Rewinkel Jos, Enthoven Mark, Golstein Irene, van der Rijst Marcel, Scholten André, van Tilborg Martin, de Weys Dirk, Wisse Jeffry, Hamersma Hans
Department of Medicinal Chemistry, NV Organon, PO Box 20, 5340 BH Oss, The Netherlands.
Bioorg Med Chem. 2008 Mar 15;16(6):2753-63. doi: 10.1016/j.bmc.2008.01.010. Epub 2008 Jan 11.
Recently, a new class (often referred to as SPRMs: selective progesterone receptor modulators) of progesterone receptor ligands with mixed agonist/antagonist properties has been described. Such compounds are envisaged, for example, as treatment for endometriosis, uterine fibroids, and leiomyomas. Existing SPRMs include Asoprisnil 1 and Uliprisnil acetate 2. In our hands, however, these compounds proved to have a predominantly or exclusively antagonistic in vitro profile, which may make this type of compound less attractive, for example, as contraceptives. We therefore aimed at a class of mixed-profile compounds that would show a more evenly balanced agonist/antagonist profile. A novel class of 11beta-[4-(heteroaryl)phenyl]-substituted pregnanes was identified that displayed the desired balance. Contrary to known SPRMs, this novel class of MPP (mixed-profile progestagen) was found to have a truly mixed activity, including a sizeable agonist component.
最近，已经描述了一类新的具有混合激动剂/拮抗剂特性的孕酮受体配体（通常称为SPRMs：选择性孕酮受体调节剂）。例如，这类化合物被设想用于治疗子宫内膜异位症、子宫肌瘤和平滑肌瘤。现有的SPRMs包括阿索普瑞尼尔1和醋酸乌利司他2。然而，在我们的研究中，这些化合物在体外表现出主要或完全的拮抗作用，这可能使这类化合物作为避孕药等的吸引力降低。因此，我们致力于寻找一类混合特性的化合物，其激动剂/拮抗剂特性能更均匀地平衡。我们鉴定出了一类新型的11β-[4-(杂芳基)phenyl]-取代孕烷，其表现出了所需的平衡。与已知的SPRMs不同，这类新型的MPP（混合特性孕激素）具有真正的混合活性，包括相当大的激动剂成分。
