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

 

 Buy Article Permissions and Reprints

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.

REFERENCES

• 1 Elger W, Bartley J, Schneider B, Kaufmann G, Schubert G, Chwalisz K. Endocrine pharmacological characterization of progesterone antagonists and progesterone receptor modulators with respect to PR-agonistic and antagonistic activity.  Steroids. 2000;  65 713-723
  CrossrefPubMedGoogle Scholar
• 2 DeManno D, Elger W, Garg R et al.. Asoprisnil (J867): a selective progesterone receptor modulator for gynecological therapy.  Steroids. 2003;  68 1019-1032
  CrossrefPubMedGoogle Scholar
• 3 Chwalisz K, DeManno D, Garg R, Larsen L, Mattia-Goldberg C, Stickler T. Therapeutic potential for the selective progesterone receptor modulator asoprisnil in the treatment of leiomyomata.  Semin Reprod Med. 2004;  22 113-119
  Article in Thieme ConnectPubMedGoogle Scholar
• 4 Chwalisz K, Garg R, Brenner R M, Schubert G, Elger W. Selective progesterone receptor modulators (SPRMs): a novel therapeutic concept in endometriosis.  Ann N Y Acad Sci. 2002;  955 373-406
  PubMedGoogle Scholar
• 5 Philibert D, Deraedt R, Teutsch G. RU 38486: a potent antiglucocorticoid in vivo. In: The VII International Congress of Pharmacology 1981 Tokyo, Japan;
  Google Scholar
• 6 Philibert D. RU38486: An original multifaceted antihormone in vivo. In: Agarwal M Adrenal Steroid Antagonism Berlin. Germany; Walter de Gruyter and Co. 1984: 77-101
  Google Scholar
• 7 Neef G, Beier S, Elger W, Henderson D, Wiechert R. New steroids with antiprogestational and antiglucocorticoid activities.  Steroids. 1984;  44 349-372
  CrossrefPubMedGoogle Scholar
• 8 Elger W, Beier S, Chwalisz K et al.. Studies on the mechanisms of action of progesterone antagonists.  J Steroid Biochem. 1986;  25 835-845
  CrossrefPubMedGoogle Scholar
• 9 Elger W, Fahnrich M, Beier S, Qing S S, Chwalisz K. Endometrial and myometrial effects of progesterone antagonists in pregnant guinea pigs.  Am J Obstet Gynecol. 1987;  157 1065-1074
  PubMedGoogle Scholar
• 10 Cook C E, Lee Y W, Wani M C, Fail P A, Petrow V. Effects of D-ring substituents on antiprogestational (antagonist) and progestational (agonist) activity of 11 beta-aryl steroids.  Hum Reprod. 1994;  9(suppl 1) 32-39
  PubMedGoogle Scholar
• 11 Kloosterboer H J, Deckers G H, van der Heuvel M J, Loozen H J. Screening of anti-progestagens by receptor studies and bioassays.  J Steroid Biochem. 1988;  31 567-571
  CrossrefPubMedGoogle Scholar
• 12 Kloosterboer L J, Deckers G H, Schoonen W GEJM et al.. Preclinical experience with two selective antiprogestins on breast and endometrium.  Steroids. 2000;  65 733-740
  CrossrefPubMedGoogle Scholar
• 13 Fuhrmann U, Hess-Stumpp H, Cleve A et al.. Synthesis and biological activity of a novel, highly potent progesterone receptor antagonist.  J Med Chem. 2000;  43 5010-5016
  CrossrefPubMedGoogle Scholar
• 14 Chwalisz K. The use of progesterone antagonists for cervical ripening and as an adjunct to labour and delivery.  Hum Reprod. 1994;  9(suppl 1) 131-161
  CrossrefPubMedGoogle Scholar
