Literature DB >> 24900457

Mitigating hERG Inhibition: Design of Orally Bioavailable CCR5 Antagonists as Potent Inhibitors of R5 HIV-1 Replication.

Renato Skerlj1, Gary Bridger2, Yuanxi Zhou2, Elyse Bourque1, Ernest McEachern2, Sanjay Danthi1, Jonathan Langille2, Curtis Harwig2, Duane Veale2, Bryon Carpenter2, Tuya Ba2, Michael Bey2, Ian Baird2, Trevor Wilson2, Markus Metz1, Ron MacFarland2, Renee Mosi2, Veronique Bodart2, Rebecca Wong2, Simon Fricker1, Dana Huskens3, Dominique Schols3.   

Abstract

A series of CCR5 antagonists representing the thiophene-3-yl-methyl ureas were designed that met the pharmacological criteria for HIV-1 inhibition and mitigated a human ether-a-go-go related gene (hERG) inhibition liability. Reducing lipophilicity was the main design criteria used to identify compounds that did not inhibit the hERG channel, but subtle structural modifications were also important. Interestingly, within this series, compounds with low hERG inhibition prolonged the action potential duration (APD) in dog Purkinje fibers, suggesting a mixed effect on cardiac ion channels.

Entities:  

Keywords:  CCR5; HIV-1; chemokine receptor; hERG

Year:  2012        PMID： 24900457      PMCID： PMC4025809          DOI： 10.1021/ml2002604

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


  17 in total

1.  Design and synthesis of pyridin-2-ylmethylaminopiperidin-1-ylbutyl amide CCR5 antagonists that are potent inhibitors of M-tropic (R5) HIV-1 replication.

Authors:  Renato Skerlj; Gary Bridger; Yuanxi Zhou; Elyse Bourque; Ernest McEachern; Jonathan Langille; Curtis Harwig; Duane Veale; Wen Yang; Tongshong Li; Yongbao Zhu; Michael Bey; Ian Baird; Michael Sartori; Markus Metz; Renee Mosi; Kim Nelson; Veronique Bodart; Rebecca Wong; Simon Fricker; Ron Mac Farland; Dana Huskens; Dominique Schols
Journal:  Bioorg Med Chem Lett       Date:  2011-10-08       Impact factor: 2.823

2.  Prospective CCR5 small molecule antagonist compound design using a combined mutagenesis/modeling approach.

Authors:  Markus Metz; Elyse Bourque; Jean Labrecque; Sanjay J Danthi; Jonathan Langille; Curtis Harwig; Wen Yang; Marilyn C Darkes; Gloria Lau; Zefferino Santucci; Gary J Bridger; Dominique Schols; Simon P Fricker; Renato T Skerlj
Journal:  J Am Chem Soc       Date:  2011-09-23       Impact factor: 15.419

Review 3.  Medicinal chemistry of hERG optimizations: Highlights and hang-ups.

Authors:  Craig Jamieson; Elizabeth M Moir; Zoran Rankovic; Grant Wishart
Journal:  J Med Chem       Date:  2006-08-24       Impact factor: 7.446

Review 4.  The influence of drug-like concepts on decision-making in medicinal chemistry.

Authors:  Paul D Leeson; Brian Springthorpe
Journal:  Nat Rev Drug Discov       Date:  2007-11       Impact factor: 84.694

Review 5.  Chemokine receptors as fusion cofactors for human immunodeficiency virus type 1 (HIV-1).

Authors:  B J Doranz; J F Berson; J Rucker; R W Doms
Journal:  Immunol Res       Date:  1997-02       Impact factor: 2.829

6.  Overcoming hERG affinity in the discovery of maraviroc; a CCR5 antagonist for the treatment of HIV.

Authors:  David A Price; Duncan Armour; Marcel de Groot; Derek Leishman; Carolyn Napier; Manos Perros; Blanda L Stammen; Anthony Wood
Journal:  Curr Top Med Chem       Date:  2008       Impact factor: 3.295

7.  Design and synthesis of pyridin-2-yloxymethylpiperidin-1-ylbutyl amide CCR5 antagonists that are potent inhibitors of M-tropic (R5) HIV-1 replication.

Authors:  Renato Skerlj; Gary Bridger; Yuanxi Zhou; Elyse Bourque; Jonathan Langille; Maria Di Fluri; David Bogucki; Wen Yang; Tongshuang Li; Letian Wang; Susan Nan; Ian Baird; Markus Metz; Marilyn Darkes; Jean Labrecque; Gloria Lau; Simon Fricker; Dana Huskens; Dominique Schols
Journal:  Bioorg Med Chem Lett       Date:  2011-02-23       Impact factor: 2.823

8.  Class III antiarrhythmic agents have a lot of potential but a long way to go. Reduced effectiveness and dangers of reverse use dependence.

Authors:  L M Hondeghem; D J Snyders
Journal:  Circulation       Date:  1990-02       Impact factor: 29.690

9.  Phase III prospective randomized double-blind placebo-controlled trial of plerixafor plus granulocyte colony-stimulating factor compared with placebo plus granulocyte colony-stimulating factor for autologous stem-cell mobilization and transplantation for patients with non-Hodgkin's lymphoma.

Authors:  John F DiPersio; Ivana N Micallef; Patrick J Stiff; Brian J Bolwell; Richard T Maziarz; Eric Jacobsen; Auayporn Nademanee; John McCarty; Gary Bridger; Gary Calandra
Journal:  J Clin Oncol       Date:  2009-08-31       Impact factor: 44.544

10.  Inhibition of T-tropic HIV strains by selective antagonization of the chemokine receptor CXCR4.

Authors:  D Schols; S Struyf; J Van Damme; J A Esté; G Henson; E De Clercq
Journal:  J Exp Med       Date:  1997-10-20       Impact factor: 14.307
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  3 in total

1.  Structure-Activity Relationship Studies Reveal New Astemizole Analogues Active against Plasmodium falciparum In Vitro.

Authors:  Dickson Mambwe; Malkeet Kumar; Richard Ferger; Dale Taylor; Mathew Njoroge; Dina Coertzen; Janette Reader; Mariëtte van der Watt; Lyn-Marie Birkholtz; Kelly Chibale
Journal:  ACS Med Chem Lett       Date:  2021-08-02       Impact factor: 4.632

2.  Discovery of Novel CCR5 Ligands as Anticolorectal Cancer Agents by Sequential Virtual Screening.

Authors:  Mariam A El-Zohairy; Darius P Zlotos; Martin R Berger; Hassan H Adwan; Yasmine M Mandour
Journal:  ACS Omega       Date:  2021-04-16

3.  Synthesis of Novel 2-(Pyridin-2-yl) Pyrimidine Derivatives and Study of Their Anti-Fibrosis Activity.

Authors:  Yi-Fei Gu; Yue Zhang; Feng-Li Yue; Shao-Tong Li; Zhuo-Qi Zhang; Jing Li; Xu Bai
Journal:  Molecules       Date:  2020-11-10       Impact factor: 4.411
  3 in total

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