Literature DB >> 27563405

Aligning Potency and Pharmacokinetic Properties for Pyridine-Based NCINIs.

Lee D Fader1, Murray Bailey1, Eric Beaulieu1, François Bilodeau1, Pierre Bonneau1, Yves Bousquet1, Rebekah J Carson1, Catherine Chabot1, René Coulombe1, Jianmin Duan1, Craig Fenwick1, Michel Garneau1, Ted Halmos1, Araz Jakalian1, Clint James1, Stephen H Kawai1, Serge Landry1, Steven R LaPlante1, Stephen W Mason1, Sebastien Morin1, Nathalie Rioux1, Bruno Simoneau1, Simon Surprenant1, Bounkham Thavonekham1, Carl Thibeault1, Thao Trinh1, Youla Tsantrizos1, Jennifer Tsoung1, Christiane Yoakim1, Dominik Wernic1.   

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.

Entities:  

Keywords:  HIV integrase; NCINI; enterohepatic recirculation

Year:  2016        PMID： 27563405      PMCID： PMC4983734          DOI： 10.1021/acsmedchemlett.6b00194

Source DB:  PubMed          Journal:  ACS Med Chem Lett        ISSN： 1948-5875            Impact factor:   4.345


  6 in total

Review 1.  Targeting HIV-1 integrase with strand transfer inhibitors.

Authors:  Yang Li; Shouyi Xuan; Yue Feng; Aixia Yan
Journal:  Drug Discov Today       Date:  2014-12-06       Impact factor: 7.851

2.  Identification of potent and orally bioavailable nucleotide competing reverse transcriptase inhibitors: in vitro and in vivo optimization of a series of benzofurano[3,2-d]pyrimidin-2-one derived inhibitors.

Authors:  Claudio F Sturino; Yves Bousquet; Clint A James; Patrick DeRoy; Martin Duplessis; Paul J Edwards; Ted Halmos; Joannie Minville; Louis Morency; Sébastien Morin; Bounkham Thavonekham; Martin Tremblay; Jianmin Duan; Maria Ribadeneira; Michel Garneau; Alex Pelletier; Sonia Tremblay; Louie Lamorte; Richard Bethell; Michael G Cordingley; Daniel Rajotte; Bruno Simoneau
Journal:  Bioorg Med Chem Lett       Date:  2013-04-25       Impact factor: 2.823

3.  Minimizing the Contribution of Enterohepatic Recirculation to Clearance in Rat for the NCINI Class of Inhibitors of HIV.

Authors:  Lee D Fader; Rebekah Carson; Sébastien Morin; François Bilodeau; Catherine Chabot; Ted Halmos; Murray D Bailey; Stephen H Kawai; René Coulombe; Steven Laplante; Kevork Mekhssian; Araz Jakalian; Michel Garneau; Jianmin Duan; Stephen W Mason; Bruno Simoneau; Craig Fenwick; Youla Tsantrizos; Christiane Yoakim
Journal:  ACS Med Chem Lett       Date:  2014-04-16       Impact factor: 4.345

4.  Preclinical profile of BI 224436, a novel HIV-1 non-catalytic-site integrase inhibitor.

Authors:  Craig Fenwick; Ma'an Amad; Murray D Bailey; Richard Bethell; Michael Bös; Pierre Bonneau; Michael Cordingley; René Coulombe; Jianmin Duan; Paul Edwards; Lee D Fader; Anne-Marie Faucher; Michel Garneau; Araz Jakalian; Stephen Kawai; Louie Lamorte; Steven LaPlante; Laibin Luo; Steve Mason; Marc-André Poupart; Nathalie Rioux; Patricia Schroeder; Bruno Simoneau; Sonia Tremblay; Youla Tsantrizos; Myriam Witvrouw; Christiane Yoakim
Journal:  Antimicrob Agents Chemother       Date:  2014-03-24       Impact factor: 5.191

