Literature DB >> 26288685

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

Scott B Hoyt1, Whitney Petrilli1, Clare London1, Gui-Bai Liang1, Jim Tata1, Qingzhong Hu2, Lina Yin3, Chris J van Koppen4, Rolf W Hartmann2, Mary Struthers1, 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, Joe Clemas1, Gaochao Zhou1, Jack Gibson1, Carrie Ann Maxwell1, Mike Lassman1, Theresa McLaughlin1, Jose Castro-Perez1, Daphne Szeto1, Gail Forrest1, Richard Hajdu1, Mark Rosenbach1, Yusheng Xiong1.   

Abstract

Hit-to-lead efforts resulted in the discovery of compound 19, a potent CYP11B2 inhibitor that displays high selectivity vs related CYPs, good pharmacokinetic properties in rat and rhesus, and lead-like physical properties. In a rhesus pharmacodynamic model, compound 19 displays robust, dose-dependent aldosterone lowering efficacy, with no apparent effect on cortisol levels.

Entities:  

Keywords:  Aldosterone synthase; CYP11B2; hit-to-lead; hypertension

Year:  2015        PMID： 26288685      PMCID： PMC4538427          DOI： 10.1021/acsmedchemlett.5b00048

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


  17 in total

1.  Aldehyde oxidase: an enzyme of emerging importance in drug discovery.

Authors:  David C Pryde; Deepak Dalvie; Qiyue Hu; Peter Jones; R Scott Obach; Thien-Duc Tran
Journal:  J Med Chem       Date:  2010-09-20       Impact factor: 7.446

Review 2.  Aldosterone and cardiovascular disease.

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

Review 3.  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

4.  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

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

10.  In vivo active aldosterone synthase inhibitors with improved selectivity: lead optimization providing a series of pyridine substituted 3,4-dihydro-1H-quinolin-2-one derivatives.

Authors:  Simon Lucas; Ralf Heim; Christina Ries; Katarzyna E Schewe; Barbara Birk; Rolf W Hartmann
Journal:  J Med Chem       Date:  2008-12-25       Impact factor: 7.446
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  4 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.  Human cytochrome P450 11B2 produces aldosterone by a processive mechanism due to the lactol form of the intermediate 18-hydroxycorticosterone.

Authors:  Michael J Reddish; F Peter Guengerich
Journal:  J Biol Chem       Date:  2019-07-11       Impact factor: 5.157

3.  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

4.  Pharmacophore Modeling and in Silico/in Vitro Screening for Human Cytochrome P450 11B1 and Cytochrome P450 11B2 Inhibitors.

Authors:  Muhammad Akram; Watcharee Waratchareeyakul; Joerg Haupenthal; Rolf W Hartmann; Daniela Schuster
Journal:  Front Chem       Date:  2017-12-19       Impact factor: 5.221
  4 in total

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