Literature DB >> 28105288

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

Whitney L Petrilli1, Scott B Hoyt1, Clare London1, Daniel McMasters1, Andreas Verras1, Mary Struthers1, Doris Cully1, Thomas Wisniewski1, Ning Ren1, Charlene Bopp1, Andrea Sok1, Qing Chen1, Ying Li1, Elaine Tung1, Wei Tang1, Gino Salituro1, Ian Knemeyer1, Bindhu Karanam1, Joseph Clemas1, Gaochao Zhou1, Jack Gibson1, Carrie Ann Shipley1, Douglas J MacNeil1, Ruth Duffy1, James R Tata1, Feroze Ujjainwalla1, Amjad Ali1, Yusheng Xiong1.   

Abstract

Herein we report the discovery and hit-to-lead optimization of a series of spirocyclic piperidine aldosterone synthase (CYP11B2) inhibitors. Compounds from this series display potent CYP11B2 inhibition, good selectivity versus related CYP enzymes, and lead-like physical and pharmacokinetic properties.

Entities:  

Keywords:  CYP11B2; aldosterone synthase; hypertension

Year:  2016        PMID： 28105288      PMCID： PMC5238464          DOI： 10.1021/acsmedchemlett.6b00455

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


  19 in total

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

Authors:  Scott B Hoyt; Min K Park; Clare London; Yusheng Xiong; Jim Tata; D Jonathan Bennett; Andrew Cooke; Jiaqiang Cai; Emma Carswell; John Robinson; John MacLean; Lindsay Brown; Simone Belshaw; Thomas R Clarkson; Kun Liu; Gui-Bai Liang; Mary Struthers; Doris Cully; Tom Wisniewski; Ning Ren; Charlene Bopp; Andrea Sok; Tian-Quan Cai; Sloan Stribling; Lee-Yuh Pai; Xiuying Ma; Joe Metzger; Andreas Verras; Daniel McMasters; Qing Chen; Elaine Tung; Wei Tang; Gino Salituro; Nicole Buist; Jeff Kuethe; Nelo Rivera; Joe Clemas; Gaochao Zhou; Jack Gibson; Carrie Ann Maxwell; Mike Lassman; Theresa McLaughlin; Jose Castro-Perez; Daphne Szeto; Gail Forrest; Richard Hajdu; Mark Rosenbach; Amjad Ali
Journal:  ACS Med Chem Lett       Date:  2015-04-07       Impact factor: 4.345

Review 2.  Progress towards clinically useful aldosterone synthase inhibitors.

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

3.  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

4.  Heteroatom insertion into 3,4-dihydro-1H-quinolin-2-ones leads to potent and selective inhibitors of human and rat aldosterone synthase.

Authors:  Cornelia M Grombein; Qingzhong Hu; Sabrina Rau; Christina Zimmer; Rolf W Hartmann
Journal:  Eur J Med Chem       Date:  2014-12-13       Impact factor: 6.514

5.  Structure-Activity Relationships, Pharmacokinetics, and in Vivo Activity of CYP11B2 and CYP11B1 Inhibitors.

Authors:  Julien P N Papillon; Christopher M Adams; Qi-Ying Hu; Changgang Lou; Alok K Singh; Chun Zhang; Jose Carvalho; Srinivan Rajan; Adam Amaral; Michael E Beil; Fumin Fu; Eric Gangl; Chii-Whei Hu; Arco Y Jeng; Daniel LaSala; Guiqing Liang; Michael Logman; Wieslawa M Maniara; Dean F Rigel; Sherri A Smith; Gary M Ksander
Journal:  J Med Chem       Date:  2015-05-21       Impact factor: 7.446

6.  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

7.  Discovery of 4-Aryl-5,6,7,8-tetrahydroisoquinolines as Potent, Selective, and Orally Active Aldosterone Synthase (CYP11B2) Inhibitors: In Vivo Evaluation in Rodents and Cynomolgus Monkeys.

Authors:  Rainer E Martin; Johannes D Aebi; Benoit Hornsperger; Hans-Jakob Krebs; Bernd Kuhn; Andreas Kuglstatter; André M Alker; Hans Peter Märki; Stephan Müller; Dominique Burger; Giorgio Ottaviani; William Riboulet; Philippe Verry; Xuefei Tan; Kurt Amrein; Alexander V Mayweg
Journal:  J Med Chem       Date:  2015-10-02       Impact factor: 7.446

8.  Novel pyridyl- or isoquinolinyl-substituted indolines and indoles as potent and selective aldosterone synthase inhibitors.

Authors:  Lina Yin; Qingzhong Hu; Juliette Emmerich; Michael Man-Chu Lo; Edward Metzger; Amjad Ali; Rolf W Hartmann
Journal:  J Med Chem       Date:  2014-06-05       Impact factor: 7.446

9.  Discovery of N-[5-(6-Chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-ethanesulfonamide, a Cortisol-Sparing CYP11B2 Inhibitor that Lowers Aldosterone in Human Subjects.

Authors:  Julien P N Papillon; Changgang Lou; Alok K Singh; Christopher M Adams; Gary M Ksander; Michael E Beil; Wei Chen; Jennifer Leung-Chu; Fumin Fu; Lu Gan; Chii-Whei Hu; Arco Y Jeng; Daniel LaSala; Guiqing Liang; Dean F Rigel; Kerry S Russell; John A Vest; Catherine Watson
Journal:  J Med Chem       Date:  2015-11-18       Impact factor: 7.446

10.  Resistant hypertension: diagnosis, evaluation, and treatment. A scientific statement from the American Heart Association Professional Education Committee of the Council for High Blood Pressure Research.

Authors:  David A Calhoun; Daniel Jones; Stephen Textor; David C Goff; Timothy P Murphy; Robert D Toto; Anthony White; William C Cushman; William White; Domenic Sica; Keith Ferdinand; Thomas D Giles; Bonita Falkner; Robert M Carey
Journal:  Hypertension       Date:  2008-04-07       Impact factor: 10.190
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  2 in total

1.  Indolyl Azaspiroketal Mannich Bases Are Potent Antimycobacterial Agents with Selective Membrane Permeabilizing Effects and in Vivo Activity.

Authors:  Samuel Agyei Nyantakyi; Ming Li; Pooja Gopal; Matthew Zimmerman; Véronique Dartois; Martin Gengenbacher; Thomas Dick; Mei-Lin Go
Journal:  J Med Chem       Date:  2018-06-25       Impact factor: 7.446

2.  N-Aryl-7-hydroxy-5-oxo-2,3-dihydro-1H,5H-pyrido-[3,2,1-ij]quinoline-6-carboxamides. The Synthesis and Effects on Urinary Output.

Authors:  Igor V Ukrainets; Lyudmila V Sidorenko; Mykola Y Golik; Igor M Chernenok; Lina A Grinevich; Alexandra A Davidenko
Journal:  Sci Pharm       Date:  2018-04-09
  2 in total

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