Discovery of BI 224436, a Noncatalytic Site Integrase Inhibitor (NCINI) of HIV-1
| Autor: | Marc Pesant, Christian Brochu, Rebekah J. Carson, Bruno Simoneau, Patricia Schroeder, Murray D. Bailey, Pierre R. Bonneau, Michael G. Cordingley, Catherine Chabot, Michel Garneau, Anne-Marie Faucher, Michael Bös, René Coulombe, Mathieu Parisien, Stephen W. Mason, Araz Jakalian, Jianmin Duan, Marc-André Poupart, Dominik Wernic, Sébastien Morin, François Bilodeau, Serge Landry, Yves Bousquet, Eric Malenfant, Stephen H. Kawai, Punit Bhardwaj, Ma’an Amad, Lee Fader, Youla S. Tsantrizos, Richard Bethell, Christiane Yoakim, Steven R. LaPlante, Paul J. Edwards, Ted Halmos, Craig Fenwick |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
biology
Organic Chemistry Quinoline Allosteric regulation Substituent Human immunodeficiency virus (HIV) Integrase inhibitor Metabolic stability medicine.disease_cause Biochemistry Combinatorial chemistry Integrase chemistry.chemical_compound chemistry Drug Discovery medicine biology.protein Potency |
| Zdroj: | ACS Medicinal Chemistry Letters. 5:422-427 |
| ISSN: | 1948-5875 |
| DOI: | 10.1021/ml500002n |
| Popis: | An assay recapitulating the 3' processing activity of HIV-1 integrase (IN) was used to screen the Boehringer Ingelheim compound collection. Hit-to-lead and lead optimization beginning with compound 1 established the importance of the C3 and C4 substituent to antiviral potency against viruses with different aa124/aa125 variants of IN. The importance of the C7 position on the serum shifted potency was established. Introduction of a quinoline substituent at the C4 position provided a balance of potency and metabolic stability. Combination of these findings ultimately led to the discovery of compound 26 (BI 224436), the first NCINI to advance into a phase Ia clinical trial. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|