Insight from molecular modeling into different conformation and SAR of natural steroids and unnatural 7-oxa-steroids.
Replacement of the 7-CH2 group of natural steroid with an oxygen atom led to identification of unnatural 7-oxa-steroids as potent and selective progesterone receptor antagonists. The unnatural 7-oxa-steroids exhibited a different structure-activity relationship (SAR) from natural steroids. Molecular modeling demonstrated that the switch of carbon to oxygen in the B-ring results in a subtle conformational change of the tetracyclic skeleton and induces a remarkable spatial shift at the terminal end of the side chain of the D-ring. This shift causes the phenyl ring on the D-ring to form a perfect parallel-displaced form of pi-pi interaction with the phenyl ring of Phe794. The unnatural 7-oxa-steroids were orally active in a rat complement C3 assay and showed comparable pharmacokinetic and metabolic profiles to those of the natural steroid, mifepristone.
Kang
Fu-An
FA
Johnson & Johnson Pharmaceutical Research and Development, LLC, 665 Stockton Drive, Exton, PA 19341, USA. fkang@prdus.jnj.com
Chen
Xin
X
Jain
Nareshkumar
N
Allan
George
G
Tannenbaum
Pamela
P
Lundeen
Scott
S
Sui
Zhihua
Z
D000818:Animals; D002244:Carbon / Q000737:chemistry; D003176:Complement C3 / Q000737:chemistry; D003198:Computer Simulation; D020128:Inhibitory Concentration 50; D015735:Mifepristone / Q000737:chemistry; D008956:Models, Chemical; D008958:Models, Molecular; D008968:Molecular Conformation; D010100:Oxygen / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D011980:Receptors, Progesterone / Q000037:antagonists & inhibitors; D013256:Steroids / Q000737:chemistry*; D013329:Structure-Activity Relationship
D003176:Complement C3; D011980:Receptors, Progesterone; D013256:Steroids; D015735:Mifepristone; D002244:Carbon; D010100:Oxygen