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

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.

• Authors: Ping Liu, Liping Wang, Byron G DuBois, Vincent J Colandrea, Rongqiang Liu, Jiaqiang Cai, Xiaoxing Du, Weiguo Quan, William Morris, Jianwu Bai, Bimjhana Bishwokarma, Mangeng Cheng, Jennifer Piesvaux, Kallol Ray, Carla Alpert, Chi-Sung Chiu, Mark Zielstorff, Joseph M Metzger, Liming Yang, Dennis Leung, Candice Alleyne, Stella H Vincent, Vincenzo Pucci, Xiaofang Li, Alejandro Crespo, Dominique Stickens, Jeffrey J Hale, Feroze Ujjainwalla, Christopher J Sinz
• Journal: ACS medicinal chemistry letters (ACS Med Chem Lett) Vol. 9 Issue 12 Pg. 1193-1198 (Dec 13 2018) ISSN: 1948-5875 [Print] United States
• PMID: 30613325 (Publication Type: Journal Article)