Synthesis and SAR study of novel pseudo-steroids as potent and selective progesterone receptor antagonists.
Synthesis of novel 7-pseudo-steroids 1c has been achieved from trenbolone 3 via an efficient 14 step sequence with overall yields of 10-15%. Various substitutions were incorporated at both the aromatic side chain as well as the D ring. The orientation of aromatic side chain at C10 plays a crucial role for progesterone receptor (PR) activity. Compound 2a (T47D=1nM) with -NMe(2) para to the aromatic group along with spirofurane groups in the D ring was the optimal substitution. All compounds were also evaluated for glucocorticoid receptor (GR) antagonist activities in vivo in a rat and found efficacious in uterine complement C3 assay via the oral route of administrations.
Jain
Nareshkumar
N
Johnson and Johnson Pharmaceutical Research and Development, Medicinal Chemistry, LLC, Exton, PA 19341, USA. drnfjain@gmail.com
Allan
George
G
Linton
Olivia
O
Tannenbaum
Pamela
P
Chen
Xin
X
Xu
Jun
J
Zhu
Peifang
P
Gunnet
Joseph
J
Demarest
Keith
K
Lundeen
Scott
S
Murray
William
W
Sui
Zhihua
Z
D000284:Administration, Oral; D000818:Animals; D001584:Benzoxepins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D005260:Female; D051381:Rats; D017207:Rats, Sprague-Dawley; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors / Q000378:metabolism; D011980:Receptors, Progesterone / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014204:Trenbolone Acetate / Q000737:chemistry
D001584:Benzoxepins; D011965:Receptors, Glucocorticoid; D011980:Receptors, Progesterone; D014204:Trenbolone Acetate