Development of a Novel Human Parathyroid Hormone Receptor 1 (hPTHR1) Agonist (CH5447240), a Potent and Orally Available Small Molecule for Treatment of Hypoparathyroidism
| Autor: | Masaru Shimizu, Yoshikazu Nishimura, Masateru Ohta, Toshito Nakagawa, Yoshiyuki Furuta, Naoki Okamoto, Yoshiaki Isshiki, Haruhiko Sato, Yoshiaki Watanabe, Hitoshi Saito, Hiroshi Noda, Tatsuya Tamura, Tomoya Kotake, Toru Esaki |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Agonist Hypoparathyroidism medicine.drug_class Administration Oral Biological Availability Parathyroid hormone 030209 endocrinology & metabolism Pharmacology Cell Line Small Molecule Libraries 03 medical and health sciences 0302 clinical medicine Drug Discovery medicine Humans Urea Sulfones Receptor Receptor Parathyroid Hormone Type 1 Sulfonyl chemistry.chemical_classification Methylurea Compounds medicine.disease Bioavailability 030104 developmental biology chemistry Hormone receptor Microsome Molecular Medicine |
| Zdroj: | Journal of Medicinal Chemistry. 61:5949-5962 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | 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-((1R,4R)-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. |
| Databáze: | OpenAIRE |
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