Nonsteroidal progestins and antiprogestins related to flutamide.
From the dual progestin/antiandrogenic properties of certain synthetic steroids (e.g. cyproterone acetate), it was apparent that the progesterone (P) and androgen (A) receptors must have some common ligand binding features. The nonsteroidal antiandrogen (aA) hydroxyflutamide was therefore considered a possible starting point for medicinal chemistry aimed at antiprogestin (aP) activity. Various modifications to the side chain and aryl ring substituents of flutamide yielded both P and aP activity, but always coupled with varying degrees of A or aA activity. Mineralocorticoid activity was present in some structures, but glucocorticoid and antiglucorticoid activities were not detected. Species (rat, rabbit and monkey) and chiral differences presented formidable difficulties in developing simple structure activity patterns, and low ( < 1%) in vitro uterine receptor binding belied in vivo potency of some aPs. One of the most active aPs, ZM172406, the R enantiomer of ZM150271, N-(3-chloro-4-cyanophenyl)-3,3, 3-trifluoro-2-hydroxy-2-methylpropanamide, had comparable oral potency to mifepristone in rats and monkeys. The racemate ZM150271 was an effective abortifacient during early pregnancy in pigtailed monkeys (3 x 10 mg/kg) but less effective in cynomolgus monkeys. One of the most active progestins (Pn), ZM182345, N-(4-nitro-3-trifluoromethylphenyl)-4-phenyl-2-hydroxy-2-trifluoromet hyl-pentanamide, was at least as potent as P in rats and rabbits but also possessed A activity.
Dukes
M
M
AstraZeneca, Alderley Park, Macclesfield, SK10 4TG, Cheshire, UK. Mike.Dukes@astrazeneca.com
Furr
B J
BJ
Hughes
L R
LR
Tucker
H
H
Woodburn
J R
JR
D000020:Abortifacient Agents, Nonsteroidal / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000028:Abortion, Induced; D000726:Androgen Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004717:Endometrium / Q000187:drug effects; D005260:Female; D005485:Flutamide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000882:Haplorhini; D008297:Male; D008600:Menstruation-Inducing Agents / Q000008:administration & dosage / Q000494:pharmacology; D011247:Pregnancy; D011372:Progestins / Q000037:antagonists & inhibitors / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D011980:Receptors, Progesterone / Q000187:drug effects / Q000378:metabolism; D045165:Testosterone Congeners / Q000494:pharmacology
D000020:Abortifacient Agents, Nonsteroidal; D000726:Androgen Antagonists; D008600:Menstruation-Inducing Agents; D011372:Progestins; D011980:Receptors, Progesterone; D045165:Testosterone Congeners; D005485:Flutamide