Carbamate and -Pyrimidine Mitigate Amide Hydrolysis: Structure-Based Drug Design of Tetrahydroquinoline IDO1 Inhibitors.
Derun Li, Yongqi Deng, Abdelghani Achab, Indu Bharathan, Brett Andrew Hopkins, Wensheng Yu, Hongjun Zhang, Sulagna Sanyal, Qinglin Pu, Hua Zhou, Kun Liu, Jongwon Lim, Xavier Fradera, Charles A Lesburg, Alfred Lammens, Theodore A Martinot, Ryan D Cohen, Amy C Doty, Heidi Ferguson, Elliott B Nickbarg, Mangeng Cheng, Peter Spacciapoli, Prasanthi Geda, Xuelei Song, Nadya Smotrov, Pravien Abeywickrema, Christine Andrews, Chad Chamberlin, Omar Mabrouk, Patrick Curran, Matthew Richards, Peter Saradjian, J Richard Miller, Ian Knemeyer, Karin M Otte, Stella Vincent, Nunzio Sciammetta, Alexander Pasternak, David Jonathan Bennett, Yongxin Han
Author Information
Derun Li: Departments of Discovery Chemistry, Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Computational and Structural Chemistry, Discovery Process Chemistry, Discovery Pharmaceutical Science, and Quantitative Biosciences, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
Yongqi Deng: Departments of Discovery Chemistry, Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Computational and Structural Chemistry, Discovery Process Chemistry, Discovery Pharmaceutical Science, and Quantitative Biosciences, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
Abdelghani Achab: Departments of Discovery Chemistry, Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Computational and Structural Chemistry, Discovery Process Chemistry, Discovery Pharmaceutical Science, and Quantitative Biosciences, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
Indu Bharathan: Departments of Discovery Chemistry, Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Computational and Structural Chemistry, Discovery Process Chemistry, Discovery Pharmaceutical Science, and Quantitative Biosciences, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
Brett Andrew Hopkins: Departments of Discovery Chemistry, Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Computational and Structural Chemistry, Discovery Process Chemistry, Discovery Pharmaceutical Science, and Quantitative Biosciences, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
Wensheng Yu: Departments of Discovery Chemistry, Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Computational and Structural Chemistry, Discovery Process Chemistry, Discovery Pharmaceutical Science, and Quantitative Biosciences, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
Hongjun Zhang: Departments of Discovery Chemistry, Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Computational and Structural Chemistry, Discovery Process Chemistry, Discovery Pharmaceutical Science, and Quantitative Biosciences, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
Sulagna Sanyal: Departments of Discovery Chemistry, Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Computational and Structural Chemistry, Discovery Process Chemistry, Discovery Pharmaceutical Science, and Quantitative Biosciences, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
Qinglin Pu: Departments of Discovery Chemistry, Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Computational and Structural Chemistry, Discovery Process Chemistry, Discovery Pharmaceutical Science, and Quantitative Biosciences, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
Hua Zhou: Departments of Discovery Chemistry, Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Computational and Structural Chemistry, Discovery Process Chemistry, Discovery Pharmaceutical Science, and Quantitative Biosciences, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
Kun Liu: Departments of Discovery Chemistry, Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Computational and Structural Chemistry, Discovery Process Chemistry, Discovery Pharmaceutical Science, and Quantitative Biosciences, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
Jongwon Lim: Departments of Discovery Chemistry, Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Computational and Structural Chemistry, Discovery Process Chemistry, Discovery Pharmaceutical Science, and Quantitative Biosciences, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
Xavier Fradera: Departments of Discovery Chemistry, Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Computational and Structural Chemistry, Discovery Process Chemistry, Discovery Pharmaceutical Science, and Quantitative Biosciences, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
Charles A Lesburg: Departments of Discovery Chemistry, Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Computational and Structural Chemistry, Discovery Process Chemistry, Discovery Pharmaceutical Science, and Quantitative Biosciences, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
Alfred Lammens: Proteros Biostructures GmbH, Bunsenstraße 7a, D-82152 Planegg-Martinsried, Germany.
Theodore A Martinot: Departments of Discovery Chemistry, Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Computational and Structural Chemistry, Discovery Process Chemistry, Discovery Pharmaceutical Science, and Quantitative Biosciences, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
Ryan D Cohen: Analytical Research & Development, Merck & Co., Inc., 126 East Lincoln Avenue, Rahway, New Jersey 07065 United States.
