Literature DB >> 26005536

Discovery of Benzimidazole CYP11B2 Inhibitors with in Vivo Activity in Rhesus Monkeys.

Scott B Hoyt1, Min K Park1, Clare London1, Yusheng Xiong1, Jim Tata1, D Jonathan Bennett2, Andrew Cooke2, Jiaqiang Cai2, Emma Carswell2, John Robinson2, John MacLean2, Lindsay Brown2, Simone Belshaw2, Thomas R Clarkson2, Kun Liu1, Gui-Bai Liang1, Mary Struthers1, Doris Cully1, Tom Wisniewski1, Ning Ren1, Charlene Bopp1, Andrea Sok1, Tian-Quan Cai1, Sloan Stribling1, Lee-Yuh Pai1, Xiuying Ma1, Joe Metzger1, Andreas Verras1, Daniel McMasters1, Qing Chen1, Elaine Tung1, Wei Tang1, Gino Salituro1, Nicole Buist1, Jeff Kuethe1, Nelo Rivera1, Joe Clemas1, Gaochao Zhou1, Jack Gibson1, Carrie Ann Maxwell1, Mike Lassman1, Theresa McLaughlin1, Jose Castro-Perez1, Daphne Szeto1, Gail Forrest1, Richard Hajdu1, Mark Rosenbach1, Amjad Ali1.   

Abstract

We report the discovery of a benzimidazole series of CYP11B2 inhibitors. Hit-to-lead and lead optimization studies identified compounds such as 32, which displays potent CYP11B2 inhibition, high selectivity versus related CYP targets, and good pharmacokinetic properties in rat and rhesus. In a rhesus pharmacodynamic model, 32 produces dose-dependent aldosterone lowering efficacy, with no apparent effect on cortisol levels.

Entities:  

Keywords:  CYP11B2; aldosterone synthase; hypertension

Year:  2015        PMID： 26005536      PMCID： PMC4434468          DOI： 10.1021/acsmedchemlett.5b00054

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


  15 in total

Review 1.  Aldosterone and cardiovascular disease.

Authors:  Robert M Carey
Journal:  Curr Opin Endocrinol Diabetes Obes       Date:  2010-06       Impact factor: 3.243

Review 2.  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

3.  Role of central nervous system aldosterone synthase and mineralocorticoid receptors in salt-induced hypertension in Dahl salt-sensitive rats.

Authors:  Bing S Huang; Roselyn A White; Arco Y Jeng; Frans H H Leenen
Journal:  Am J Physiol Regul Integr Comp Physiol       Date:  2008-12-31       Impact factor: 3.619

4.  Coexpression of CYP11B2 or CYP11B1 with adrenodoxin and adrenodoxin reductase for assessing the potency and selectivity of aldosterone synthase inhibitors.

Authors:  Daniel LaSala; Yasuhiko Shibanaka; Arco Y Jeng
Journal:  Anal Biochem       Date:  2009-07-19       Impact factor: 3.365

Review 5.  Progress towards clinically useful aldosterone synthase inhibitors.

Authors:  Matthew A Cerny
Journal:  Curr Top Med Chem       Date:  2013       Impact factor: 3.295

6.  Effects of a novel aldosterone synthase inhibitor for treatment of primary hypertension: results of a randomized, double-blind, placebo- and active-controlled phase 2 trial.

Authors:  David A Calhoun; William B White; Henry Krum; Weinong Guo; Georgina Bermann; Angelo Trapani; Martin P Lefkowitz; Joël Ménard
Journal:  Circulation       Date:  2011-10-10       Impact factor: 29.690

7.  Discovery and in Vivo Evaluation of Potent Dual CYP11B2 (Aldosterone Synthase) and CYP11B1 Inhibitors.

Authors:  Erik L Meredith; Gary Ksander; Lauren G Monovich; Julien P N Papillon; Qian Liu; Karl Miranda; Patrick Morris; Chang Rao; Robin Burgis; Michael Capparelli; Qi-Ying Hu; Alok Singh; Dean F Rigel; Arco Y Jeng; Michael Beil; Fumin Fu; Chii-Whei Hu; Daniel LaSala
Journal:  ACS Med Chem Lett       Date:  2013-10-17       Impact factor: 4.345

