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Aligning Potency and Pharmacokinetic Properties for Pyridine-Based NCINIs.
Lee D Fader1, Murray Bailey1, Eric Beaulieu1
1Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.
ACS Medicinal Chemistry Letters
|August 27, 2016
Summary
Researchers optimized pyridine-based noncatalytic site integrase inhibitors (NCINIs) to create new HIV treatments. Compound 20 effectively inhibits HIV integrase variants with reduced liver recirculation, offering a promising clinical option.
Area of Science:
- Medicinal Chemistry
- Virology
- Pharmacology
Background:
- HIV integrase (IN) is a key viral target for antiretroviral therapy.
- Noncatalytic site integrase inhibitors (NCINIs) represent a promising class of antiviral agents.
- Development of NCINIs is challenged by viral resistance and pharmacokinetic properties like enterohepatic recirculation.
Purpose of the Study:
- To optimize pyridine-based NCINIs for enhanced potency against HIV integrase variants.
- To minimize enterohepatic recirculation and improve pharmacokinetic profiles in preclinical models.
- To identify a clinically viable starting point for a new HIV treatment.
Main Methods:
- Structure-activity relationship (SAR) studies were conducted on pyridine-based NCINIs.
- Chemical modifications focused on the C6 and C4 positions of the inhibitor scaffold.
- Inhibition assays were performed against HIV integrase variants.
- Pharmacokinetic assessments, including enterohepatic recirculation, were evaluated in rat models.
Main Results:
- Optimization at the C6 position reduced enterohepatic recirculation in rats.
- Desymmetrization of the C4 substituent enhanced potency against N124 integrase variants.
- Compound 20 demonstrated balanced antiviral potency and minimized biliary excretion in rats.
- Compound 20 exhibits characteristics suitable for further clinical development.
Conclusions:
- The optimized pyridine-based NCINIs show potential as a new therapeutic strategy for HIV.
- Minimizing enterohepatic recirculation is crucial for improving the pharmacokinetic profile of NCINIs.
- Compound 20 represents a promising candidate for the treatment of HIV infection, including cases with specific integrase variants.
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