AI Article Synopsis
- - Compound 13 was developed by modifying an ATR biochemical hit, leading to improved selectivity and potency but facing issues with pharmacokinetics (PK) and hERG ion channel inhibition.
- - DMPK studies revealed that metabolism by CYP P450 and AO, along with efflux by Pgp and BCRP, were key factors negatively affecting PK.
- - To solve medicinal chemistry challenges, adjustments like adding fluorine or nitrogen to the 6-azaindole structure improved the compound’s properties.
Article 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.
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Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4291699 | PMC |
| http://dx.doi.org/10.1021/ml500352s | DOI Listing |
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