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Carbamate and n-pyrimidine mitigate amide hydrolysis: Structure-based drug design of tetrahydroquinoline IDO1 inhibitors

DOI: 10.1021/acsmedchemlett.0c00525 DOI Help

Authors: Derun Li (Merck & Co) , Yongqi Deng (Merck & Co., Inc) , Abdelghani Achab (Merck & Co., Inc) , Indu Bharathan (Merck & Co., Inc) , Brett Andrew Hopkins (Merck & Co., Inc) , Wensheng Yu (Merck & Co., Inc) , Hongjun Zhang (Merck & Co., Inc) , Sulagna Sanyal (Merck & Co., Inc) , Qinglin Pu (Merck & Co., Inc) , Hua Zhou (Merck & Co., Inc) , Kun Liu (Merck & Co., Inc) , Jongwon Lim (Merck & Co., Inc) , Xavier Fradera (Merck & Co., Inc) , Charles A. Lesburg (Merck & Co., Inc) , Alfred Lammens (Proteros Biostructures GmbH) , Theodore A. Martinot (Merck & Co., Inc) , Ryan D. Cohen (Merck & Co., Inc) , Amy C. Doty (Merck & Co., Inc) , Heidi Ferguson (Merck & Co., Inc) , Elliott B. Nickbarg (Merck & Co., Inc) , Mangeng Cheng (Merck & Co., Inc) , Peter Spacciapoli (Merck & Co., Inc) , Prasanthi Geda (Merck & Co., Inc) , Xuelei Song (Merck & Co., Inc) , Nadya Smotrov (Merck & Co., Inc) , Pravien Abeywickrema (Merck & Co., Inc) , Christine Andrews (Merck & Co., Inc) , Chad Chamberlin (Merck & Co., Inc) , Omar Mabrouk (Merck & Co., Inc) , Patrick Curran (Merck & Co., Inc) , Matthew Richards (Merck & Co., Inc) , Peter Saradjian (Merck & Co., Inc) , J. Richard Miller (Merck & Co., Inc) , Ian Knemeyer (Merck & Co., Inc) , Karin M. Otte (Merck & Co., Inc) , Stella Vincent (Merck & Co., Inc) , Nunzio Sciammetta (Merck & Co., Inc) , Alexander Pasternak (Merck & Co., Inc) , David Jonathan Bennett (Merck & Co., Inc) , Yongxin Han (Merck & Co., Inc)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Acs Medicinal Chemistry Letters , VOL 12 , PAGES 389 - 396

State: Published (Approved)
Published: March 2021

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.

Journal Keywords: IDO1; structure-based drug design; carbamate; N-pyrimidine; amide isostere; pharmacokinetic

Diamond Keywords: Immunotherapy

Subject Areas: Biology and Bio-materials, Chemistry, Medicine

Instruments: I04-1-Macromolecular Crystallography (fixed wavelength)

Added On: 11/03/2021 08:47

Discipline Tags:

Non-Communicable Diseases Health & Wellbeing Cancer Biochemistry Chemistry Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)