Synthesis and Biological Evaluations of Novel Human Parathyroid Hormone 1 Receptor (hPTHR1) Agonists Bearing Bicyclic Aromatic Moiety

We have previously shown that the small molecule hPTHR1 agonist PCO371 (1) orally and dose‐dependently induces PTH‐like calcemic and hypophostemic activity in thyroparathyroidectomized rats. Compound 2a, bearing a bicyclic aromatic ring, was identified as a novel hPTHR1 agonist during hit to lead mo...

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Published in:ChemMedChem 2024-03, Vol.19 (5), p.e202300589-n/a
Main Authors: Nishimura, Yoshikazu, Esaki, Toru, Isshiki, Yoshiaki, Furuta, Yoshiyuki, Emura, Takashi, Watanabe, Yoshiaki, Ohta, Masateru, Arai, Shinichi, Noda, Hiroshi, Shimizu, Masaru, Tamura, Tatsuya, Sato, Haruhiko
Format: Article
Language:English
Subjects:
Agonists
Animals
Antipsychotic Agents
Aromatic compounds
Bone mineral density
Human parathyroid hormone
Humans
Indoles
Liver microsome stability
Microsomes, Liver
Osteoporosis
Parathyroid hormone
Parathyroid Hormone - pharmacology
PTHR1 agonist
Rats
Solubility
Structure-Activity Relationship
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Summary:We have previously shown that the small molecule hPTHR1 agonist PCO371 (1) orally and dose‐dependently induces PTH‐like calcemic and hypophostemic activity in thyroparathyroidectomized rats. Compound 2a, bearing a bicyclic aromatic ring, was identified as a novel hPTHR1 agonist during hit to lead modification. It showed moderate PTHR1 agonistic activity with an EC20 value of 15 μM, and its metabolic stability in human liver microsome (hLM) as well as its solubility in phosphate buffer (PPb) and Fasted state simulated intestinal fluid (FaSSIF) were found to be poor. As results of the initial derivatization of 2a, we identified the indole derivatives as another scaffold. In this article, we report on the structure‐activity relationship (SAR), structure‐metabolism relationship (SMR), and structure‐solubility relationship (SSR) of bicyclic aromatic derivatives, and the in vivo efficacy of 2j. This study provides a synthesis and structure‐activity relationship of biaryl spiroimidazolone compounds with PTHR1 agonist activity. The aromatic group and ethyl linker of compound 2a were converted to improve activity and solubility. The resulting compound 2j increased the bone mineral density of ovariectomized rats as PTH1–34. The SAR and in vivo effects are discussed.
ISSN:1860-7179
1860-7187
DOI:10.1002/cmdc.202300589