title: Synthesis and SAR study of novel pseudo-steroids as potent and selective progesterone receptor antagonists.
abstract: 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.
authors.affiliation: Johnson and Johnson Pharmaceutical Research and Development, Medicinal Chemistry, LLC, Exton, PA 19341, USA. drnfjain@gmail.com
authors.forename: Nareshkumar
authors.initials: N
authors.lastname: Jain
authors.forename: George
authors.initials: G
authors.lastname: Allan
authors.forename: Olivia
authors.initials: O
authors.lastname: Linton
authors.forename: Pamela
authors.initials: P
authors.lastname: Tannenbaum
authors.forename: Xin
authors.initials: X
authors.lastname: Chen
authors.forename: Jun
authors.initials: J
authors.lastname: Xu
authors.forename: Peifang
authors.initials: P
authors.lastname: Zhu
authors.forename: Joseph
authors.initials: J
authors.lastname: Gunnet
authors.forename: Keith
authors.initials: K
authors.lastname: Demarest
authors.forename: Scott
authors.initials: S
authors.lastname: Lundeen
authors.forename: William
authors.initials: W
authors.lastname: Murray
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Sui
mesh_terms: 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
chemical_list: D001584:Benzoxepins; D011965:Receptors, Glucocorticoid; D011980:Receptors, Progesterone; D014204:Trenbolone Acetate