5.  Discovery of BI 224436, a Noncatalytic Site Integrase Inhibitor (NCINI) of HIV-1.

Authors:  Lee D Fader; Eric Malenfant; Mathieu Parisien; Rebekah Carson; François Bilodeau; Serge Landry; Marc Pesant; Christian Brochu; Sébastien Morin; Catherine Chabot; Ted Halmos; Yves Bousquet; Murray D Bailey; Stephen H Kawai; René Coulombe; Steven LaPlante; Araz Jakalian; Punit K Bhardwaj; Dominik Wernic; Patricia Schroeder; Ma'an Amad; Paul Edwards; Michel Garneau; Jianmin Duan; Michael Cordingley; Richard Bethell; Stephen W Mason; Michael Bös; Pierre Bonneau; Marc-André Poupart; Anne-Marie Faucher; Bruno Simoneau; Craig Fenwick; Christiane Yoakim; Youla Tsantrizos
Journal:  ACS Med Chem Lett       Date:  2014-01-22       Impact factor: 4.345

6.  A new class of multimerization selective inhibitors of HIV-1 integrase.

Authors:  Amit Sharma; Alison Slaughter; Nivedita Jena; Lei Feng; Jacques J Kessl; Hind J Fadel; Nirav Malani; Frances Male; Li Wu; Eric Poeschla; Frederic D Bushman; James R Fuchs; Mamuka Kvaratskhelia
Journal:  PLoS Pathog       Date:  2014-05-29       Impact factor: 6.823
  6 in total
  8 in total

Review 1.  Multifaceted HIV integrase functionalities and therapeutic strategies for their inhibition.

Authors:  Alan N Engelman
Journal:  J Biol Chem       Date:  2019-08-29       Impact factor: 5.157

2.  Allosteric HIV Integrase Inhibitors Promote Formation of Inactive Branched Polymers via Homomeric Carboxy-Terminal Domain Interactions.

Authors:  Kushol Gupta; Audrey Allen; Carolina Giraldo; Grant Eilers; Robert Sharp; Young Hwang; Hemma Murali; Katrina Cruz; Paul Janmey; Frederic Bushman; Gregory D Van Duyne
Journal:  Structure       Date:  2020-12-23       Impact factor: 5.006

3.  Structure-function analyses unravel distinct effects of allosteric inhibitors of HIV-1 integrase on viral maturation and integration.

Authors:  Damien Bonnard; Erwann Le Rouzic; Sylvia Eiler; Céline Amadori; Igor Orlov; Jean-Michel Bruneau; Julie Brias; Julien Barbion; Francis Chevreuil; Danièle Spehner; Sophie Chasset; Benoit Ledoussal; François Moreau; Ali Saïb; Bruno P Klaholz; Stéphane Emiliani; Marc Ruff; Alessia Zamborlini; Richard Benarous
Journal:  J Biol Chem       Date:  2018-03-05       Impact factor: 5.157

4.  Retroviral integrase: Structure, mechanism, and inhibition.

Authors:  Dario Oliveira Passos; Min Li; Robert Craigie; Dmitry Lyumkis
Journal:  Enzymes       Date:  2021-08-23

Review 5.  Development of Protein-Protein Interaction Inhibitors for the Treatment of Infectious Diseases.

Authors:  Andrew F Voter; James L Keck
Journal:  Adv Protein Chem Struct Biol       Date:  2017-08-24       Impact factor: 3.507

6.  HIV-1 integrase tetramers are the antiviral target of pyridine-based allosteric integrase inhibitors.

Authors:  Pratibha C Koneru; Ashwanth C Francis; Nanjie Deng; Stephanie V Rebensburg; Ashley C Hoyte; Jared Lindenberger; Daniel Adu-Ampratwum; Ross C Larue; Michael F Wempe; Alan N Engelman; Dmitry Lyumkis; James R Fuchs; Ronald M Levy; Gregory B Melikyan; Mamuka Kvaratskhelia
Journal:  Elife       Date:  2019-05-23       Impact factor: 8.140

7.  Identification and Optimization of a Novel HIV-1 Integrase Inhibitor.

Authors:  Daniel Adu-Ampratwum; Yuhan Pan; Pratibha C Koneru; Janet Antwi; Ashley C Hoyte; Jacques Kessl; Patrick R Griffin; Mamuka Kvaratskhelia; James R Fuchs; Ross C Larue
Journal:  ACS Omega       Date:  2022-01-24

Review 8.  HIV-1 Maturation: Lessons Learned from Inhibitors.

Authors:  Alex B Kleinpeter; Eric O Freed
Journal:  Viruses       Date:  2020-08-26       Impact factor: 5.048
  8 in total

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