SAR studies of 6-(arylamino)-4,4-disubstituted-1-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-ones as progesterone receptor antagonists.
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.
Kern
Jeffrey C
JC
Chemical and Screening Sciences, Wyeth Research, 500 Arcola Road, Collegeville, PA 19426, USA.
Terefenko
Eugene A
EA
Fensome
Andrew
A
Unwallla
Ray
R
Wrobel
Jay
J
Zhu
Yuan
Y
Cohen
Jeffrey
J
Winneker
Richard
R
Zhang
Zhiming
Z
Zhang
Puwen
P
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
D048588:Benzoxazines; D003271:Contraceptive Agents, Female; D011980:Receptors, Progesterone