title: 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.
authors.affiliation: Global Discovery Chemistry/Oncology, Novartis Institutes for Biomedical Research , 5300 Chiron Way, Emeryville, California 94608, United States.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Barsanti
authors.affiliation: Global Discovery Chemistry/Oncology, Novartis Institutes for Biomedical Research , 5300 Chiron Way, Emeryville, California 94608, United States.
authors.forename: Yue
authors.initials: Y
authors.lastname: Pan
authors.affiliation: Global Discovery Chemistry/Oncology, Novartis Institutes for Biomedical Research , 5300 Chiron Way, Emeryville, California 94608, United States.
authors.forename: Yipin
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Global Discovery Chemistry/Oncology, Novartis Institutes for Biomedical Research , 5300 Chiron Way, Emeryville, California 94608, United States.
authors.forename: Rama
authors.initials: R
authors.lastname: Jain
authors.affiliation: Global Discovery Chemistry/Oncology, Novartis Institutes for Biomedical Research , 5300 Chiron Way, Emeryville, California 94608, United States.
authors.forename: Matthew
authors.initials: M
authors.lastname: Cox
authors.affiliation: Global Discovery Chemistry/Oncology, Novartis Institutes for Biomedical Research , 5300 Chiron Way, Emeryville, California 94608, United States.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Aversa
authors.affiliation: Global Discovery Chemistry/Oncology, Novartis Institutes for Biomedical Research , 5300 Chiron Way, Emeryville, California 94608, United States.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Dillon
authors.affiliation: Global Discovery Chemistry/Oncology, Novartis Institutes for Biomedical Research , 5300 Chiron Way, Emeryville, California 94608, United States.
authors.forename: Robert
authors.initials: R
authors.lastname: Elling
authors.affiliation: Global Discovery Chemistry/Oncology, Novartis Institutes for Biomedical Research , 5300 Chiron Way, Emeryville, California 94608, United States.
authors.forename: Cheng
authors.initials: C
authors.lastname: Hu
authors.affiliation: Global Discovery Chemistry/Oncology, Novartis Institutes for Biomedical Research , 5300 Chiron Way, Emeryville, California 94608, United States.
authors.forename: Xianming
authors.initials: X
authors.lastname: Jin
authors.affiliation: Global Discovery Chemistry/Oncology, Novartis Institutes for Biomedical Research , 5300 Chiron Way, Emeryville, California 94608, United States.
authors.forename: Mark
authors.initials: M
authors.lastname: Knapp
authors.affiliation: Global Discovery Chemistry/Oncology, Novartis Institutes for Biomedical Research , 5300 Chiron Way, Emeryville, California 94608, United States.
authors.forename: Jiong
authors.initials: J
authors.lastname: Lan
authors.affiliation: Global Discovery Chemistry/Oncology, Novartis Institutes for Biomedical Research , 5300 Chiron Way, Emeryville, California 94608, United States.
authors.forename: Savithri
authors.initials: S
authors.lastname: Ramurthy
authors.affiliation: Global Discovery Chemistry/Oncology, Novartis Institutes for Biomedical Research , 5300 Chiron Way, Emeryville, California 94608, United States.
authors.forename: Patrick
authors.initials: P
authors.lastname: Rudewicz
authors.affiliation: Global Discovery Chemistry/Oncology, Novartis Institutes for Biomedical Research , 5300 Chiron Way, Emeryville, California 94608, United States.
authors.forename: Lina
authors.initials: L
authors.lastname: Setti
authors.affiliation: Global Discovery Chemistry/Oncology, Novartis Institutes for Biomedical Research , 5300 Chiron Way, Emeryville, California 94608, United States.
authors.forename: Sharadha
authors.initials: S
authors.lastname: Subramanian
authors.affiliation: Global Discovery Chemistry/Oncology, Novartis Institutes for Biomedical Research , 5300 Chiron Way, Emeryville, California 94608, United States.
authors.forename: Michelle
authors.initials: M
authors.lastname: Mathur
authors.affiliation: Global Discovery Chemistry/Oncology, Novartis Institutes for Biomedical Research , 5300 Chiron Way, Emeryville, California 94608, United States.
authors.forename: Lorena
authors.initials: L
authors.lastname: Taricani
authors.affiliation: Global Discovery Chemistry/Oncology, Novartis Institutes for Biomedical Research , 5300 Chiron Way, Emeryville, California 94608, United States.
authors.forename: George
authors.initials: G
authors.lastname: Thomas
authors.affiliation: Global Discovery Chemistry/Oncology, Novartis Institutes for Biomedical Research , 5300 Chiron Way, Emeryville, California 94608, United States.
authors.forename: Linda
authors.initials: L
authors.lastname: Xiao
authors.affiliation: Global Discovery Chemistry/Oncology, Novartis Institutes for Biomedical Research , 5300 Chiron Way, Emeryville, California 94608, United States.
authors.forename: Qin
authors.initials: Q
authors.lastname: Yue
keywords: ATR; CYP3A4 TDI; aldehyde oxidase; structure-based drug design