Discovery of Orally Bioavailable and Liver-Targeted Hypoxia-Inducible Factor Prolyl Hydroxylase (HIF-PHD) Inhibitors for the Treatment of Anemia.

Liu, Ping; Wang, Liping; DuBois, Byron G; Colandrea, Vincent J; Liu, Rongqiang; Cai, Jiaqiang; Du, Xiaoxing; Quan, Weiguo; Morris, William; Bai, Jianwu; Bishwokarma, Bimjhana; Cheng, Mangeng; Piesvaux, Jennifer; Ray, Kallol; Alpert, Carla; Chiu, Chi-Sung; Zielstorff, Mark; Metzger, Joseph M; Yang, Liming; Leung, Dennis; Alleyne, Candice; Vincent, Stella H; Pucci, Vincenzo; Li, Xiaofang; Crespo, Alejandro; Stickens, Dominique; Hale, Jeffrey J; Ujjainwalla, Feroze; Sinz, Christopher J

Liu, Ping; Wang, Liping; DuBois, Byron G; Colandrea, Vincent J; Liu, Rongqiang; Cai, Jiaqiang; Du, Xiaoxing; Quan, Weiguo; Morris, William; Bai, Jianwu; Bishwokarma, Bimjhana; Cheng, Mangeng; Piesvaux, Jennifer; Ray, Kallol; Alpert, Carla; Chiu, Chi-Sung; Zielstorff, Mark; Metzger, Joseph M; Yang, Liming; Leung, Dennis; Alleyne, Candice; Vincent, Stella H; Pucci, Vincenzo; Li, Xiaofang; Crespo, Alejandro; Stickens, Dominique; Hale, Jeffrey J; Ujjainwalla, Feroze; Sinz, Christopher J.

