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Structure-Based Discovery of Proline-Derived Arginase Inhibitors with Improved Oral Bioavailability for Immuno-Oncology.
Lu, Min; Zhang, Hongjun; Li, Derun; Childers, Matthew; Pu, Qinglin; Palte, Rachel L; Gathiaka, Symon; Lyons, Thomas W; Palani, Anandan; Fan, Peter W; Spacciapoli, Peter; Miller, J Richard; Cho, Hyelim; Cheng, Mangeng; Chakravarthy, Kalyan; O'Neil, Jennifer; Eangoor, Padmanabhan; Beard, Adam; Kim, Hai-Young; Saurí, Josep; Gunaydin, Hakan; Sloman, David L; Siliphaivanh, Phieng; Cumming, Jared; Fischer, Christian.
Afiliação
  • Lu M; Discovery Chemistry, Computational and Structural Chemistry, Quantitative Biosciences, Discovery Process Chemistry, Discovery Oncology, Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, and Analytical Research and Development, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachuse
  • Zhang H; Discovery Chemistry, Computational and Structural Chemistry, Quantitative Biosciences, Discovery Process Chemistry, Discovery Oncology, Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, and Analytical Research and Development, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachuse
  • Li D; Discovery Chemistry, Computational and Structural Chemistry, Quantitative Biosciences, Discovery Process Chemistry, Discovery Oncology, Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, and Analytical Research and Development, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachuse
  • Childers M; Discovery Chemistry, Computational and Structural Chemistry, Quantitative Biosciences, Discovery Process Chemistry, Discovery Oncology, Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, and Analytical Research and Development, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachuse
  • Pu Q; Discovery Chemistry, Computational and Structural Chemistry, Quantitative Biosciences, Discovery Process Chemistry, Discovery Oncology, Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, and Analytical Research and Development, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachuse
  • Palte RL; Discovery Chemistry, Computational and Structural Chemistry, Quantitative Biosciences, Discovery Process Chemistry, Discovery Oncology, Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, and Analytical Research and Development, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachuse
  • Gathiaka S; Discovery Chemistry, Computational and Structural Chemistry, Quantitative Biosciences, Discovery Process Chemistry, Discovery Oncology, Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, and Analytical Research and Development, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachuse
  • Lyons TW; Discovery Chemistry, Computational and Structural Chemistry, Quantitative Biosciences, Discovery Process Chemistry, Discovery Oncology, Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, and Analytical Research and Development, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachuse
  • Palani A; Discovery Chemistry, Computational and Structural Chemistry, Quantitative Biosciences, Discovery Process Chemistry, Discovery Oncology, Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, and Analytical Research and Development, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachuse
  • Fan PW; Discovery Chemistry, Computational and Structural Chemistry, Quantitative Biosciences, Discovery Process Chemistry, Discovery Oncology, Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, and Analytical Research and Development, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachuse
  • Spacciapoli P; Discovery Chemistry, Computational and Structural Chemistry, Quantitative Biosciences, Discovery Process Chemistry, Discovery Oncology, Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, and Analytical Research and Development, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachuse
  • Miller JR; Discovery Chemistry, Computational and Structural Chemistry, Quantitative Biosciences, Discovery Process Chemistry, Discovery Oncology, Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, and Analytical Research and Development, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachuse
  • Cho H; Discovery Chemistry, Computational and Structural Chemistry, Quantitative Biosciences, Discovery Process Chemistry, Discovery Oncology, Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, and Analytical Research and Development, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachuse
  • Cheng M; Discovery Chemistry, Computational and Structural Chemistry, Quantitative Biosciences, Discovery Process Chemistry, Discovery Oncology, Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, and Analytical Research and Development, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachuse
  • Chakravarthy K; Discovery Chemistry, Computational and Structural Chemistry, Quantitative Biosciences, Discovery Process Chemistry, Discovery Oncology, Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, and Analytical Research and Development, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachuse
  • O'Neil J; Discovery Chemistry, Computational and Structural Chemistry, Quantitative Biosciences, Discovery Process Chemistry, Discovery Oncology, Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, and Analytical Research and Development, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachuse
  • Eangoor P; Discovery Chemistry, Computational and Structural Chemistry, Quantitative Biosciences, Discovery Process Chemistry, Discovery Oncology, Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, and Analytical Research and Development, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachuse
  • Beard A; Discovery Chemistry, Computational and Structural Chemistry, Quantitative Biosciences, Discovery Process Chemistry, Discovery Oncology, Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, and Analytical Research and Development, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachuse
  • Kim HY; Discovery Chemistry, Computational and Structural Chemistry, Quantitative Biosciences, Discovery Process Chemistry, Discovery Oncology, Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, and Analytical Research and Development, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachuse
  • Saurí J; Discovery Chemistry, Computational and Structural Chemistry, Quantitative Biosciences, Discovery Process Chemistry, Discovery Oncology, Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, and Analytical Research and Development, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachuse
  • Gunaydin H; Discovery Chemistry, Computational and Structural Chemistry, Quantitative Biosciences, Discovery Process Chemistry, Discovery Oncology, Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, and Analytical Research and Development, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachuse
  • Sloman DL; Discovery Chemistry, Computational and Structural Chemistry, Quantitative Biosciences, Discovery Process Chemistry, Discovery Oncology, Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, and Analytical Research and Development, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachuse
  • Siliphaivanh P; Discovery Chemistry, Computational and Structural Chemistry, Quantitative Biosciences, Discovery Process Chemistry, Discovery Oncology, Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, and Analytical Research and Development, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachuse
  • Cumming J; Discovery Chemistry, Computational and Structural Chemistry, Quantitative Biosciences, Discovery Process Chemistry, Discovery Oncology, Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, and Analytical Research and Development, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachuse
  • Fischer C; Discovery Chemistry, Computational and Structural Chemistry, Quantitative Biosciences, Discovery Process Chemistry, Discovery Oncology, Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, and Analytical Research and Development, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachuse
ACS Med Chem Lett ; 12(9): 1380-1388, 2021 Sep 09.
Article em En | MEDLINE | ID: mdl-34527178
ABSTRACT
Recent data suggest that the inhibition of arginase (ARG) has therapeutic potential for the treatment of a number of indications ranging from pulmonary and vascular disease to cancer. Thus, high demand exists for selective small molecule ARG inhibitors with favorable druglike properties and good oral bioavailability. In light of the significant challenges associated with the unique physicochemical properties of previously disclosed ARG inhibitors, we use structure-based drug design combined with a focused optimization strategy to discover a class of boronic acids featuring a privileged proline scaffold with superior potency and oral bioavailability. These compounds, exemplified by inhibitors 4a, 18, and 27, demonstrated a favorable overall profile, and 4a was well tolerated following multiple days of dosing at concentrations that exceed those required for serum arginase inhibition and concomitant arginine elevation in a syngeneic mouse carcinoma model.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Revista: ACS Med Chem Lett Ano de publicação: 2021 Tipo de documento: Article
Texto completo
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PubMed Links
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Revista: ACS Med Chem Lett Ano de publicação: 2021 Tipo de documento: Article