Potent nonsteroidal progesterone receptor agonists: synthesis and SAR study of 6-aryl benzoxazines.
Novel 6-aryl benzoxazines were prepared and examined as progesterone receptor (PR) modulators. In contrast to the structurally related 6-aryl dihydroquinoline PR antagonists, the 6-aryl benzoxazines were potent PR agonists. Compounds 4e, 5b, and 6a with the 2,4,4-trimethyl-1,4-dihydro-2H-benzo[d][1,3]oxazine core were the most potent PR agonists in the series with sub-nanomolar activities (EC(50) 0.20-0.35nM). Compound 6a was more potent than progesterone (P4) in the in vivo decidualization assay in an ovariectomized female rat model by subcutaneous administration with an ED(50) of 1.5mg/kg (vs 5.62mg/kg for P4).
Zhang
Puwen
P
Medicinal Chemistry I, Chemical Sciences, Wyeth Research, 500 Arcola Road, Collegeville, PA 19426, USA. zhangp@war.wyeth.com
Terefenko
Eugene A
EA
Fensome
Andrew
A
Zhang
Zhiming
Z
Zhu
Yuan
Y
Cohen
Jeffrey
J
Winneker
Richard
R
Wrobel
Jay
J
Yardley
John
J
D000818:Animals; D005260:Female; D007279:Injections, Subcutaneous; D023421:Models, Animal; D015394:Molecular Structure; D010052:Ovariectomy; D010078:Oxazines / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology*; D051381:Rats; D011980:Receptors, Progesterone / Q000819:agonists*; D013329:Structure-Activity Relationship
D010078:Oxazines; D011980:Receptors, Progesterone