8.  Functional and pharmacological properties of canine ERG potassium channels.

Authors:  Jixin Wang; Kimberly Della Penna; Hao Wang; Jerzy Karczewski; Thomas M Connolly; Kenneth S Koblan; Paul B Bennett; Joseph J Salata
Journal:  Am J Physiol Heart Circ Physiol       Date:  2002-10-03       Impact factor: 4.733

Review 9.  Aldosterone and arterial hypertension.

Authors:  Andreas Tomaschitz; Stefan Pilz; Eberhard Ritz; Barbara Obermayer-Pietsch; Thomas R Pieber
Journal:  Nat Rev Endocrinol       Date:  2009-12-22       Impact factor: 43.330

Review 10.  Aldosterone blockade and the mineralocorticoid receptor in the management of chronic kidney disease: current concepts and emerging treatment paradigms.

Authors:  Linda Shavit; Meyer D Lifschitz; Murray Epstein
Journal:  Kidney Int       Date:  2012-02-15       Impact factor: 10.612
View more
  5 in total

1.  Discovery of Spirocyclic Aldosterone Synthase Inhibitors as Potential Treatments for Resistant Hypertension.

Authors:  Whitney L Petrilli; Scott B Hoyt; Clare London; Daniel McMasters; Andreas Verras; Mary Struthers; Doris Cully; Thomas Wisniewski; Ning Ren; Charlene Bopp; Andrea Sok; Qing Chen; Ying Li; Elaine Tung; Wei Tang; Gino Salituro; Ian Knemeyer; Bindhu Karanam; Joseph Clemas; Gaochao Zhou; Jack Gibson; Carrie Ann Shipley; Douglas J MacNeil; Ruth Duffy; James R Tata; Feroze Ujjainwalla; Amjad Ali; Yusheng Xiong
Journal:  ACS Med Chem Lett       Date:  2016-11-22       Impact factor: 4.345

2.  Development of Highly Selective Pyrimidine-Based Aldosterone Synthase (CYP11B2) Inhibitors.

Authors:  Steven M Sparks; Dana P Danger; William J Hoekstra; Tony Leesnitzer; Robert J Schotzinger; Christopher M Yates; J David Becherer
Journal:  ACS Med Chem Lett       Date:  2019-06-07       Impact factor: 4.345

3.  An efficient one-pot conversion of carboxylic acids into benzimidazoles via an HBTU-promoted methodology.

Authors:  Leonard Barasa; Sabesan Yoganathan
Journal:  RSC Adv       Date:  2018-10-19       Impact factor: 4.036

4.  Development of [18F]AldoView as the First Highly Selective Aldosterone Synthase PET Tracer for Imaging of Primary Hyperaldosteronism.

Authors:  Kerstin Sander; Thibault Gendron; Klaudia A Cybulska; Fatih Sirindil; Junhua Zhou; Tammy L Kalber; Mark F Lythgoe; Tom R Kurzawinski; Morris J Brown; Bryan Williams; Erik Årstad
Journal:  J Med Chem       Date:  2021-06-17       Impact factor: 7.446

5.  2-aminobenzimidazoles for leishmaniasis: From initial hit discovery to in vivo profiling.

Authors:  Rafael Augusto Alves Ferreira; Celso de Oliveira Rezende Junior; Pablo David Grigol Martinez; Paul John Koovits; Bruna Miranda Soares; Leonardo L G Ferreira; Simone Michelan-Duarte; Rafael Consolin Chelucci; Adriano D Andricopulo; Mariana K Galuppo; Silvia R B Uliana; An Matheeussen; Guy Caljon; Louis Maes; Simon Campbell; Jadel M Kratz; Charles E Mowbray; Luiz Carlos Dias
Journal:  PLoS Negl Trop Dis       Date:  2021-02-22
  5 in total

北京卡尤迪生物科技股份有限公司 © 2022-2023.