5-Alkylated thiazolidinones as follicle-stimulating hormone (FSH) receptor agonists

• Published in: Bioorganic & medicinal chemistry 2006-08, Vol.14 (16), p.5729-5741
• Main Authors: Wrobel, Jay, Jetter, James, Kao, Wenling, Rogers, John, Di, Li, Chi, Jamin, Peréz, M. Claudia, Chen, Gi-Chung, Shen, Emily S.
• Format: Article
• Language: English
• Subjects: Alkylation; Animals; Biological and medical sciences; Cell Line; CHO Cells; Cricetinae; Cyclic AMP - biosynthesis; Female; Follicle Stimulating Hormone - metabolism; Follicle Stimulating Hormone - pharmacology; Follicle-stimulating hormone; FSH; FSH receptor agonist; Genital system. Reproduction; Hormones. Endocrine system; Humans; Luciferases - genetics; Luciferases - metabolism; Medical sciences; Ovary - drug effects; Ovary - metabolism; Pharmacology. Drug treatments; Receptors, FSH - agonists; Receptors, FSH - metabolism; Recombinant Proteins - genetics; Recombinant Proteins - metabolism; Structure-Activity Relationship; Thiazolidinediones - chemical synthesis; Thiazolidinediones - pharmacology; Thiazolidinone
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2006.04.012

5-Alkylated thiazolidine analogs ( 3) potent FSH agonists 1 were prepared and evaluated for FSH activity. We prepared analogs of potent thiazolidinone-based follicle-stimulating hormone (FSH) agonists 1, that is, 3 that contained an additional 5-alkyl substituent. This extra substituent was added to reduce synthetic problems that arose during preparation of analogs of 1. These compounds ( 3) were evaluated in a Chinese hamster ovary (CHO) cell line that expressed recombinant human FSH receptor (FSHR) and a luciferase reporter gene regulated by a cAMP response element (CRE). Selected compounds were also tested on a CHO-cell line that over expressed the FSHR for the ability to induce cAMP production. When the 5-alkyl substituent was a methyl group as in analog 16a, similar FSH activity (i.e., EC 50 = 51 nM, 100% efficacy relative to hFSH) to the analogous 5-hydrogen series compound (e.g., 2) was observed; thus, proving that a small 5-alkyl substituent was well tolerated. New derivatives of 3, in which the potentially hydrolytically labile secondary amide function of 1 (–CONH–) was modified to other moieties (e.g., –CH 2NH–, –CH 2S–, and –CH 2OCONH–), were also prepared and evaluated. These congeners (namely 21, 22, and 24) also displayed good potency in the CRE-luciferase assay.