Afiliação

Liu P; Departments of Medicinal Chemistry, Discovery Process Chemistry, Immunology, In Vitro Pharmacology, In Vivo Pharmacology, Basic Pharmaceutical Sciences, Pharmacokinetics, Pharmacodynamics and Drug Metabolism, and Chemical Modeling and Informatics, Merck & Co., Inc., 2015 Galloping Hill Road, Ken
Wang L; Departments of Medicinal Chemistry, Discovery Process Chemistry, Immunology, In Vitro Pharmacology, In Vivo Pharmacology, Basic Pharmaceutical Sciences, Pharmacokinetics, Pharmacodynamics and Drug Metabolism, and Chemical Modeling and Informatics, Merck & Co., Inc., 2015 Galloping Hill Road, Ken
DuBois BG; Departments of Medicinal Chemistry, Discovery Process Chemistry, Immunology, In Vitro Pharmacology, In Vivo Pharmacology, Basic Pharmaceutical Sciences, Pharmacokinetics, Pharmacodynamics and Drug Metabolism, and Chemical Modeling and Informatics, Merck & Co., Inc., 2015 Galloping Hill Road, Ken
Colandrea VJ; Departments of Medicinal Chemistry, Discovery Process Chemistry, Immunology, In Vitro Pharmacology, In Vivo Pharmacology, Basic Pharmaceutical Sciences, Pharmacokinetics, Pharmacodynamics and Drug Metabolism, and Chemical Modeling and Informatics, Merck & Co., Inc., 2015 Galloping Hill Road, Ken
Liu R; Departments of Medicinal Chemistry, Discovery Process Chemistry, Immunology, In Vitro Pharmacology, In Vivo Pharmacology, Basic Pharmaceutical Sciences, Pharmacokinetics, Pharmacodynamics and Drug Metabolism, and Chemical Modeling and Informatics, Merck & Co., Inc., 2015 Galloping Hill Road, Ken
Cai J; WuXi PharmaTech, No. 1 Building, 288 Fute Zhong Road, WaiGaoQiao Free Trade Zone, Shanghai 200131, China.
Du X; WuXi PharmaTech, No. 1 Building, 288 Fute Zhong Road, WaiGaoQiao Free Trade Zone, Shanghai 200131, China.
Quan W; WuXi PharmaTech, No. 1 Building, 288 Fute Zhong Road, WaiGaoQiao Free Trade Zone, Shanghai 200131, China.
Morris W; Departments of Medicinal Chemistry, Discovery Process Chemistry, Immunology, In Vitro Pharmacology, In Vivo Pharmacology, Basic Pharmaceutical Sciences, Pharmacokinetics, Pharmacodynamics and Drug Metabolism, and Chemical Modeling and Informatics, Merck & Co., Inc., 2015 Galloping Hill Road, Ken
Bai J; Departments of Medicinal Chemistry, Discovery Process Chemistry, Immunology, In Vitro Pharmacology, In Vivo Pharmacology, Basic Pharmaceutical Sciences, Pharmacokinetics, Pharmacodynamics and Drug Metabolism, and Chemical Modeling and Informatics, Merck & Co., Inc., 2015 Galloping Hill Road, Ken
Bishwokarma B; Departments of Medicinal Chemistry, Discovery Process Chemistry, Immunology, In Vitro Pharmacology, In Vivo Pharmacology, Basic Pharmaceutical Sciences, Pharmacokinetics, Pharmacodynamics and Drug Metabolism, and Chemical Modeling and Informatics, Merck & Co., Inc., 2015 Galloping Hill Road, Ken
Cheng M; Departments of Medicinal Chemistry, Discovery Process Chemistry, Immunology, In Vitro Pharmacology, In Vivo Pharmacology, Basic Pharmaceutical Sciences, Pharmacokinetics, Pharmacodynamics and Drug Metabolism, and Chemical Modeling and Informatics, Merck & Co., Inc., 2015 Galloping Hill Road, Ken
Piesvaux J; Departments of Medicinal Chemistry, Discovery Process Chemistry, Immunology, In Vitro Pharmacology, In Vivo Pharmacology, Basic Pharmaceutical Sciences, Pharmacokinetics, Pharmacodynamics and Drug Metabolism, and Chemical Modeling and Informatics, Merck & Co., Inc., 2015 Galloping Hill Road, Ken
Ray K; Departments of Medicinal Chemistry, Discovery Process Chemistry, Immunology, In Vitro Pharmacology, In Vivo Pharmacology, Basic Pharmaceutical Sciences, Pharmacokinetics, Pharmacodynamics and Drug Metabolism, and Chemical Modeling and Informatics, Merck & Co., Inc., 2015 Galloping Hill Road, Ken
Alpert C; Departments of Medicinal Chemistry, Discovery Process Chemistry, Immunology, In Vitro Pharmacology, In Vivo Pharmacology, Basic Pharmaceutical Sciences, Pharmacokinetics, Pharmacodynamics and Drug Metabolism, and Chemical Modeling and Informatics, Merck & Co., Inc., 2015 Galloping Hill Road, Ken
Chiu CS; Departments of Medicinal Chemistry, Discovery Process Chemistry, Immunology, In Vitro Pharmacology, In Vivo Pharmacology, Basic Pharmaceutical Sciences, Pharmacokinetics, Pharmacodynamics and Drug Metabolism, and Chemical Modeling and Informatics, Merck & Co., Inc., 2015 Galloping Hill Road, Ken
Zielstorff M; Departments of Medicinal Chemistry, Discovery Process Chemistry, Immunology, In Vitro Pharmacology, In Vivo Pharmacology, Basic Pharmaceutical Sciences, Pharmacokinetics, Pharmacodynamics and Drug Metabolism, and Chemical Modeling and Informatics, Merck & Co., Inc., 2015 Galloping Hill Road, Ken
