Novel pyrrole-containing progesterone receptor modulators.
A series of 1,4-dihydro-2H-[d][3,1]-benzoxazin-2-one and 1,3-dihydro-[3H]-indol-2-one containing 6- or 5-, respectively, appended substituted pyrrole moieties were synthesized and evaluated for their ability to modulate the activity of the progesterone receptor (PR). Key structural changes to the pyrrole moieties of these molecules were shown to have a predictive influence as to whether the compounds behaved as PR agonists or antagonists. Compounds with the 5(')-cyano-2(')-pyrrole moiety (e.g., 32, 33, and 38) were shown to be potent PR agonists (EC(50)'s of 1.1, 1.8, and 2.8 nM, respectively). Compounds with the 5(')-nitro-2(')-pyrrole moiety (e.g., 34 and 36) were shown to be PR antagonists (IC(50)'s of 180 and 36 nM, respectively).
Collins
Mark A
MA
Chemical and Screening Sciences, Wyeth Research, 500 Arcola Road, Collegeville, PA 19426, USA.
Hudak
Valerie
V
Bender
Reinhold
R
Fensome
Andrew
A
Zhang
Puwen
P
Miller
Lori
L
Winneker
Richard C
RC
Zhang
Zhiming
Z
Zhu
Yuan
Y
Cohen
Jeffrey
J
Unwalla
Rayomond J
RJ
Wrobel
Jay
J
D048588:Benzoxazines / Q000737:chemistry / Q000494:pharmacology*; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D011758:Pyrroles / Q000737:chemistry*; D011980:Receptors, Progesterone / Q000187:drug effects*
D048588:Benzoxazines; D007211:Indoles; D011758:Pyrroles; D011980:Receptors, Progesterone