Aligning Potency and Pharmacokinetic Properties for Pyridine-Based NCINIs

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• 作者：Lee D. Fader ; Murray Bailey ; Eric Beaulieu ; François Bilodeau ; Pierre Bonneau ; Yves Bousquet ; Rebekah J. Carson ; Catherine Chabot ; René 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
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：August 11, 2016
• 年：2016
• 卷：7
• 期：8
• 页码：797-801
• 全文大小：278K
• 年卷期：0
• ISSN：1948-5875

文摘

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.