• 15 Klein Hitpass L, Cato A C, Henderson D. Ryffel GU. Two types of antiprogestins identified by their differential action in transcriptionally active extracts from T47D cells.  Nucleic Acids Res. 1991;  19 1227-1234
  CrossrefPubMedGoogle Scholar
• 16 Gass E K, Leonhardt S A, Nordeen S K, Edwards D P. The antagonists RU486 and ZK98299 stimulate progesterone receptor binding to deoxyribonucleic acid in vitro and in vivo, but have distinct effects on receptor conformation.  Endocrinology. 1998;  139 1905-1919
  CrossrefPubMedGoogle Scholar
• 17 Delabre K, Guiochon-Mantel A, Milgrom E. In vivo evidence against the existence of antiprogestins disrupting receptor binding to DNA.  Proc Natl Acad Sci USA. 1993;  90 4421-4425
  PubMedGoogle Scholar
• 18 Sartorius C A, Tung L, Takimoto G S, Horwitz K B. Antagonist-occupied human progesterone receptors bound to DNA are functionally switched to transcriptional agonists by cAMP.  J Biol Chem. 1993;  268 9262-9266
  PubMedGoogle Scholar
• 19 Horwitz K B, Sartorius C A, Hovland A R et al.. Surprises with antiprogestins: novel mechanisms of progesterone receptor action.  Ciba Found Symp. 1995;  191 235-253
  PubMedGoogle Scholar
• 20 Beck C A, Estes P A, Bona B J, Muro-Cacho C A, Nordeen S K, Edwards D P. The steroid antagonist RU486 exerts different effects on the glucocorticoid and progesterone receptors.  Endocrinology. 1993;  133 728-740
  CrossrefPubMedGoogle Scholar
• 21 Wolf J P, Hsiu J G, Anderson T L, Ulmann A, Baulieu E E, Hodgen G D. Noncompetitive antiestrogenic effect of RU 486 in blocking the estrogen-stimulated luteinizing hormone surge and the proliferative action of estradiol on endometrium in castrate monkeys.  Fertil Steril. 1989;  52 1055-1060
  PubMedGoogle Scholar
• 22 Hodgen G D, van Uem J F, Chillik C F et al.. Non-competitive anti-oestrogenic activity of progesterone antagonists in primate models.  Hum Reprod. 1994;  9(suppl 1) 77-81
  PubMedGoogle Scholar
• 23 Chwalisz K, Hegele-Hartung C, Fritzemeier K H, Beier H M, Elger W. Inhibition of the estradiol-mediated endometrial gland formation by the antigestagen onapristone in rabbits: relationship to uterine estrogen receptors.  Endocrinology. 1991;  129 312-322
  PubMedGoogle Scholar
• 24 Brenner R M, Slayden O D. Oestrogen action in the endometrium and oviduct of rhesus monkeys during RU486 treatment.  Hum Reprod. 1994;  9(suppl 1) 82-97
  PubMedGoogle Scholar
• 25 Slayden O D, Hirst J J, Brenner R M. Estrogen action in the reproductive tract of rhesus monkeys during antiprogestin treatment.  Endocrinology. 1993;  132 1845-1856
  CrossrefPubMedGoogle Scholar
• 26 Brenner R M, Slayden O D, Critchley H O. Anti-proliferative effects of progesterone antagonists in the primate endometrium: a potential role for the androgen receptor.  Reproduction. 2002;  124 167-172
  CrossrefPubMedGoogle Scholar
• 27 Chwalisz K, Brenner R M, Fuhrmann U U, Hess-Stumpp H, Elger W. Antiproliferative effects of progesterone antagonists and progesterone receptor modulators on the endometrium.  Steroids. 2000;  65 741-751
  CrossrefPubMedGoogle Scholar
