Nonsteroidal progesterone receptor ligands (II); synthesis and SAR of new tetrahydrobenzindolone derivatives.

The human progesterone receptor (PR) binding affinity and the PR agonistic or antagonistic potency of tetrahydronaphthofuranone derivatives were shown previously to be markedly influenced by substituents at the 6- and 7-positions. Here, we synthesized tetrahydrobenzindolones possessing a lactam ring, which enabled us to modify the 6- and 7-positions more freely, since tetrahydrobenzindolones are chemically more stable than tetrahydronaphthofuranones. The tetrahydrobenzindolone derivatives generally showed higher PR binding affinity than the corresponding tetrahydronaphthofuranones. We also succeeded in separating the agonistic and antagonistic activities by choosing suitable substituent groups at the 6- and/or 7-position(s) of the tetrahydrobenzindolone. The effects of representative agonists, 12c (CP8668), and 14a (CP8816), and a representative antagonist, 15f (CP8661), were confirmed in in vivo tests. In this report, we mainly describe the synthesis and structure-activity relationships (SAR) of tetrahydrobenzindolone derivatives, as new nonsteroidal PR ligands.

Nonsteroidal progesterone receptor ligands (I): synthesis and SAR of new tetrahydronaphthofuranone derivatives.

We have synthesized a series of nonsteroidal progesterone receptor (PR) ligands, tetrahydronaphthofuranones, structurally based on the fungal metabolite PF1092C. Structure-activity relationship studies revealed that substituents at the 6- and 7-positions were critical for PR binding affinity and for agonist or antagonist activity. Compounds in this series, exemplified by 19i, exhibited high affinity and high specificity for PR over other steroid hormone receptors and acted as selective PR antagonists. Further modification of PF1092C may generate compounds of potential pharmacological interest.

Endocrinological properties of two novel nonsteroidal progesterone receptor modulators, CP8816 and CP8863.

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 Antibiot 50:304-308; Tabata Y, Hatsu M, Kurata Y, Miyajima K, Tani M, Sasaki T, Kodama Y, Tsuruoka T, and Omoto S (1997) J Antibiot 50:309-313]. 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.

CP8668, a novel orally active nonsteroidal progesterone receptor modulator with tetrahydrobenzindolone skeleton.

We investigated progestational activity of a new nonsteroidal compound, CP8668, ((4aR,5R,6R,7R)-7-methoxy-6-(N-propylaminocarbonyl)oxy-4a,5,6,7-tetrahydro-1,3,4a,5-tetramethylbenz[f]indol-2(4H)-one). CP8668 showed selective affinity for human progesterone receptor equal in strength to other steroidal progestins. CP8668 showed no significant affinity for human glucocorticoid receptor or human estrogen receptor and very weak affinity for rat androgen receptor. In endogenous and exogenous progesterone-dependent enzyme expression assays using human mammary carcinoma T47D, CP8668 showed mixed agonist-antagonist activity. However, in a rabbit endometrial transformation test, CP8668 showed good progestational activity following s.c. and p.o. administration. These results suggest that CP8668 is a selective and orally active progesterone receptor modulator, which shows mixed agonist-antagonist activity in in vitro transcription tests and agonist activity in endometrial transformation assays in rabbits, and that it is potentially a promising lead compound for a new type of orally active progesterone receptor modulator.

In vitro and in vivo characterization of novel nonsteroidal progesterone receptor antagonists derived from the fungal metabolite PF1092C.

We studied the pharmacological effects of novel nonsteroidal progesterone receptor antagonists CP8661 and CP8754, which were synthesized from the fungal metabolite PF1092C. CP8661 possess a tetrahydrobenzindolone skeleton and CP8754 possess a tetrahydronaphthofuranone skeleton. In binding assays for steroid receptors, CP8661 and CP8754 inhibited [(3)H]-progesterone binding to human progesterone receptors (hPR), though they are less potent than RU486. CP8661 also showed moderate affinity to rat androgen receptors (rAR), although CP8754 did not. Neither compound showed affinity to human glucocorticoid receptors (hGR) or human estrogen receptors (hER). In exogeneous and endogeneous PR-dependent enzyme expression assays using human mammary carcinoma T47D, CP8661 and CP8754 showed pure antagonistic activity. In a rabbit endometrial transformation test, CP8661 and CP8754 showed anti-progestational activity by s.c. administration in a dose-dependent manner; meanwhile, these compounds showed no progestational activity at the same dose. These results suggested that CP8661 and CP8754 are in vivo effective pure progesterone receptor antagonists and presented the possibility of synthesizing pure progesterone receptor antagonists from both tetrahydronaphthofuranone and tetrahydrobenzindolone skeletons.