Discovery of Novel Transient Receptor Potential Vanilloid 4 (TRPV4) Agonists as Regulators of Chondrogenic Differentiation: Identification of Quinazolin-4(3H)‑ones and in Vivo Studies on a Surgically Induced Rat Model of Osteoarthritis

Osteoarthritis (OA) is a degenerative disease characterized by joint destruction and loss of cartilage. There are many unmet needs in the treatment of OA and there are few promising candidates for disease-modifying OA drugs, particularly, anabolic agents. Here, we describe the identification of nove...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2019-02, Vol.62 (3), p.1468-1483
Main Authors: Atobe, Masakazu, Nagami, Takamichi, Muramatsu, Shuji, Ohno, Takeshi, Kitagawa, Masayuki, Suzuki, Hiroko, Ishiguro, Masashi, Watanabe, Atsushi, Kawanishi, Masashi
Format: Article
Language:English
Subjects:
Aggrecans - genetics
Animals
Cartilage, Articular - pathology
Cell Differentiation - drug effects
Chondrocytes - metabolism
HEK293 Cells
Humans
Male
Menisci, Tibial - pathology
Mice
Molecular Structure
Osteoarthritis - drug therapy
Osteoarthritis - pathology
Quinazolinones - chemical synthesis
Quinazolinones - chemistry
Quinazolinones - therapeutic use
Rats, Sprague-Dawley
RNA, Messenger - metabolism
SOX9 Transcription Factor - genetics
Structure-Activity Relationship
TRPV Cation Channels - agonists
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Summary:Osteoarthritis (OA) is a degenerative disease characterized by joint destruction and loss of cartilage. There are many unmet needs in the treatment of OA and there are few promising candidates for disease-modifying OA drugs, particularly, anabolic agents. Here, we describe the identification of novel quinazolin-4­(3H)-one derivatives, which stimulate chondrocyte cartilage matrix production via TRPV4 and mitigate damaged articular cartilage. We successfully identified the water-soluble, highly potent quinazolin-4­(3H)-one derivative 36 and studied its intra-articular physicochemical profile to use in in vivo surgical OA model studies. Compound 36·HCl provided relief from OA damage in a rat medial meniscal tear (MT) model. Specifically, 36·HCl dose-dependently suppressed cartilage degradation and enhanced the messenger RNA expression of aggrecan and SOX9 in cartilage isolated from MT-operated rat knees compared with knees treated with vehicle. These results suggest that 36 induces anabolic changes in articular cartilage and consequently reduces OA progression.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.8b01615