Aligning Potency and Pharmacokinetic Properties for Pyridine-Based NCINIs.

Autor:	Fader LD; Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada., Bailey M; Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada., Beaulieu E; Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada., Bilodeau F; Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada., Bonneau P; Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada., Bousquet Y; Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada., Carson RJ; Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada., Chabot C; Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada., Coulombe R; Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada., Duan J; Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada., Fenwick C; Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada., Garneau M; Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada., Halmos T; Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada., Jakalian A; Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada., James C; Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada., Kawai SH; Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada., Landry S; Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada., LaPlante SR; Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada., Mason SW; Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada., Morin S; Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada., Rioux N; Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada., Simoneau B; Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada., Surprenant S; Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada., Thavonekham B; Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada., Thibeault C; Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada., Trinh T; Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada., Tsantrizos Y; Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada., Tsoung J; Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada., Yoakim C; Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada., Wernic D; Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.
Jazyk:	angličtina
Zdroj:	ACS medicinal chemistry letters [ACS Med Chem Lett] 2016 Jun 09; Vol. 7 (8), pp. 797-801. Date of Electronic Publication: 2016 Jun 09 (Print Publication: 2016).
DOI:	10.1021/acsmedchemlett.6b00194
Abstrakt:	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.
Databáze:	MEDLINE
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