| Literature DB >> 33738066 |
Derun Li1, Yongqi Deng1, Abdelghani Achab1, Indu Bharathan1, Brett Andrew Hopkins1, Wensheng Yu1, Hongjun Zhang1, Sulagna Sanyal1, Qinglin Pu1, Hua Zhou1, Kun Liu1, Jongwon Lim1, Xavier Fradera1, Charles A Lesburg1, Alfred Lammens2, Theodore A Martinot1, Ryan D Cohen3, Amy C Doty1, Heidi Ferguson1, Elliott B Nickbarg1, Mangeng Cheng1, Peter Spacciapoli1, Prasanthi Geda1, Xuelei Song1, Nadya Smotrov1, Pravien Abeywickrema1, Christine Andrews1, Chad Chamberlin1, Omar Mabrouk1, Patrick Curran1, Matthew Richards1, Peter Saradjian1, J Richard Miller1, Ian Knemeyer1, Karin M Otte1, Stella Vincent1, Nunzio Sciammetta1, Alexander Pasternak1, David Jonathan Bennett1, Yongxin Han1.
Abstract
Indoleamine-2,3-dioxygenase-1 (IDO1) has emerged as an attractive target for cancer immunotherapy. An automated ligand identification system screen afforded the tetrahydroquinoline class of novel IDO1 inhibitors. Potency and pharmacokinetic (PK) were key issues with this class of compounds. Structure-based drug design and strategic incorporation of polarity enabled the rapid improvement on potency, solubility, and oxidative metabolic stability. Metabolite identification studies revealed that amide hydrolysis in the D-pocket was the key clearance mechanism for this class. Strategic survey of amide isosteres revealed that carbamates and N-pyrimidines, which maintained exquisite potencies, mitigated the amide hydrolysis issue and led to an improved rat PK profile. The lead compound 28 is a potent IDO1 inhibitor, with clean off-target profiles and the potential for quaque die dosing in humans.Entities:
Year: 2021 PMID： 33738066 PMCID： PMC7957919 DOI： 10.1021/acsmedchemlett.0c00525
Source DB: PubMed Journal: ACS Med Chem Lett ISSN： 1948-5875 Impact factor: 4.345