• 28 Leonhardt S A, Edwards D P. Mechanism of action of progesterone antagonists.  Exp Biol Med (Maywood). 2002;  227 969-980
  PubMedGoogle Scholar
• 29 Pulkkinen M O, Csapo A I. The effect of ibuprofen on the intrauterine pressure and menstrual pain of dysmenorrheic patients.  Prostaglandins. 1978;  15 1055-1062
  CrossrefPubMedGoogle Scholar
• 30 Murphy A A, Kettel L M, Morales A J, Roberts V, Parmley T, Yen S S. Endometrial effects of long-term low-dose administration of RU486.  Fertil Steril. 1995;  63 761-766
  PubMedGoogle Scholar
• 31 Archer D F, Philput C A, Weber M E. Management of irregular uterine bleeding and spotting associated with Norplant.  Hum Reprod. 1996;  11(suppl 2) 24-30
  PubMedGoogle Scholar
• 32 Slayden O D, Zelinski-Wooten M B, Chwalisz K, Stouffer R L, Brenner R M. Chronic treatment of cycling rhesus monkeys with low doses of the antiprogestin ZK 137 316: morphometric assessment of the uterus and oviduct.  Hum Reprod. 1998;  13 269-277
  CrossrefPubMedGoogle Scholar
• 33 Slayden O D, Chwalisz K, Brenner R M. Reversible suppression of menstruation with progesterone antagonists in rhesus macaques.  Hum Reprod. 2001;  16 1562-1574
  CrossrefPubMedGoogle Scholar
• 34 Elger W, Eskola J, Csapo A I. Mechanism of action of an orally active PGE1-analogue in pregnant guinea-pigs.  Prostaglandins. 1981;  21 259-266
  CrossrefPubMedGoogle Scholar
• 35 Pierdet A, Vignau M S. Noveau medicament notamment pour le traitment des traubles dus a une insuffisance desecretion du corps jaune. French Patent 5183 1966
  Google Scholar
• 36 Teutsch G, Klich M, Bouchoux F, Cerede E, Philibert D. Synthesis of a fluorescent steroid derivative with high affinities for the glucocorticoid and progesterone receptors.  Steroids. 1994;  59 22-26
  CrossrefPubMedGoogle Scholar
• 37 Menzenbach B, Hübner M, Sahm R, Ponsold K. Synthese potentieller Metaboliten der STS 557 (Dienogest) Teil 3: 17a-Hydroxymethyl-17β-hydroxyestra-4,9-dien-3-on.  Pharmazie. 1984;  39 496-497
  PubMedGoogle Scholar
• 38 Nedelec L. Sur l'epoxidation des estradienes-5(10,9(11).  Bull Soc Chim France. 1970;  25 2548-2556
  PubMedGoogle Scholar
• 39 Ratcliffe C T, Hardin C V, Anderson L R, Fox W B. A convenient synthesis of trifluormethyl hydroperoxide.  J Chem Soc Chem Commun. 1971;  15 784
  PubMedGoogle Scholar
• 40 Kasch H, Bertram G, Ponsold K et al.. 11b-Aryl-gona-4,9-dien-3-one. European Patent Application EP0 411 733. In: Chemical Abstracts 1991: 229226
  Google Scholar
• 41 Kasch H. A novel highly effective and stereoselective epoxidation of allylic and homoallylic alkohols using chloral hydrate and hydrogen peroxide.  Tetrahedron Lett. 1996;  30 2051-2054
  PubMedGoogle Scholar
• 42 Teutsch G. Regio and stereospecific synthesis of 11b-substituted 19-norsteroids.  Tetrahedron Lett. 1979;  30 2051-2054
  PubMedGoogle Scholar
• 43 Belanger A, Philibert D, Teutsch G. Regio and stereospecific synthesis of 11 beta-substituted 19-norsteroids. Influence of 11 beta-substitution on progesterone receptor affinity-(1).  Steroids. 1981;  37 361-382
  CrossrefPubMedGoogle Scholar
