Aligning Potency and Pharmacokinetic Properties for Pyridine-Based NCINIs

Overview

Journal ACS Med Chem Lett

Publisher American Chemical Society

Specialty Chemistry

Date 2016 Aug 27

PMID 27563405

Citations 9

Authors

Lee D Fader

Murray Bailey

Eric Beaulieu

Francois Bilodeau

Pierre Bonneau

Yves Bousquet

Rebekah J Carson

Catherine Chabot

Rene Coulombe

Jianmin Duan

Craig Fenwick

Michel Garneau

Ted Halmos

Araz Jakalian

Clint James

Stephen H Kawai

Serge Landry

Steven R LaPlante

Stephen W Mason

Sebastien Morin

Nathalie Rioux

Bruno Simoneau

Simon Surprenant

Bounkham Thavonekham

Carl Thibeault

Thao Trinh

Youla Tsantrizos

Jennifer Tsoung

Christiane Yoakim

Dominik Wernic

Affiliations

Soon will be listed here.

Abstract

Optimization of pyridine-based noncatalytic site integrase inhibitors (NCINIs) based on compound 2 has led to the discovery of molecules capable of inhibiting virus harboring N124 variants of HIV integrase (IN) while maintaining minimal contribution of enterohepatic recirculation to clearance in rat. Structure-activity relationships at the C6 position established chemical space where the extent of enterohepatic recirculation in the rat is minimized. Desymmetrization of the C4 substituent allowed for potency optimization against virus having the N124 variant of integrase. Combination of these lessons led to the discovery of compound 20, having balanced serum-shifted antiviral potency and minimized excretion in to the biliary tract in rat, potentially representing a clinically viable starting point for a new treatment option for individuals infected with HIV.

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References

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