title: Potent nonsteroidal progesterone receptor agonists: synthesis and SAR study of 6-aryl benzoxazines.
abstract: 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).
authors.affiliation: Medicinal Chemistry I, Chemical Sciences, Wyeth Research, 500 Arcola Road, Collegeville, PA 19426, USA. zhangp@war.wyeth.com
authors.forename: Puwen
authors.initials: P
authors.lastname: Zhang
authors.forename: Eugene A
authors.initials: EA
authors.lastname: Terefenko
authors.forename: Andrew
authors.initials: A
authors.lastname: Fensome
authors.forename: Zhiming
authors.initials: Z
authors.lastname: Zhang
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhu
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Cohen
authors.forename: Richard
authors.initials: R
authors.lastname: Winneker
authors.forename: Jay
authors.initials: J
authors.lastname: Wrobel
authors.forename: John
authors.initials: J
authors.lastname: Yardley
mesh_terms: 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
chemical_list: D010078:Oxazines; D011980:Receptors, Progesterone