Literature DB >> 25941555

Discovery of benzimidazole oxazolidinediones as novel and selective nonsteroidal mineralocorticoid receptor antagonists.

Christine Yang1, Jaume Balsells1, Hong D Chu1, Jason M Cox1, Alejandro Crespo1, Xiuying Ma1, Lisa Contino1, Patricia Brown1, Sheng Gao1, Beata Zamlynny1, Judyann Wiltsie1, Joseph Clemas1, JeanMarie Lisnock1, Jack Gibson1, Gaochao Zhou1, Margarita Garcia-Calvo1, Thomas J Bateman1, Vincent Tong1, Ling Xu1, Martin Crook1, Peter Sinclair1, Hong C Shen1.   

Abstract

Elaboration of the oxazolidinedione series led to replacement of the exocyclic amides with substituted benzimidazoles. The structure-activity relationship (SAR) exploration resulted in the discovery of potent and selective nonsteroidal mineralocorticoid receptor (MR) antagonists with significantly improved microsomal stability and pharmacokinetic (PK) profile relative to the HTS hit 1a. One compound 2p possessed comparable efficacy as spironolactone (SPL) at 100 mg/kg (p.o.) in the rat natriuresis model. As such, this series was validated as a lead series for further optimization.

Entities:  

Keywords:  amide replacement; antagonist; mineralocorticoid receptor; natriuresis effect; oxazolidinedione

Year:  2015        PMID： 25941555      PMCID： PMC4416436          DOI： 10.1021/acsmedchemlett.5b00010

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


  16 in total

1.  Stereochemical requirements for the mineralocorticoid receptor antagonist activity of dihydropyridines.

Authors:  Graciela B Arhancet; Scott S Woodard; Jessica D Dietz; Danny J Garland; Grace M Wagner; Kaliappan Iyanar; Joe T Collins; James R Blinn; Randal E Numann; Xiao Hu; Horng-Chih Huang
Journal:  J Med Chem       Date:  2010-05-27       Impact factor: 7.446

2.  (S)-N-{3-[1-cyclopropyl-1-(2,4-difluoro-phenyl)-ethyl]-1H-indol-7-yl}-methanesulfonamide: a potent, nonsteroidal, functional antagonist of the mineralocorticoid receptor.

Authors:  Michael G Bell; Douglas L Gernert; Timothy A Grese; Matthew D Belvo; Peter S Borromeo; Sally A Kelley; Joseph H Kennedy; Stanley P Kolis; Peter A Lander; Rachel Richey; V Scott Sharp; Gregory A Stephenson; Jeffrey D Williams; Hannah Yu; Karen M Zimmerman; Mitchell I Steinberg; Prabhakar K Jadhav
Journal:  J Med Chem       Date:  2007-11-27       Impact factor: 7.446

Review 3.  Glucocorticoid and mineralocorticoid receptors: biology and clinical relevance.

Authors:  J W Funder
Journal:  Annu Rev Med       Date:  1997       Impact factor: 13.739

4.  Discovery of (3S,3aR)-2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic acid (PF-3882845), an orally efficacious mineralocorticoid receptor (MR) antagonist for hypertension and nephropathy.

Authors:  Marvin J Meyers; Graciela B Arhancet; Susan L Hockerman; Xiangyang Chen; Scott A Long; Matthew W Mahoney; Joseph R Rico; Danny J Garland; James R Blinn; Joe T Collins; Shengtian Yang; Horng-Chih Huang; Kevin F McGee; Jay M Wendling; Jessica D Dietz; Maria A Payne; Bruce L Homer; Marcia I Heron; David B Reitz; Xiao Hu
Journal:  J Med Chem       Date:  2010-08-26       Impact factor: 7.446

Review 5.  Mineralocorticoid receptor antagonists for the treatment of hypertension and diabetic nephropathy.

