Antiandrogenic steroidal sulfonyl heterocycles. Utility of electrostatic complementarity in defining bioisosteric sulfonyl heterocycles.
Complementarity of electrostatic potential surface maps was utilized in defining bioisosteric steroidal androgen receptor antagonists. Semiempirical and ab initio level calculations performed on a series of methanesulfonyl heterocycles indicated the requirement for a partial negative charge at the heteroatom attached to C-3 of the steroid nucleus to attain androgen receptor affinity. Synthesis and testing of six heterocycle A-ring-fused dihydroethisterone derivatives support this hypothesis, and we have identified two new androgen receptor antagonists of this class.
Mallamo
J P
JP
Department of Medicinal Chemistry, Sterling Winthrop Pharmaceuticals Research Division, Rensselaer, New York 12144.
Pilling
G M
GM
Wetzel
J R
JR
Kowalczyk
P J
PJ
Bell
M R
MR
Kullnig
R K
RK
Batzold
F H
FH
Juniewicz
P E
PE
Winneker
R C
RC
Luss
H R
HR
D000726:Androgen Antagonists / Q000737:chemistry* / Q000145:classification; D059002:Androgen Receptor Antagonists; D004563:Electrochemistry; D006571:Heterocyclic Compounds / Q000737:chemistry*; D011944:Receptors, Androgen / Q000378:metabolism; D013379:Substrate Specificity; D014961:X-Ray Diffraction
D000726:Androgen Antagonists; D059002:Androgen Receptor Antagonists; D006571:Heterocyclic Compounds; D011944:Receptors, Androgen