Discovery of 5-Phenyl-N-(pyridin-2-ylmethyl)-2-(pyrimidin-5-yl)quinazolin-4-amine as a Potent I Kur Inhibitor

Heather J Finlay; James A Johnson; John L Lloyd; Ji Jiang; James Neels; Prashantha Gunaga; Abhisek Banerjee; Naveen Dhondi; Anjaneya Chimalakonda; Sandhya Mandlekar; Mary Lee Conder; Harinath Sale; Dezhi Xing; Paul Levesque; Ruth R Wexler

doi:10.1021/acsmedchemlett.6b00117

Discovery of 5-Phenyl-N-(pyridin-2-ylmethyl)-2-(pyrimidin-5-yl)quinazolin-4-amine as a Potent I Kur Inhibitor

ACS Med Chem Lett. 2016 Jun 9;7(9):831-4. doi: 10.1021/acsmedchemlett.6b00117. eCollection 2016 Sep 8.

Authors

Affiliations

¹ Departments of Discovery Chemistry, Biology, and Preclinical Candidate Optimization, Bristol-Myers Squibb, Research and Development , P.O. Box 5400, Princeton, New Jersey 08543-5400, United States.
² Departments of Discovery Chemistry, Biology, and Preclinical Candidate Optimization, Biocon Bristol-Myers Squibb Research Center (BBRC) , Bangalore 560099, India.

Abstract

A new series of phenylquinazoline inhibitors of Kv 1.5 is disclosed. The series was optimized for Kv 1.5 potency, selectivity versus hERG, pharmacokinetic exposure, and pharmacodynamic potency. 5-Phenyl-N-(pyridin-2-ylmethyl)-2-(pyrimidin-5-yl)quinazolin-4-amine (13k) was identified as a potent and ion channel selective inhibitor with robust efficacy in the preclinical rat ventricular effective refractory period (VERP) model and the rabbit atrial effective refractory period (AERP) model.

Keywords: Kv 1.5; atrial effective refractory period; phenylquinazoline; ventricular effective refractory period.