| Literature DB >> 25589928 |
Paul A Barsanti1, Yue Pan1, Yipin Lu1, Rama Jain1, Matthew Cox1, Robert J Aversa1, Michael P Dillon1, Robert Elling1, Cheng Hu1, Xianming Jin1, Mark Knapp1, Jiong Lan1, Savithri Ramurthy1, Patrick Rudewicz1, Lina Setti1, Sharadha Subramanian1, Michelle Mathur1, Lorena Taricani1, George Thomas1, Linda Xiao1, Qin Yue1.
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.Entities:
Keywords: ATR; CYP3A4 TDI; aldehyde oxidase; structure-based drug design
Year: 2014 PMID： 25589928 PMCID： PMC4291699 DOI： 10.1021/ml500352s
Source DB: PubMed Journal: ACS Med Chem Lett ISSN： 1948-5875 Impact factor: 4.345