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

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.

SUBMITTER: Barsanti PA

PROVIDER: S-EPMC4291699 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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

Barsanti Paul A PA Pan Yue Y Lu Yipin Y Jain Rama R Cox Matthew M Aversa Robert J RJ Dillon Michael P MP Elling Robert R Hu Cheng C Jin Xianming X Knapp Mark M Lan Jiong J Ramurthy Savithri S Rudewicz Patrick P Setti Lina L Subramanian Sharadha S Mathur Michelle M Taricani Lorena L Thomas George G Xiao Linda L Yue Qin Q

ACS medicinal chemistry letters 20141030 1

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 ...[more]

PMID: 25589928

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