Discovery of Orally Bioavailable and Liver-Targeted Hypoxia-Inducible Factor Prolyl Hydroxylase (HIF-PHD) Inhibitors for the Treatment of Anemia
| Autor: | Jiaqiang Cai, Bimjhana Bishwokarma, Dennis Leung, William J. Morris, Feroze Ujjainwalla, Candice Alleyne, Xiaoxing Du, Vincent J. Colandrea, Jennifer Piesvaux, Jianwu Bai, Liming Yang, Carla Alpert, Joseph M. Metzger, Vincenzo Pucci, Xiaofang Li, Jeffrey J. Hale, Dominique Stickens, Weiguo Quan, Byron G. DuBois, Rongqiang Liu, Mark Zielstorff, Chi-Sung Chiu, Christopher Joseph Sinz, Mangeng Cheng, Kallol Ray, Liping Wang, Ping Liu, Stella H. Vincent, Alejandro Crespo |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Chemistry Anemia Organic Chemistry Increased hemoglobin Pharmacology medicine.disease 030226 pharmacology & pharmacy Biochemistry In vitro Bioavailability 03 medical and health sciences 030104 developmental biology 0302 clinical medicine Orally active Hypoxia-inducible factors Oral administration Drug Discovery medicine |
| Zdroj: | ACS Medicinal Chemistry Letters. 9:1193-1198 |
| ISSN: | 1948-5875 |
| DOI: | 10.1021/acsmedchemlett.8b00274 |
| Popis: | [Image: see text] 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. |
| Databáze: | OpenAIRE |
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