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

Bioorg Med Chem. 2006 Aug 15;14(16):5729-41. doi: 10.1016/j.bmc.2006.04.012. Epub 2006 May 3.

Abstract

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(2)NH-, -CH(2)S-, and -CH(2)OCONH-), were also prepared and evaluated. These congeners (namely 21, 22, and 24) also displayed good potency in the CRE-luciferase assay.

MeSH terms

  • Alkylation
  • Animals
  • CHO Cells
  • Cell Line
  • Cricetinae
  • Cyclic AMP / biosynthesis
  • Female
  • Follicle Stimulating Hormone / metabolism
  • Follicle Stimulating Hormone / pharmacology*
  • Humans
  • Luciferases / genetics
  • Luciferases / metabolism
  • Ovary / drug effects*
  • Ovary / metabolism
  • Receptors, FSH / agonists*
  • Receptors, FSH / metabolism
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Structure-Activity Relationship
  • Thiazolidinediones / chemical synthesis
  • Thiazolidinediones / pharmacology*

Substances

  • Receptors, FSH
  • Recombinant Proteins
  • Thiazolidinediones
  • Follicle Stimulating Hormone
  • Cyclic AMP
  • Luciferases