Abstract

We have isolated PF1092A, B, and C, novel nonsteroidal progesterone ligands with preferential affinity for the progesterone receptor, from fermentation broth of a fungus [Tabata Y, Miike N, Hatsu M, Kurata Y, Yaguchi T, Someya A, Miyadoh S, Hoshiko S, Tsuruoka T, and Omoto S (1997) J Antibiot50:304–308; Tabata Y, Hatsu M, Kurata Y, Miyajima K, Tani M, Sasaki T, Kodama Y, Tsuruoka T, and Omoto S (1997) J Antibiot50:309–313]. The original skeleton of PF1092, tetrahydronaphthofuranone, was modified synthetically to produce a new skeleton, tetrahydrobenzindrone, and in the present study, biological activities of two derivatives, CP8816 [(4aR,5R,6R,7R)-6-(N,N-dimethylaminocarbonyl)oxy-7-methoxy-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one] and CP8863 [(4aR,5R,6R,7R)-7-hydroxy-6-(N-methylcarbamoyl)oxy-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one], were investigated. Both CP8816 and CP8863 demonstrated selective binding to progesterone receptor and partial agonistic activity in a progesterone-dependent endogenous alkaline phosphatase expression assay. In the Clauberg-McPhail test, progestational activity of CP8816 (0.1 mg/kg s.c. or 10 mg/kg p.o.) was comparable to that of progesterone (0.15 mg/kg s.c.), and oral administration of CP8863 at more than 1.0 mg/kg also exerted similar effects. Anti-estrogenic (antiuterotropic) activity was confirmed on daily oral application of more than 0.1 mg/kg CP8863 for 3 days by inhibition of estrogen-dependent uterine wet weight gain in ovariectomized rats. CP8816 also exerted antiuterotropic activity at doses of 10 mg/kg (s.c.) and 100 mg/kg (p.o.). These results indicate that our nonsteroidal progesterone ligands have affinity for the progesterone receptor with partial progestational activity in vitro and clear progestational effects in vivo. Thus, these progesterone receptor modulator profiles suggest that CP8863 and CP8816 are good candidate compounds for treatment of hormone-dependent gynecological disorders.