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ACS Med Chem Lett. 2016 Jun 9;7(8):797-801. doi: 10.1021/acsmedchemlett.6b00194. eCollection 2016 Aug 11.

Aligning Potency and Pharmacokinetic Properties for Pyridine-Based NCINIs.

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Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Qu├ębec H7S 2G5, Canada.


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.


HIV integrase; NCINI; enterohepatic recirculation

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