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...

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Published in:Bioorganic & medicinal chemistry 2007-10, Vol.15 (20), p.6556-6564
Main Authors: PUWEN ZHANG, TEREFENKO, Eugene, LACAVA, Margaret, WINNEKER, Richard C, ZHIMING ZHANG, KERN, Jeffrey, FENSOME, Andrew, TRYBULSKI, Eugene, UNWALLA, Ray, WROBEL, Jay, LOCKHEAD, Susan, YUAN ZHU, COHEN, Jeffrey
Format: Article
Language:English
Subjects:
Administration, Oral
Alkaline Phosphatase - metabolism
Animals
Biological and medical sciences
Cell Line, Tumor
Female
Hormones. Endocrine system
Medical sciences
Models, Molecular
Molecular Structure
Nitriles - chemistry
Nitriles - pharmacology
Pharmacology. Drug treatments
Pyrroles - chemistry
Pyrroles - pharmacology
Rats
Rats, Sprague-Dawley
Receptors, Progesterone - agonists
Receptors, Progesterone - metabolism
Steroids - chemistry
Steroids - pharmacology
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Summary: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.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2007.07.011