test...
Source: European Journal of Medicinal Chemistry - July 25, 2022 Category: Chemistry Authors: Romain Musti ère Prisca Lagard ère S ébastien Hutter Viviana Dell'Orco Nadia Amanzougaghene Shahin Tajeri Jean-Fran çois Franetich Sophie Corvaisier Marc Since Aur élie Malzert-Fréon Nicolas Masurier Vincent Lisowski Pierre Verhaeghe Dominique Mazie Source Type: research

Design, synthesis and activity evaluation of isopropylsulfonyl-substituted 2,4- diarylaminopyrimidine derivatives as FAK inhibitors for the potential treatment of pancreatic cancer
Eur J Med Chem. 2022 Jul 19;241:114607. doi: 10.1016/j.ejmech.2022.114607. Online ahead of print.ABSTRACTA series of isopropylsulfonyl-substituted 2,4-diarylaminopyrimidine derivatives were designed and synthesized as FAK inhibitors to evaluate their biological activity against pancreatic cancer. One of the most promising compound, 9h, effectively interfered with FAK-mediated phosphorylation and suppressed the proliferation of human pancreatic cancer AsPC-1 cells with half maximal inhibitory concentration (IC50) values of 0.1165 nM and 0.1596 μM, respectively. In addition, 9h also exhibited relatively low toxicity against...
Source: European Journal of Medicinal Chemistry - July 25, 2022 Category: Chemistry Authors: Xu Zheng Xing Li Liangliang Tian Bin Wu Jiawen Yu Changyuan Wang Xiuli Sun Xiaodong Ma Lixue Chen Yanxia Li Source Type: research

Discovery of potent ebola entry inhibitors with (3S,4aS,8aS)-2-(3-amino-2-hydroxypropyl) decahydroisoquinoline-3-carboxamide scaffold
In this study, we discovered a series of potent Ebola entry inhibitors with the (3S,4aS,8aS)-2-(3-amino-2-hydroxypropyl)decahydroisoquinoline-3-carboxamide scaffold from high-throughput screening in reported pseudotyped virus system. Further optimization resulted a most potent compound 28 (IC50= 0.05 μM, SI = 98), which displayed 3-fold potency compared to the known inhibitor Toremifene (IC50= 0.17 μM, SI = 55). Moreover, compound 28 exhibited the remarkable selectivity between EBOV-GP and VSV-G (Spec. Index = 58), thus could exclude nonspecific effects. Structure-activity relationship and molecular docking analysis of t...
Source: European Journal of Medicinal Chemistry - July 25, 2022 Category: Chemistry Authors: Sheng Han Heng Li Weixiong Chen Li Yang Xiankun Tong Jianping Zuo Youhong Hu Source Type: research

Identification and structural analysis of a selective tropomyosin receptor kinase C (TRKC) inhibitor
Eur J Med Chem. 2022 Jul 19;241:114601. doi: 10.1016/j.ejmech.2022.114601. Online ahead of print.ABSTRACTTropomyosin receptor kinases (TRKs) are a family of TRKA, TRKB and TRKC isoforms. It has been widely reported that TRKs are implicated in a variety of tumors with several Pan-TRK inhibitors currently being used or evaluated in clinical treatment. However, off-target adverse events frequently occur in the clinical use of Pan-TRK inhibitors, which result in poor patient compliance, even drug discontinuation. Although a subtype-selectivity TRK inhibitor may avert the potential off-target adverse events and can act as a mor...
Source: European Journal of Medicinal Chemistry - July 25, 2022 Category: Chemistry Authors: Zhijie Wang Jiwei Ren Kun Jia Yuming Zhao Li Liang Zitian Cheng Fei Huang Xiaofei Zhao Jie Cheng Shiyu Song Tiancheng Sheng Weiqi Wan Qingqing Shu Donglin Wu Junhao Zhang Tao Lu Yadong Chen Ting Ran Shuai Lu Source Type: research

Synthesis of antiplasmodial 2-aminothieno[3,2-d]pyrimidin-4(3H)-one analogues using the scaffold hopping strategy
Eur J Med Chem. 2022 Jul 20;241:114619. doi: 10.1016/j.ejmech.2022.114619. Online ahead of print.ABSTRACTGamhepathiopine (also known as M1), is a multi-stage acting antiplasmodial 2-tert-butylaminothieno[3,2-d]pyrimidin-4(3H)-one hydrochloride that was first described in 2015. The development of this compound is limited by poor microsomal stability, insufficient aqueous solubility and low intestinal permeability. In order to obtain new optimized derivatives, we conducted a scaffold hopping strategy from compound M1, resulting in the synthesis of 20 new compounds belonging to six chemical series. All the compounds were test...
Source: European Journal of Medicinal Chemistry - July 25, 2022 Category: Chemistry Authors: Romain Musti ère Prisca Lagard ère S ébastien Hutter Viviana Dell'Orco Nadia Amanzougaghene Shahin Tajeri Jean-Fran çois Franetich Sophie Corvaisier Marc Since Aur élie Malzert-Fréon Nicolas Masurier Vincent Lisowski Pierre Verhaeghe Dominique Mazie Source Type: research