Metzger JM; Departments of Medicinal Chemistry, Discovery Process Chemistry, Immunology, In Vitro Pharmacology, In Vivo Pharmacology, Basic Pharmaceutical Sciences, Pharmacokinetics, Pharmacodynamics and Drug Metabolism, and Chemical Modeling and Informatics, Merck & Co., Inc., 2015 Galloping Hill Road, Ken
Yang L; Departments of Medicinal Chemistry, Discovery Process Chemistry, Immunology, In Vitro Pharmacology, In Vivo Pharmacology, Basic Pharmaceutical Sciences, Pharmacokinetics, Pharmacodynamics and Drug Metabolism, and Chemical Modeling and Informatics, Merck & Co., Inc., 2015 Galloping Hill Road, Ken
Leung D; Departments of Medicinal Chemistry, Discovery Process Chemistry, Immunology, In Vitro Pharmacology, In Vivo Pharmacology, Basic Pharmaceutical Sciences, Pharmacokinetics, Pharmacodynamics and Drug Metabolism, and Chemical Modeling and Informatics, Merck & Co., Inc., 2015 Galloping Hill Road, Ken
Alleyne C; Departments of Medicinal Chemistry, Discovery Process Chemistry, Immunology, In Vitro Pharmacology, In Vivo Pharmacology, Basic Pharmaceutical Sciences, Pharmacokinetics, Pharmacodynamics and Drug Metabolism, and Chemical Modeling and Informatics, Merck & Co., Inc., 2015 Galloping Hill Road, Ken
Vincent SH; Departments of Medicinal Chemistry, Discovery Process Chemistry, Immunology, In Vitro Pharmacology, In Vivo Pharmacology, Basic Pharmaceutical Sciences, Pharmacokinetics, Pharmacodynamics and Drug Metabolism, and Chemical Modeling and Informatics, Merck & Co., Inc., 2015 Galloping Hill Road, Ken
Pucci V; Departments of Medicinal Chemistry, Discovery Process Chemistry, Immunology, In Vitro Pharmacology, In Vivo Pharmacology, Basic Pharmaceutical Sciences, Pharmacokinetics, Pharmacodynamics and Drug Metabolism, and Chemical Modeling and Informatics, Merck & Co., Inc., 2015 Galloping Hill Road, Ken
Li X; Departments of Medicinal Chemistry, Discovery Process Chemistry, Immunology, In Vitro Pharmacology, In Vivo Pharmacology, Basic Pharmaceutical Sciences, Pharmacokinetics, Pharmacodynamics and Drug Metabolism, and Chemical Modeling and Informatics, Merck & Co., Inc., 2015 Galloping Hill Road, Ken
Crespo A; Departments of Medicinal Chemistry, Discovery Process Chemistry, Immunology, In Vitro Pharmacology, In Vivo Pharmacology, Basic Pharmaceutical Sciences, Pharmacokinetics, Pharmacodynamics and Drug Metabolism, and Chemical Modeling and Informatics, Merck & Co., Inc., 2015 Galloping Hill Road, Ken
Stickens D; Departments of Medicinal Chemistry, Discovery Process Chemistry, Immunology, In Vitro Pharmacology, In Vivo Pharmacology, Basic Pharmaceutical Sciences, Pharmacokinetics, Pharmacodynamics and Drug Metabolism, and Chemical Modeling and Informatics, Merck & Co., Inc., 2015 Galloping Hill Road, Ken
Hale JJ; Departments of Medicinal Chemistry, Discovery Process Chemistry, Immunology, In Vitro Pharmacology, In Vivo Pharmacology, Basic Pharmaceutical Sciences, Pharmacokinetics, Pharmacodynamics and Drug Metabolism, and Chemical Modeling and Informatics, Merck & Co., Inc., 2015 Galloping Hill Road, Ken
Ujjainwalla F; Departments of Medicinal Chemistry, Discovery Process Chemistry, Immunology, In Vitro Pharmacology, In Vivo Pharmacology, Basic Pharmaceutical Sciences, Pharmacokinetics, Pharmacodynamics and Drug Metabolism, and Chemical Modeling and Informatics, Merck & Co., Inc., 2015 Galloping Hill Road, Ken
Sinz CJ; Departments of Medicinal Chemistry, Discovery Process Chemistry, Immunology, In Vitro Pharmacology, In Vivo Pharmacology, Basic Pharmaceutical Sciences, Pharmacokinetics, Pharmacodynamics and Drug Metabolism, and Chemical Modeling and Informatics, Merck & Co., Inc., 2015 Galloping Hill Road, Ken

ACS Med Chem Lett ; 9(12): 1193-1198, 2018 Dec 13.

Article em En | MEDLINE | ID: mdl-30613325

ABSTRACT

ABSTRACT

We report herein the design and synthesis of a series of orally active, liver-targeted hypoxia-inducible factor prolyl hydroxylase (HIF-PHD) inhibitors for the treatment of anemia. In order to mitigate the concerns for potential systemic side effects, we pursued liver-targeted HIF-PHD inhibitors relying on uptake via organic anion transporting polypeptides (OATPs). Starting from a systemic HIF-PHD inhibitor (1), medicinal chemistry efforts directed toward reducing permeability and, at the same time, maintaining oral absorption led to the synthesis of an array of structurally diverse hydroxypyridone analogues. Compound 28a was chosen for further profiling, because of its excellent in vitro profile and liver selectivity. This compound significantly increased hemoglobin levels in rats, following chronic QD oral administration, and displayed selectivity over systemic effects.

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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Revista: ACS Med Chem Lett Ano de publicação: 2018 Tipo de documento: Article