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Semin Reprod Med 2005; 23(1): 58-73
DOI: 10.1055/s-2005-864034
Copyright © 2005 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

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

Gerd Schubert1 , Walter Elger2 , Günter Kaufmann1 , Birgitt Schneider2 , Gudrun Reddersen2 , Kristof Chwalisz3
  • 1Jenapharm GmbH & Co. KG, Jena, Germany
  • 2EnTec GmbH, Hamburg and Jena, Germany
  • 3TAP Pharmaceutical Products Inc., Lake Forest, Ilinois
Further Information

Publication History

Publication Date:
15 February 2005 (online)

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ABSTRACT

Asoprisnil (J 867; benzaldehyde, 4-[(11β, 17β)-17-methoxy-17-(methoxymethyl)-3-oxoestra-4, 9-dien-11β-yl]-, 1-oxime) is the prototype of a novel class 11β-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 11β-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 11β-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.

KEYWORDS

Selective progesterone receptor modulators - asoprisril - progesterone receptor - leiomyoma - endometriosis

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Kristof ChwaliszM.D. Ph.D. 

TAP Pharmaceutical Products Inc.

675 N. Field Drive, Lake Forest, IL 60045

Email: Kristof.Chwalisz@TAP.com