1. Discovery of JTZ-951: A HIF Prolyl Hydroxylase Inhibitor for the Treatment of Renal Anemia
- Author
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Mitani Ikuo, Motoda Dai, Masakazu Terashita, Kenji Fukui, Yasunori Hase, Yokota Masahiro, Hotta Takahiro, Soichiro Ito, Hiroyuki Abe, Yosuke Ogoshi, Katsuya Deai, Hiromi Yoshiuchi, Ito Takashi, Kazuhito Ueyama, and Takuya Matsui
- Subjects
0301 basic medicine ,Chemistry ,Organic Chemistry ,030232 urology & nephrology ,HIF prolyl-hydroxylase inhibitor ,Pharmacology ,Biochemistry ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Hypoxia-inducible factors ,Oral administration ,Erythropoietin ,In vivo ,Drug Discovery ,medicine ,Potency ,Triazolopyridine ,Pharmacophore ,medicine.drug - Abstract
Inhibition of hypoxia inducible factor prolyl hydroxylase (PHD) represents a promising strategy for the discovery of a next generation treatment for renal anemia. We identified several 5,6-fused ring systems as novel scaffolds of the PHD inhibitor on the basis of pharmacophore analysis. In particular, triazolopyridine derivatives showed potent PHD2 inhibitory activities. Examination of the predominance of the triazolopyridines in potency by electrostatic calculations suggested favorable π–π stacking interactions with Tyr310. Lead optimization to improve the efficacy of erythropoietin release in cells and in vivo by improving cell permeability led to the discovery of JTZ-951 (compound 14), with a 5-phenethyl substituent on the triazolopyridine group, which increased hemoglobin levels with daily oral dosing in rats. Compound 14 was rapidly absorbed after oral administration and disappeared shortly thereafter, which could be advantageous in terms of safety. Compound 14 was selected as a clinical candidate.
- Published
- 2017