| Autor: |
Lina Setti, Robert J. Aversa, Rama Jain, George Thomas, Savithri Ramurthy, Lorena Taricani, Robert Elling, Mark Knapp, Paul A. Barsanti, Yipin Lu, Matthew Cox, Michelle Mathur, Yue Pan, Xianming Jin, Patrick J Rudewicz, Cheng Hu, Michael Patrick Dillon, Qin Yue, Sharadha Subramanian, Jiong Lan, Linda Xiao |
| Jazyk: |
angličtina |
| Rok vydání: |
2014 |
| Předmět: |
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| Popis: |
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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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