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.
Zhang
Puwen
P
Chemical and Screening Sciences, Wyeth Research, S-2250B, 500 Arcola Road, Collegeville, PA 19426, USA.
Terefenko
Eugene
E
Kern
Jeffrey
J
Fensome
Andrew
A
Trybulski
Eugene
E
Unwalla
Ray
R
Wrobel
Jay
J
Lockhead
Susan
S
Zhu
Yuan
Y
Cohen
Jeffrey
J
Lacava
Margaret
M
Winneker
Richard C
RC
Zhang
Zhiming
Z
D000284:Administration, Oral; D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D008958:Models, Molecular; D015394:Molecular Structure; D009570:Nitriles / Q000737:chemistry / Q000494:pharmacology*; D011758:Pyrroles / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011980:Receptors, Progesterone / Q000819:agonists* / Q000378:metabolism*; D013256:Steroids / Q000737:chemistry / Q000494:pharmacology
C524570:5-(3-cyclopentyl-2-thioxo-2,3-dihydro-1H-benzimidazol-5-yl)-1-methyl-1H-pyrrole-2-carbonitrile; D009570:Nitriles; D011758:Pyrroles; D011980:Receptors, Progesterone; D013256:Steroids; D000469:Alkaline Phosphatase