AI Article Synopsis
- Optimization of pyridine-based noncatalytic site integrase inhibitors (NCINIs) has led to new molecules that can effectively inhibit HIV integrase variants while reducing enterohepatic recirculation in rats.
- Structure-activity relationships identified modifications at the C6 position that minimized enterohepatic recirculation and allowed for better potency against HIV variants.
- The final result is compound 20, which shows promising antiviral efficacy and reduced biliary excretion, making it a potential candidate for clinical HIV treatment.
Article 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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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4983734 | PMC |
| http://dx.doi.org/10.1021/acsmedchemlett.6b00194 | DOI Listing |
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