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Carbamate and N-Pyrimidine Mitigate Amide Hydrolysis: Structure-Based Drug Design of Tetrahydroquinoline IDO1 Inhibitors.
Li, Derun; Deng, Yongqi; Achab, Abdelghani; Bharathan, Indu; Hopkins, Brett Andrew; Yu, Wensheng; Zhang, Hongjun; Sanyal, Sulagna; Pu, Qinglin; Zhou, Hua; Liu, Kun; Lim, Jongwon; Fradera, Xavier; Lesburg, Charles A; Lammens, Alfred; Martinot, Theodore A; Cohen, Ryan D; Doty, Amy C; Ferguson, Heidi; Nickbarg, Elliott B; Cheng, Mangeng; Spacciapoli, Peter; Geda, Prasanthi; Song, Xuelei; Smotrov, Nadya; Abeywickrema, Pravien; Andrews, Christine; Chamberlin, Chad; Mabrouk, Omar; Curran, Patrick; Richards, Matthew; Saradjian, Peter; Miller, J Richard; Knemeyer, Ian; Otte, Karin M; Vincent, Stella; Sciammetta, Nunzio; Pasternak, Alexander; Bennett, David Jonathan; Han, Yongxin.
Afiliación
  • Li D; 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 0211
  • Deng Y; 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 0211
  • Achab A; 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 0211
  • Bharathan I; 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 0211
  • Hopkins BA; 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 0211
  • Yu W; 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 0211
  • Zhang H; 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 0211
  • Sanyal S; 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 0211
  • Pu Q; 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 0211
  • Zhou H; 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 0211
  • Liu K; 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 0211
  • Lim J; 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 0211
  • Fradera X; 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 0211
  • Lesburg CA; 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 0211
  • Lammens A; Proteros Biostructures GmbH, Bunsenstraße 7a, D-82152 Planegg-Martinsried, Germany.
  • Martinot TA; 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 0211
  • Cohen RD; Analytical Research & Development, Merck & Co., Inc., 126 East Lincoln Avenue, Rahway, New Jersey 07065 United States.
  • Doty AC; 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 0211
  • Ferguson H; 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 0211
  • Nickbarg EB; 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 0211
  • Cheng M; 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 0211
  • Spacciapoli P; 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 0211
  • Geda P; 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 0211
  • Song X; 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 0211
  • Smotrov N; 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 0211
  • Abeywickrema P; 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 0211
  • Andrews C; 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 0211
  • Chamberlin C; 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 0211
  • Mabrouk O; 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 0211
  • Curran P; 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 0211
  • Richards M; 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 0211
  • Saradjian P; 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 0211
  • Miller JR; 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 0211
  • Knemeyer I; 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 0211
  • Otte KM; 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 0211
  • Vincent S; 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 0211
  • Sciammetta N; 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 0211
  • Pasternak A; 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 0211
  • Bennett DJ; 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 0211
  • Han Y; 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 0211
ACS Med Chem Lett ; 12(3): 389-396, 2021 Mar 11.
Article en En | MEDLINE | ID: mdl-33738066
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: ACS Med Chem Lett Año: 2021 Tipo del documento: Article
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: ACS Med Chem Lett Año: 2021 Tipo del documento: Article