Referenced in: none

Automatically associated channels: Kv11.1

Title: Structure-Based Drug Design of Novel, Potent, and Selective Azabenzimidazoles (ABI) as ATR Inhibitors.

Authors: Paul A Barsanti, Yue Pan, Yipin Lu, Rama Jain, Matthew Cox, Robert J Aversa, Michael P Dillon, Robert Elling, Cheng Hu, Xianming Jin, Mark Knapp, Jiong Lan, Savithri Ramurthy, Patrick Rudewicz, Lina Setti, Sharadha Subramanian, Michelle Mathur, Lorena Taricani, George Thomas, Linda Xiao, Qin Yue

Journal, date & volume: ACS Med Chem Lett, 2015 Jan 8 , 6, 42-6

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/25589928

Abstract
Compound 13 was discovered through morphing of the ATR biochemical HTS hit 1. The ABI series was potent and selective for ATR. Incorporation of a 6-azaindole afforded a marked increase in cellular potency but was associated with poor PK and hERG ion channel inhibition. DMPK experiments established that CYP P450 and AO metabolism in conjunction with Pgp and BCRP efflux were major causative mechanisms for the observed PK. The series also harbored the CYP3A4 TDI liability driven by the presence of both a morpholine and an indole moiety. Incorporation of an adjacent fluorine or nitrogen into the 6-azaindole addressed many of the various medicinal chemistry issues encountered.