Discovery, Chemistry, and Reproductive Pharmacology of Asoprisnil and Related 11β-Benzaldoxime Substituted Selective Progesterone Receptor Modulators (SPRMs)

Abstract

Asoprisnil (J 867; benzaldehyde, 4-[(11beta, 17beta)-17-methoxy-17-(methoxymethyl)-3-oxoestra-4, 9-dien-11beta-yl]-, 1-oxime) is the prototype of a novel class 11beta-benzaldoxime-substituted selective progesterone receptor modulators (SPRMs) and the first-in-class SPRM to reach an advanced stage of clinical development for the treatment of uterine fibroids and endometriosis. This compound was selected in a drug discovery program aimed to identify progesterone receptor (PR) ligands with predominant agonist but also some antagonist activities. The screening program included a range of receptor binding studies and a hierarchy of in vivo tests. A series of 11beta-benzaldoxime-substituted steroidal compounds exhibiting mixed PR agonist/antagonist effects were synthesized and characterized. For inclusion in this class of compounds, two methods of synthesis were developed and optimized. The 11beta-benzaldoxime-substituted SPRMs showed high PR binding affinities, reduced glucocorticoid receptor affinities compared with the antiprogestin mifepristone, marginal androgen receptor binding affinities, and no binding to estrogen receptors. Animal tests in guinea pigs (luteolysis inhibition assay) and rabbits (McPhail test) constituted the secondary screening tests. A mosaic of progesterone agonist and antagonist effects were found in various models. The most agonistic compounds were selected for further evaluation in animal models with respect to labor induction and endometrial effects. Unlike progesterone antagonists, asoprisnil and related compounds showed marginal effects on labor and parturition in guinea pigs. Proof-of-concept studies in nonhuman primates revealed endometrial antiproliferative effects of selected compounds, including asoprisnil and J 1042, in the presence of amenorrhea and follicular phase estradiol concentrations. Asoprisnil was selected for further clinical development. It shows promising results in the treatment of uterine leiomyomata and endometriosis.

The spectrum of endometrial pathology induced by progesterone receptor modulators

“…The pharmacological effects of PRMs are, however, not purely antagonistic, nor is their effect restricted to the progesterone receptor itself. Some PRMs exert anti-estrogenic effects, either through partial progesterone receptor agonist activity, 6,7 or, exert these effects independently of the progesterone receptor itself, that is by upregulation of the androgen receptor response. 8,9 These PRM effects are evident as dose-dependent suppression of estrogen-induced mitotic activity, [10][11][12] and appearance of glandular secretory changes.…”

A Novel Selective Progesterone Receptor Modulator Asoprisnil (J867) Inhibits Proliferation and Induces Apoptosis in Cultured Human Uterine Leiomyoma Cells in the Absence of Comparable Effects on Myometrial Cells

“…It has high PR specificity with no antiglucocorticoid and marginal androgenic effects in humans (15). Asoprisnil shows a high degree of selectivity in the endometrium of animals and humans (15)(16)(17). In premenopausal women, asoprisnil is reported to suppress menstruation and induce mixed P4 agonist/antagonist effects on the glandular epithelium, stroma, and clusters of thick-walled arterial vessels in the endometrium without showing the endometrial hyperplasia indicative of unopposed estrogen effects (18).…”

“…SPRMs are PR ligands that exert clinically relevant, tissue-selective P4 agonist, antagonist, partial, or mixed agonist/antagonist effects on various P4 target tissues in an in vivo situation depending on the biological action studied (15). Asoprisnil shows mixed P4 agonist/ antagonist and tissue-selective effects in various animal models (16,17). It has high PR specificity with no antiglucocorticoid and marginal androgenic effects in humans (15).…”

Treatment of symptomatic uterine leiomyomas with selective progesterone receptor modulators

“…One of the first was asoprisnil. Asoprisnil is a new SPRM with progesterone receptor agonist/antagonist properties, a lower level of gluco corticoid Editorial and estrogen receptor affinity as compared with mifepristone, and a marginal androgen receptor affinity [17,18]. Phase I studies with asoprisnil showed reversible suppression of menstruation and variable effects on ovulation.…”