Nonsteroidal progestins and antiprogestins related to flutamide

From the dual progestin/antiandrogenic properties of certain synthetic ster oids (e.g. cyproterone acetate), it was apparent that the progesterone (P) and androgen (A) receptors must have some common ligand binding features. T he 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 substit uents 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 wer e not detected. Species (rat, rabbit and monkey) and chiral differences pre sented formidable difficulties in developing simple structure activity patt erns, and low ( < 1%) in vitro uterine receptor binding belied in vivo pote ncy 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-methylprop anamide, had comparable oral potency to mifepristone in rats and monkeys. T he racemate ZM150271 was an effective abortifacient during early pregnancy in pigtailed monkeys (3 x 10 mg/kg) but less effective in cynomolgus monkey s. One of the most active progestins (Pn), ZM182345, N-(4-nitro-3-trifluoro methylphenyl)-4-phenyl-2-hydroxy-2-trifluoromethyl-pentanamide, was at leas t as potent as P in rats and rabbits but also possessed A activity. (C) 200 0 Published by Elsevier Science Inc.