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

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

doi:10.1021/acsmedchemlett.6b00455

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

ACS Med Chem Lett. 2016 Nov 22;8(1):128-132. doi: 10.1021/acsmedchemlett.6b00455. eCollection 2017 Jan 12.

Authors

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

Affiliation

¹ Departments of Discovery Chemistry, Chemistry Modeling & Informatics, Hypertension, Drug Metabolism & Pharmacokinetics, and In Vitro Pharmacology, Merck Research Laboratories , Rahway, New Jersey 07065, United States.

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.

Keywords: CYP11B2; aldosterone synthase; hypertension.