Amy C Doty: Departments of Discovery Chemistry, Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Computational and Structural Chemistry, Discovery Process Chemistry, Discovery Pharmaceutical Science, and Quantitative Biosciences, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
Heidi Ferguson: Departments of Discovery Chemistry, Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Computational and Structural Chemistry, Discovery Process Chemistry, Discovery Pharmaceutical Science, and Quantitative Biosciences, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
Elliott B Nickbarg: Departments of Discovery Chemistry, Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Computational and Structural Chemistry, Discovery Process Chemistry, Discovery Pharmaceutical Science, and Quantitative Biosciences, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
Mangeng Cheng: Departments of Discovery Chemistry, Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Computational and Structural Chemistry, Discovery Process Chemistry, Discovery Pharmaceutical Science, and Quantitative Biosciences, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
Peter Spacciapoli: Departments of Discovery Chemistry, Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Computational and Structural Chemistry, Discovery Process Chemistry, Discovery Pharmaceutical Science, and Quantitative Biosciences, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
Prasanthi Geda: Departments of Discovery Chemistry, Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Computational and Structural Chemistry, Discovery Process Chemistry, Discovery Pharmaceutical Science, and Quantitative Biosciences, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
Xuelei Song: Departments of Discovery Chemistry, Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Computational and Structural Chemistry, Discovery Process Chemistry, Discovery Pharmaceutical Science, and Quantitative Biosciences, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
Nadya Smotrov: Departments of Discovery Chemistry, Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Computational and Structural Chemistry, Discovery Process Chemistry, Discovery Pharmaceutical Science, and Quantitative Biosciences, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
Pravien Abeywickrema: Departments of Discovery Chemistry, Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Computational and Structural Chemistry, Discovery Process Chemistry, Discovery Pharmaceutical Science, and Quantitative Biosciences, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
Christine Andrews: Departments of Discovery Chemistry, Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Computational and Structural Chemistry, Discovery Process Chemistry, Discovery Pharmaceutical Science, and Quantitative Biosciences, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
Chad Chamberlin: Departments of Discovery Chemistry, Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Computational and Structural Chemistry, Discovery Process Chemistry, Discovery Pharmaceutical Science, and Quantitative Biosciences, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
Omar Mabrouk: Departments of Discovery Chemistry, Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Computational and Structural Chemistry, Discovery Process Chemistry, Discovery Pharmaceutical Science, and Quantitative Biosciences, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
Patrick Curran: Departments of Discovery Chemistry, Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Computational and Structural Chemistry, Discovery Process Chemistry, Discovery Pharmaceutical Science, and Quantitative Biosciences, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
Matthew Richards: Departments of Discovery Chemistry, Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Computational and Structural Chemistry, Discovery Process Chemistry, Discovery Pharmaceutical Science, and Quantitative Biosciences, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
Peter Saradjian: Departments of Discovery Chemistry, Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Computational and Structural Chemistry, Discovery Process Chemistry, Discovery Pharmaceutical Science, and Quantitative Biosciences, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
J Richard Miller: Departments of Discovery Chemistry, Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Computational and Structural Chemistry, Discovery Process Chemistry, Discovery Pharmaceutical Science, and Quantitative Biosciences, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
Ian Knemeyer: Departments of Discovery Chemistry, Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Computational and Structural Chemistry, Discovery Process Chemistry, Discovery Pharmaceutical Science, and Quantitative Biosciences, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
Karin M Otte: Departments of Discovery Chemistry, Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Computational and Structural Chemistry, Discovery Process Chemistry, Discovery Pharmaceutical Science, and Quantitative Biosciences, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
Stella Vincent: Departments of Discovery Chemistry, Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Computational and Structural Chemistry, Discovery Process Chemistry, Discovery Pharmaceutical Science, and Quantitative Biosciences, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
Nunzio Sciammetta: Departments of Discovery Chemistry, Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Computational and Structural Chemistry, Discovery Process Chemistry, Discovery Pharmaceutical Science, and Quantitative Biosciences, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
Alexander Pasternak: Departments of Discovery Chemistry, Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Computational and Structural Chemistry, Discovery Process Chemistry, Discovery Pharmaceutical Science, and Quantitative Biosciences, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
David Jonathan Bennett: Departments of Discovery Chemistry, Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Computational and Structural Chemistry, Discovery Process Chemistry, Discovery Pharmaceutical Science, and Quantitative Biosciences, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
Yongxin Han: Departments of Discovery Chemistry, Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Computational and Structural Chemistry, Discovery Process Chemistry, Discovery Pharmaceutical Science, and Quantitative Biosciences, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
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 -pyrimidines, which maintained exquisite potencies, mitigated the amide hydrolysis issue and led to an improved rat PK profile. The lead compound is a potent IDO1 inhibitor, with clean off-target profiles and the potential for quaque die dosing in humans.
References
J Med Chem. 2015 Nov 12;58(21):8315-59
[PMID: 26200936]
