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

Overview

Journal ACS Med Chem Lett

Publisher American Chemical Society

Specialty Chemistry

Date 2014 Jun 20

PMID 24944749

Citations 7

Authors

Lee D Fader

Rebekah Carson

Sebastien Morin

Francois Bilodeau

Catherine Chabot

Ted Halmos

Murray D Bailey

Stephen H Kawai

Rene Coulombe

Steven Laplante

Kevork Mekhssian

Araz Jakalian

Michel Garneau

Jianmin Duan

Stephen W Mason

Bruno Simoneau

Craig Fenwick

Youla Tsantrizos

Christiane Yoakim

Affiliations

Soon will be listed here.

Abstract

A scaffold replacement approach was used to identifying the pyridine series of noncatalytic site integrase inhibitors. These molecules bind with higher affinity to a tetrameric form compared to a dimeric form of integrase. Optimization of the C6 and C4 positions revealed that viruses harboring T124 or A124 amino acid substitutions are highly susceptible to these inhibitors, but viruses having the N124 amino acid substitution are about 100-fold less susceptible. Compound 20 had EC50 values <10 nM against viruses having T124 or A124 substitutions in IN and >800 nM in viruses having N124 substitions. Compound 20 had an excellent in vitro ADME profile and demonstrated reduced contribution of biliary excretion to in vivo clearance compared to BI 224436, the lead compound from the quinoline series of NCINIs.

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References

Tsiang M, Jones G, Niedziela-Majka A, Kan E, Lansdon E, Huang W . New class of HIV-1 integrase (IN) inhibitors with a dual mode of action. J Biol Chem. 2012; 287(25):21189-203. PMC: 3375541. DOI: 10.1074/jbc.M112.347534. View

de Bethune M . Non-nucleoside reverse transcriptase inhibitors (NNRTIs), their discovery, development, and use in the treatment of HIV-1 infection: a review of the last 20 years (1989-2009). Antiviral Res. 2009; 85(1):75-90. DOI: 10.1016/j.antiviral.2009.09.008. View

Bocker A, Bonneau P, Hucke O, Jakalian A, Edwards P . Development of specific "drug-like property" rules for carboxylate-containing oral drug candidates. ChemMedChem. 2010; 5(12):2102-13. DOI: 10.1002/cmdc.201000355. View

Cihlar T, Ray A . Nucleoside and nucleotide HIV reverse transcriptase inhibitors: 25 years after zidovudine. Antiviral Res. 2009; 85(1):39-58. DOI: 10.1016/j.antiviral.2009.09.014. View

Roberts M, Magnusson B, Burczynski F, Weiss M . Enterohepatic circulation: physiological, pharmacokinetic and clinical implications. Clin Pharmacokinet. 2002; 41(10):751-90. DOI: 10.2165/00003088-200241100-00005. View

Jurado K, Wang H, Slaughter A, Feng L, Kessl J, Koh Y . Allosteric integrase inhibitor potency is determined through the inhibition of HIV-1 particle maturation. Proc Natl Acad Sci U S A. 2013; 110(21):8690-5. PMC: 3666754. DOI: 10.1073/pnas.1300703110. View

McColl D, Chen X . Strand transfer inhibitors of HIV-1 integrase: bringing IN a new era of antiretroviral therapy. Antiviral Res. 2009; 85(1):101-18. DOI: 10.1016/j.antiviral.2009.11.004. View

Sun H, Tawa G, Wallqvist A . Classification of scaffold-hopping approaches. Drug Discov Today. 2011; 17(7-8):310-24. PMC: 3328312. DOI: 10.1016/j.drudis.2011.10.024. View

Feng L, Sharma A, Slaughter A, Jena N, Koh Y, Shkriabai N . The A128T resistance mutation reveals aberrant protein multimerization as the primary mechanism of action of allosteric HIV-1 integrase inhibitors. J Biol Chem. 2013; 288(22):15813-20. PMC: 3668738. DOI: 10.1074/jbc.M112.443390. View

10.

Ballatore C, Huryn D, Smith 3rd A . Carboxylic acid (bio)isosteres in drug design. ChemMedChem. 2013; 8(3):385-95. PMC: 3640829. DOI: 10.1002/cmdc.201200585. View

11.

Fader L, Malenfant E, Parisien M, Carson R, Bilodeau F, Landry S . Discovery of BI 224436, a Noncatalytic Site Integrase Inhibitor (NCINI) of HIV-1. ACS Med Chem Lett. 2014; 5(4):422-7. PMC: 4027581. DOI: 10.1021/ml500002n. View

12.

Adamson C, Freed E . Novel approaches to inhibiting HIV-1 replication. Antiviral Res. 2009; 85(1):119-41. PMC: 2815006. DOI: 10.1016/j.antiviral.2009.09.009. View

13.

Christ F, Shaw S, Demeulemeester J, Desimmie B, Marchand A, Butler S . Small-molecule inhibitors of the LEDGF/p75 binding site of integrase block HIV replication and modulate integrase multimerization. Antimicrob Agents Chemother. 2012; 56(8):4365-74. PMC: 3421592. DOI: 10.1128/AAC.00717-12. View

14.

Wensing A, van Maarseveen N, Nijhuis M . Fifteen years of HIV Protease Inhibitors: raising the barrier to resistance. Antiviral Res. 2009; 85(1):59-74. DOI: 10.1016/j.antiviral.2009.10.003. View

15.

Tilton J, Doms R . Entry inhibitors in the treatment of HIV-1 infection. Antiviral Res. 2009; 85(1):91-100. DOI: 10.1016/j.antiviral.2009.07.022. View

16.

Balakrishnan M, Yant S, Tsai L, OSullivan C, Bam R, Tsai A . Non-catalytic site HIV-1 integrase inhibitors disrupt core maturation and induce a reverse transcription block in target cells. PLoS One. 2013; 8(9):e74163. PMC: 3767657. DOI: 10.1371/journal.pone.0074163. View

17.

Raffi F, Wainberg M . Multiple choices for HIV therapy with integrase strand transfer inhibitors. Retrovirology. 2012; 9:110. PMC: 3549750. DOI: 10.1186/1742-4690-9-110. View