Authors:  David W Piotrowski
Journal:  J Med Chem       Date:  2012-08-15       Impact factor: 7.446

6.  Mineralocorticoid receptor antagonists: identification of heterocyclic amide replacements in the oxazolidinedione series.

Authors:  Jason M Cox; Hong D Chu; Christine Yang; Hong C Shen; Zhicai Wu; Jaume Balsells; Alejandro Crespo; Patricia Brown; Beata Zamlynny; Judyann Wiltsie; Joseph Clemas; Jack Gibson; Lisa Contino; JeanMarie Lisnock; Gaochao Zhou; Margarita Garcia-Calvo; Thomas Bateman; Ling Xu; Xinchun Tong; Martin Crook; Peter Sinclair
Journal:  Bioorg Med Chem Lett       Date:  2014-03-01       Impact factor: 2.823

7.  3,3-Bisaryloxindoles as mineralocorticoid receptor antagonists.

Authors:  David A Neel; Matthew L Brown; Peter A Lander; Timothy A Grese; Jean M Defauw; Robert A Doti; Todd Fields; Sally Ann Kelley; Stephon Smith; Karen M Zimmerman; Mitchell I Steinberg; Prabhakar K Jadhav
Journal:  Bioorg Med Chem Lett       Date:  2005-05-16       Impact factor: 2.823

8.  A double-blind, randomized study comparing the antihypertensive effect of eplerenone and spironolactone in patients with hypertension and evidence of primary aldosteronism.

Authors:  Hari K Parthasarathy; Joel Ménard; William B White; William F Young; Gordon H Williams; Bryan Williams; Luis Miguel Ruilope; Gordon T McInnes; John M Connell; Thomas M MacDonald
Journal:  J Hypertens       Date:  2011-05       Impact factor: 4.844

9.  Discovery of novel oxazolidinedione derivatives as potent and selective mineralocorticoid receptor antagonists.

Authors:  Christine Yang; Hong C Shen; Zhicai Wu; Hong D Chu; Jason M Cox; Jaume Balsells; Alejandro Crespo; Patricia Brown; Beata Zamlynny; Judyann Wiltsie; Joseph Clemas; Jack Gibson; Lisa Contino; Jeanmarie Lisnock; Gaochao Zhou; Margarita Garcia-Calvo; Tom Bateman; Ling Xu; Xinchun Tong; Martin Crook; Peter Sinclair
Journal:  Bioorg Med Chem Lett       Date:  2013-06-04       Impact factor: 2.823

10.  Identification of (R)-6-(1-(4-cyano-3-methylphenyl)-5-cyclopentyl-4,5-dihydro-1H-pyrazol-3-yl)-2-methoxynicotinic acid, a highly potent and selective nonsteroidal mineralocorticoid receptor antagonist.

Authors:  Agustin Casimiro-Garcia; David W Piotrowski; Catherine Ambler; Graciela B Arhancet; Mary Ellen Banker; Tereece Banks; Carine M Boustany-Kari; Cuiman Cai; Xiangyang Chen; Rena Eudy; David Hepworth; Catherine A Hulford; Sandra M Jennings; Paula M Loria; Marvin J Meyers; Donna N Petersen; Neil K Raheja; Matthew Sammons; Li She; Kun Song; Derek Vrieze; Liuqing Wei
Journal:  J Med Chem       Date:  2014-04-30       Impact factor: 7.446
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  2 in total

Review 1.  Third-generation Mineralocorticoid Receptor Antagonists: Why Do We Need a Fourth?

Authors:  Elise P Gomez-Sanchez
Journal:  J Cardiovasc Pharmacol       Date:  2016-01       Impact factor: 3.105

2.  The use of a novel non-steroidal mineralocorticoid receptor antagonist finerenone for the treatment of chronic heart failure: A systematic review and meta-analysis.

Authors:  Hui Pei; Wei Wang; Di Zhao; Lei Wang; Guo-Hai Su; Zhuo Zhao
Journal:  Medicine (Baltimore)       Date:  2018-04       Impact factor: 1.889
  2 in total

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