Fungal metabolites, PF1092 compounds and their derivatives, are nonsteroidal and selective progesterone receptor...

The potential of new nonsteroidal progesterone receptor ligands, the derivatives of PF1092C ((4aR,5R,6R,7S)-6,7-dihydroxy-4a,5,6,7-tetrahydro-3,4a,5-trimethylnaphtho[2,3-b]furan-2(4H)-one) discovered from fungal metabolites, was evaluated. PF1092A ((4aR,5R,6R,7S)-6-acetoxy-7-hydroxy-4a,5,6,7-tetrahydro-3,4a,5-trimethylnaphtho[2,3-b]furan-2(4H)-one) showed good and moderate affinity for porcine and human progesterone receptors in in vitro receptor binding assays, respectively, and partial agonist activity for the progesterone receptor, as determined in assays of two types of progesterone-dependent enzymes in human mammary carcinoma T47D cells. The derivative of PF1092C, CP8481, ((4aR,5R,6R,7S)-6-(2-furancarbonyloxy)-7-hydroxy-4a,5,6,7-tetrahydro-3,4a,5-trimethylnaphtho[2,3-b]furan-2(4H)-one) possessed better affinity for both progesterone receptors and showed less cross-reactivity for other steroid receptors, such as rat androgen receptor, human glucocorticoid receptor, and human estrogen receptor, and was a more potent modulator of the progesterone receptor than PF1092A. CP8400 ((4aR,5R,6R,7S)-6,7-diacetoxy-4a,5,6,7-tetrahydro-3,4a,5-trimethylnaphtho[2,3-b]furan-2(4H)-one) and CP8401 ((4aR,5R,6R,7S)-6,7-dipropionyloxy-4a,5,6,7-tetrahydro-3,4a,5-trimethylnaphtho[2,3-b]furan-2(4H)-one), other derivatives, were indicated to be progesterone receptor antagonists. These results suggest that PF1092 compounds can serve as a new pharmacophore for potent and specific nonsteroidal progesterone receptor modulators.