Design, synthesis and activity evaluation of isopropylsulfonyl-substituted 2,4- diarylaminopyrimidine derivatives as FAK inhibitors for the potential treatment of pancreatic cancer
Eur J Med Chem. 2022 Jul 19;241:114607. doi: 10.1016/j.ejmech.2022.114607. Online ahead of print.ABSTRACTA series of isopropylsulfonyl-substituted 2,4-diarylaminopyrimidine derivatives were designed and synthesized as FAK inhibitors to evaluate their biological activity against pancreatic cancer. One of the most promising compound, 9h, effectively interfered with FAK-mediated phosphorylation and suppressed the proliferation of human pancreatic cancer AsPC-1 cells with half maximal inhibitory concentration (IC50) values of 0.1165 nM and 0.1596 μM, respectively. In addition, 9h also exhibited relatively low toxicity against...
Source: European Journal of Medicinal Chemistry - July 25, 2022 Category: Chemistry Authors: Xu Zheng Xing Li Liangliang Tian Bin Wu Jiawen Yu Changyuan Wang Xiuli Sun Xiaodong Ma Lixue Chen Yanxia Li Source Type: research

Discovery of potent ebola entry inhibitors with (3S,4aS,8aS)-2-(3-amino-2-hydroxypropyl) decahydroisoquinoline-3-carboxamide scaffold
In this study, we discovered a series of potent Ebola entry inhibitors with the (3S,4aS,8aS)-2-(3-amino-2-hydroxypropyl)decahydroisoquinoline-3-carboxamide scaffold from high-throughput screening in reported pseudotyped virus system. Further optimization resulted a most potent compound 28 (IC50= 0.05 μM, SI = 98), which displayed 3-fold potency compared to the known inhibitor Toremifene (IC50= 0.17 μM, SI = 55). Moreover, compound 28 exhibited the remarkable selectivity between EBOV-GP and VSV-G (Spec. Index = 58), thus could exclude nonspecific effects. Structure-activity relationship and molecular docking analysis of t...
Source: European Journal of Medicinal Chemistry - July 25, 2022 Category: Chemistry Authors: Sheng Han Heng Li Weixiong Chen Li Yang Xiankun Tong Jianping Zuo Youhong Hu Source Type: research

Identification and structural analysis of a selective tropomyosin receptor kinase C (TRKC) inhibitor
Eur J Med Chem. 2022 Jul 19;241:114601. doi: 10.1016/j.ejmech.2022.114601. Online ahead of print.ABSTRACTTropomyosin receptor kinases (TRKs) are a family of TRKA, TRKB and TRKC isoforms. It has been widely reported that TRKs are implicated in a variety of tumors with several Pan-TRK inhibitors currently being used or evaluated in clinical treatment. However, off-target adverse events frequently occur in the clinical use of Pan-TRK inhibitors, which result in poor patient compliance, even drug discontinuation. Although a subtype-selectivity TRK inhibitor may avert the potential off-target adverse events and can act as a mor...
Source: European Journal of Medicinal Chemistry - July 25, 2022 Category: Chemistry Authors: Zhijie Wang Jiwei Ren Kun Jia Yuming Zhao Li Liang Zitian Cheng Fei Huang Xiaofei Zhao Jie Cheng Shiyu Song Tiancheng Sheng Weiqi Wan Qingqing Shu Donglin Wu Junhao Zhang Tao Lu Yadong Chen Ting Ran Shuai Lu Source Type: research

Synthesis of antiplasmodial 2-aminothieno[3,2-d]pyrimidin-4(3H)-one analogues using the scaffold hopping strategy
Eur J Med Chem. 2022 Jul 20;241:114619. doi: 10.1016/j.ejmech.2022.114619. Online ahead of print.ABSTRACTGamhepathiopine (also known as M1), is a multi-stage acting antiplasmodial 2-tert-butylaminothieno[3,2-d]pyrimidin-4(3H)-one hydrochloride that was first described in 2015. The development of this compound is limited by poor microsomal stability, insufficient aqueous solubility and low intestinal permeability. In order to obtain new optimized derivatives, we conducted a scaffold hopping strategy from compound M1, resulting in the synthesis of 20 new compounds belonging to six chemical series. All the compounds were test...
Source: European Journal of Medicinal Chemistry - July 25, 2022 Category: Chemistry Authors: Romain Musti ère Prisca Lagard ère S ébastien Hutter Viviana Dell'Orco Nadia Amanzougaghene Shahin Tajeri Jean-Fran çois Franetich Sophie Corvaisier Marc Since Aur élie Malzert-Fréon Nicolas Masurier Vincent Lisowski Pierre Verhaeghe Dominique Mazie Source Type: research

Design, synthesis and activity evaluation of isopropylsulfonyl-substituted 2,4- diarylaminopyrimidine derivatives as FAK inhibitors for the potential treatment of pancreatic cancer
Eur J Med Chem. 2022 Jul 19;241:114607. doi: 10.1016/j.ejmech.2022.114607. Online ahead of print.ABSTRACTA series of isopropylsulfonyl-substituted 2,4-diarylaminopyrimidine derivatives were designed and synthesized as FAK inhibitors to evaluate their biological activity against pancreatic cancer. One of the most promising compound, 9h, effectively interfered with FAK-mediated phosphorylation and suppressed the proliferation of human pancreatic cancer AsPC-1 cells with half maximal inhibitory concentration (IC50) values of 0.1165 nM and 0.1596 μM, respectively. In addition, 9h also exhibited relatively low toxicity against...
Source: European Journal of Medicinal Chemistry - July 25, 2022 Category: Chemistry Authors: Xu Zheng Xing Li Liangliang Tian Bin Wu Jiawen Yu Changyuan Wang Xiuli Sun Xiaodong Ma Lixue Chen Yanxia Li Source Type: research