5-(3-Cyclopentyl-2-thioxo-2,3-dihydro-1H-benzimidazol-5-yl)-1-methyl-1H-pyrrole-2-carbonitrile: A novel, highly potent, selective, and orally active non-steroidal progesterone receptor agonist.

We have recently discovered 5-(3-cyclopentyl-2-thioxo-2,3-dihydro-1H-benzimidazol-5-yl)-1-methyl-1H-pyrrole-2-carbonitrile (14) as a potent, selective, and orally active non-steroidal progesterone receptor (PR) agonist. Compound 14 and its analog 13 possessed sub-nanomolar in vitro potency (EC(50) 0.1-0.5nM) in the T47D alkaline phosphatase assay, similar to that of the steroidal PR agonist medroxyprogesterone acetate (MPA). In contrast to MPA, 14 was highly selective (>500-fold) for the PR over both glucocorticoid and androgen receptors. In the rat uterine decidualization and complement component C3 models, 14 had oral ED(50) values of 0.02 and 0.003mg/kg, respectively, and was from 6- to 20-fold more potent than MPA. In the monkey ovulation inhibition model, compound 14 was also highly efficacious and potent with an oral ED(100) of 0.03mg/kg.