title: SAR studies of 6-(arylamino)-4,4-disubstituted-1-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-ones as progesterone receptor antagonists.
abstract: We previously disclosed that 6-aryl benzoxazin-2-ones were PR modulators. In a continuation of this work we examined the SAR of new 6-arylamino benzoxazinones and found the targets 1-25, with an extra amino linker between the pendent 6-aryl groups and benzoxazinone or benzoxazine-2-thione core, were PR antagonists. A series of compounds with substituents at the 1- and 4-positions as well as different 6-aryl groups were prepared and tested in the T47D cell alkaline phosphatase assay. Interestingly, the SAR unveiled from the 6-arylamino benzoxazinones was quite different from those of their parent compounds. For example, in contrast to the 6-aryl benzoxazinones, methyl substitution at the 1-position significantly increased the potency of 6-arylamino benzoxazinones. Several 6-arylamino benzoxazinones (e.g., 12, IC(50)=5.0 nM) had low nanomolar in vitro potency as PR antagonists in the T47D cell alkaline phosphatase assay.
authors.affiliation: Chemical and Screening Sciences, Wyeth Research, 500 Arcola Road, Collegeville, PA 19426, USA.
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Kern
authors.forename: Eugene A
authors.initials: EA
authors.lastname: Terefenko
authors.forename: Andrew
authors.initials: A
authors.lastname: Fensome
authors.forename: Ray
authors.initials: R
authors.lastname: Unwallla
authors.forename: Jay
authors.initials: J
authors.lastname: Wrobel
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: Zhiming
authors.initials: Z
authors.lastname: Zhang
authors.forename: Puwen
authors.initials: P
authors.lastname: Zhang
mesh_terms: D048588:Benzoxazines / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003271:Contraceptive Agents, Female / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D011980:Receptors, Progesterone / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D048588:Benzoxazines; D003271:Contraceptive Agents, Female; D011980:Receptors, Progesterone