• 44 Teutsch G, Belanger A, Philibert D, Tournemine C. Synthesis of 11 beta-vinyl-19-norsteroids as potent progestins.  Steroids. 1982;  39 607-615
  CrossrefPubMedGoogle Scholar
• 45 Teutsch G, Costerousse G, Philibert D, Deraedt R. Nouveaux médicaments stéroides substitués en 11β, procédé et intermédiares de préparation, leur application comme médicament et les compositions les renfermant. European Patent EP 0057115 1982
  Google Scholar
• 46 Neef G, Beier S, Elger W, Henderson D, Ottow E, Rhode R. 11β-Phenylgonane, deren Herstellung und diese enthaltende pharmazeutische Präparate. German Patent DE 35 04 421. In: Chemical Abstracts 1987 106: 5324
  Google Scholar
• 47 Franzen V, Driesen H E. Methylenierung mit Sulfonium - Yliden.  Tetrahedron Lett. 1962;  3 661-662
  CrossrefPubMedGoogle Scholar
• 48 Corey E J, Chaykowsky M. Dimethylsulfonium metylide, a reagent for selective oxirane synthesis from aldehydes and ketones.  J Am Chem Soc. 1962;  83 3782-3783
  PubMedGoogle Scholar
• 49 Drefahl G, Ponsold K, Schick H. Umsetzung von Steroidketonen mit Sulfonium-Yliden.  Chem Ber. 1964;  97 3529-3535
  PubMedGoogle Scholar
• 50 Cook C E, Corley R C, Wall M E. Steroids. LXXIX. Synthesis and reactions of oxiranes obtained from 3- and 17-keto steroids.  J Org Chem. 1968;  33 2789-2793
  PubMedGoogle Scholar
• 51 Hübner M, Noack I. Ein vereinfachtes Verfahren zur Darstellung von Steroid-Spirooxiranen.  J Prakt Chem. 1972;  314 667-668
  PubMedGoogle Scholar
• 52 Ponsold K, Hübner M, Schnabel R, Strecke J. Synthese und uterotrope Wirkung neuartiger gebremster Östrogene vom Typ 17a-substituierter Derivate des Östradiol-3-methyläthers.  Arzneim-Forsch. 1974;  24 896-900
  PubMedGoogle Scholar
• 53 Ponsold K, Hübner M, Schade W, Oettel M, Freund R. Progestagene vom Typ 17a-CH2X substituierter 19-Nortestosteronderivate.  Pharmazie. 1978;  33 792-798
  PubMedGoogle Scholar
• 54 Schubert G, Kaufmann G, Sobek L, Oettel M, Elger W, Kurischko A. Neue Benzaldoximestradien-Derivate, Verfahren zu ihrer Herstellung und diese Verbindungen enthaltende Arzneimittel.  Chemical Abstracts. 1993;  123 56389
  PubMedGoogle Scholar
• 55 Schubert G, Kaufmann G, Sobek L, Oettel M, Elger W, Kurischko A. 11β-Benzaldoxim-17β-methoxy-17a-methoxymethyl-estradien-Derivate, Verfahren zu ihrer Herstellung und diese enthaltende Arzneimittel. German Patent DE 4332284, Chemical Abstracts 1995 123: 9760
  Google Scholar
• 56 Schubert G, Ring S, Kaufmann G, Elger W, Schneider B. S-substituted 11β-Benzaldoxime-estra-4,9-diene-carbonic acid thiolesters, method for the production thereof and pharmaceutical preparations containing these compounds. German Patent DE 198 098 45 1998
  Google Scholar
• 57 Schubert G, Ring S, Erhardt B. Method for the production of 4-[17a-substituted-3-oxoestra-4,9-dien-11β-yl]benzaldehyde (1E or 1Z)-oximes. US Patent Application. US 2004 10053905 (March 18, 2004)
  Google Scholar
• 58 Elger W, Hasan S G. Studies on the mechanism of action of antifertile PG in animal models.  Acta Physiol Hung. 1985;  65 415-432
  PubMedGoogle Scholar
