Development of a Novel Human Parathyroid Hormone Receptor 1 (hPTHR1) Agonist (CH5447240), a Potent and Orally Available Small Molecule for Treatment of Hypoparathyroidism.

Autor:	Nishimura Y; Research Division , Chugai Pharmaceutical Co., Ltd. , Komakado 1-135 , Gotemba , Shizuoka 412-8513 , Japan., Esaki T; Research Division , Chugai Pharmaceutical Co., Ltd. , Komakado 1-135 , Gotemba , Shizuoka 412-8513 , Japan., Isshiki Y; Research Division , Chugai Pharmaceutical Co., Ltd. , Komakado 1-135 , Gotemba , Shizuoka 412-8513 , Japan., Okamoto N; Research Division , Chugai Pharmaceutical Co., Ltd. , Komakado 1-135 , Gotemba , Shizuoka 412-8513 , Japan., Furuta Y; Research Division , Chugai Pharmaceutical Co., Ltd. , Komakado 1-135 , Gotemba , Shizuoka 412-8513 , Japan., Kotake T; Research Division , Chugai Pharmaceutical Co., Ltd. , Komakado 1-135 , Gotemba , Shizuoka 412-8513 , Japan., Watanabe Y; Research Division , Chugai Pharmaceutical Co., Ltd. , Komakado 1-135 , Gotemba , Shizuoka 412-8513 , Japan., Ohta M; Research Division , Chugai Pharmaceutical Co., Ltd. , Komakado 1-135 , Gotemba , Shizuoka 412-8513 , Japan., Nakagawa T; Research Division , Chugai Pharmaceutical Co., Ltd. , Komakado 1-135 , Gotemba , Shizuoka 412-8513 , Japan., Noda H; Research Division , Chugai Pharmaceutical Co., Ltd. , Komakado 1-135 , Gotemba , Shizuoka 412-8513 , Japan., Shimizu M; Research Division , Chugai Pharmaceutical Co., Ltd. , Komakado 1-135 , Gotemba , Shizuoka 412-8513 , Japan., Saito H; Research Division , Chugai Pharmaceutical Co., Ltd. , Komakado 1-135 , Gotemba , Shizuoka 412-8513 , Japan., Tamura T; Research Division , Chugai Pharmaceutical Co., Ltd. , Komakado 1-135 , Gotemba , Shizuoka 412-8513 , Japan., Sato H; Research Division , Chugai Pharmaceutical Co., Ltd. , Komakado 1-135 , Gotemba , Shizuoka 412-8513 , Japan.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2018 Jul 26; Vol. 61 (14), pp. 5949-5962. Date of Electronic Publication: 2018 Jul 03.
DOI:	10.1021/acs.jmedchem.8b00182
Abstrakt:	During the course of derivatization of HTS hit 4a, we have identified a novel small-molecule hPTHR1 agonist, 1-(3,5-dimethyl-4-(2-((2-((1 R,4 R)-4-methylcyclohexyl)-4-oxo-1,3,8-triazaspiro[4.5]dec-1-en-8-yl)sulfonyl)ethyl)phenyl)-1-methylurea (CH5447240, 14l). Compound 14l exhibited a potent in vitro hPTHR1 agonist effect with EC 20 of 3.0 μM and EC 50 of 12 μM and showed excellent physicochemical properties, such as high solubility in fasted state simulated intestinal fluid and good metabolic stability in human liver microsomes. Importantly, 14l showed 55% oral bioavailability and a significantly elevated serum calcium level in hypocalcemic model rats.
Databáze:	MEDLINE
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