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.

Effect of indomethacin on the injection-abortion interval of 15(S) 15 methyl PGF2 alpha-induced mid-trimester abortions--a randomized study.

There have been conflicting reports on the effect of non-steroidal anti-inflammatory drugs on the abortifacient effect of prostaglandins. The efficacy of intra-amniotic 1.5 mg 15(S) 15 methyl PGF2 alpha (15 me PGF2 alpha) in terminating mid-trimester pregnancy in 10 subjects has been compared with the effect of the same medication given to 10 others who had had indomethacin 25 mg and 50 mg orally three and one hour before the PG administration. In the subjects who had the PG analogue only the injection-abortion interval was 17.0 hours. This was significantly shorter (P less than 0.01) than in those who had also received indomethacin (25.4 hours).

[Abortive activity of mimosine and its prevention (author's transl)]. / Acción abortiva de la mimosina y su prevención.

18 out of 19 female mice treated orally with different levels of mimosine in the drinking water were fertile. Subcutaneous injection of mimosine (400 mg/kg) to 23 pregnant mice, in a single dose on days 5, 10, 15 or 17, resulted in death and resorption or expulsion of dead embryos, except in one, early inoculated. L-Phenylalanine (600 mg/kg) injected subcutaneously on day 17 prevented abortion in 4 out of 5 mice subsequently injected with mimosine.