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

  • J Med Chem. 2018 Jul 26;61(14):5949-5962. doi: 10.1021/acs.jmedchem.8b00182.
Yoshikazu Nishimura  1 ,  Toru Esaki  1 ,  Yoshiaki Isshiki  1 ,  Naoki Okamoto  1 ,  Yoshiyuki Furuta  1 ,  Tomoya Kotake  1 ,  Yoshiaki Watanabe  1 ,  Masateru Ohta  1 ,  Toshito Nakagawa  1 ,  Hiroshi Noda  1 ,  Masaru Shimizu  1 ,  Hitoshi Saito  1 ,  Tatsuya Tamura  1 ,  Haruhiko Sato  1
Affiliations
  • 1. Research Division , Chugai Pharmaceutical Co., Ltd. , Komakado 1-135 , Gotemba , Shizuoka 412-8513 , Japan.
PMID: 29932656 DOI: 10.1021/acs.jmedchem.8b00182
Abstract

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 EC20 of 3.0 μM and EC50 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.

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