Structure-based amelioration of PXR transactivation in a novel series of macrocyclic allosteric inhibitors of HIV-1 integrase.

Structure-based amelioration of PXR transactivation in a novel series of macrocyclic allosteric inhibitors of HIV-1 integrase.
Bioorg Med Chem Lett. 2020 Sep 02;:127531
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
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 potential of rational structural modifications designed to abrogate PXR. The introduction of bulky basic amines at the C-8 position provided macrocyclic IZP derivatives that displayed potent HIV-1 inhibitory activity in cell culture with no detectable PXR transactivation at the highest concentration tested.
PMID: 32890685 [PubMed - as supplied by publisher]

Source: Bioorganic and Medicinal Chemistry Letters - September 1, 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