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Carbamate and N-Pyrimidine Mitigate Amide Hydrolysis: Structure-Based Drug Design of Tetrahydroquinoline IDO1 Inhibitors.

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.

SUBMITTER: Li D 

PROVIDER: S-EPMC7957919 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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Carbamate and <i>N</i>-Pyrimidine Mitigate Amide Hydrolysis: Structure-Based Drug Design of Tetrahydroquinoline IDO1 Inhibitors.

Li Derun D   Deng Yongqi Y   Achab Abdelghani A   Bharathan Indu I   Hopkins Brett Andrew BA   Yu Wensheng W   Zhang Hongjun H   Sanyal Sulagna S   Pu Qinglin Q   Zhou Hua H   Liu Kun K   Lim Jongwon J   Fradera Xavier X   Lesburg Charles A CA   Lammens Alfred A   Martinot Theodore A TA   Cohen Ryan D RD   Doty Amy C AC   Ferguson Heidi H   Nickbarg Elliott B EB   Cheng Mangeng M   Spacciapoli Peter P   Geda Prasanthi P   Song Xuelei X   Smotrov Nadya N   Abeywickrema Pravien P   Andrews Christine C   Chamberlin Chad C   Mabrouk Omar O   Curran Patrick P   Richards Matthew M   Saradjian Peter P   Miller J Richard JR   Knemeyer Ian I   Otte Karin M KM   Vincent Stella S   Sciammetta Nunzio N   Pasternak Alexander A   Bennett David Jonathan DJ   Han Yongxin Y  

ACS medicinal chemistry letters 20210226 3

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 ami  ...[more]

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