• 59 Elger W, Ivell R, Nandy A, Rasch A, Triller A, Chwalisz K. Modulation of uterine prostaglandin secretion by the selective progesterone receptor modulator (SPRM) asoprisnil, progestins, and antiprogestins in cycling and ovariectomized guinea pigs.  Fertil Steril. 2004;  82(suppl 2) S316
  PubMedGoogle Scholar
• 60 Chwalisz K, Garfield R E. Antiprogestins in the induction of labor.  Ann N Y Acad Sci. 1994;  734 387-413
  PubMedGoogle Scholar
• 61 Chwalisz K, Garfield R E. Role of progesterone during pregnancy: models of parturition and preeclampsia.  Z Geburtshilfe Perinatol. 1994;  198 170-180
  PubMedGoogle Scholar
• 62 Chwalisz K, Fahrenholz F, Hackenberg M, Garfield R, Elger W. The progesterone antagonist onapristone increases the effectiveness of oxytocin to produce delivery without changing the myometrial oxytocin receptor concentrations.  Am J Obstet Gynecol. 1991;  165 1760-1770
  PubMedGoogle Scholar
• 63 Slayden O D, Brenner R M. RU 486 action after estrogen priming in the endometrium and oviducts of rhesus monkeys (Macaca mulatta).  J Clin Endocrinol Metab. 1994;  78 440-448
  CrossrefPubMedGoogle Scholar
• 64 Eisinger S H, Meldrum S, Fiscella K, le Roux H D, Guzick D S. Low-dose mifepristone for uterine leiomyomata.  Obstet Gynecol. 2003;  101 243-250
  CrossrefPubMedGoogle Scholar
• 65 Spitz I M, Bardin C W. Clinical pharmacology of RU 486-an antiprogestin and antiglucocorticoid.  Contraception. 1993;  48 403-444
  CrossrefPubMedGoogle Scholar
• 66 Spitz I M, Van Look P F, Coelingh Bennink H J. The use of progesterone antagonists and progesterone receptor modulators in contraception.  Steroids. 2000;  65 817-823
  CrossrefPubMedGoogle Scholar
• 67 Spitz I. Progesterone antagonists and progesterone receptor modulators: an overview.  Steroids. 2003;  68 981-993
  CrossrefPubMedGoogle Scholar
• 68 Chwalisz K, Stockemann K, Fritzemeier K H, Fuhrmann U. Modulation of oestrogenic effects by progesterone antagonists in the rat uterus.  Hum Reprod Update. 1998;  4 570-583
  CrossrefPubMedGoogle Scholar
• 69 Chwalisz K, Elger W, McCrary K, Beckman P, Larsen L. Reversible suppression of menstruation in normal women irrespective of the effect on ovulation with the novel selective progesterone receptor modulator (SPRM) J867.  J Soc Gynecol Invest. 2002;  9(suppl 1 abstract 49)
  PubMedGoogle Scholar
• 70 Chwalisz K, Larsen L, McCrary K, Edmonds A. Effects of the novel selective progesterone receptor modulator (SPRM) Asoprisnil on bleeding patterns in subjects with leiomyomata.  J Soc Gynecol Invest. 2004;  11(suppl 2:abstract 728)
  PubMedGoogle Scholar
• 71 Chwalisz K, Lamar Parker R, Williamson S, Larsen L, McCrary K, Elger W. Treatment of uterine leiomyomas with the novel selective progesterone receptor modulator (SPRM).  J Soc Gynecol Invest. 2003;  10(suppl:abstract 636)
  PubMedGoogle Scholar
• 72 Chwalisz K, Mattia-Goldberg C, Lee R, Elger W, Edmonds A. Treatment of endometriosis with the novel selective progesterone receptor modulator (SPRM) asoprisnil.  Fertil Steril. 2004;  82(suppl 2):S83
  PubMedGoogle Scholar

Kristof ChwaliszM.D. Ph.D. 

TAP Pharmaceutical Products Inc.

675 N. Field Drive, Lake Forest, IL 60045

Email: Kristof.Chwalisz@TAP.com