Download PDF
Semin Reprod Med 2005; 23(1): 46-57
DOI: 10.1055/s-2005-864033
Copyright © 2005 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

Nonsteroidal Progesterone Receptor Modulators: Structure Activity Relationships

Richard C. Winneker1 , Andrew Fensome2 , Jay E. Wrobel2 , Zhiming Zhang1 , Puwen Zhang2
  • 1Endocrinology and Reproductive Disorders Division, Women's Health Research Institute
  • 2Chemical & Screening Sciences, Wyeth Research, Collegeville, Pennsylvania
Further Information

Publication History

Publication Date:
15 February 2005 (online)

    Permissions and Reprints

ABSTRACT

Progesterone, acting primarily via the progesterone receptor (PR), plays an essential role in the regulation of female reproduction. Steroidal progestins (i.e., PR agonists) are commonly used in women's health, such as in contraception and hormone therapy and for the treatment of gynecological disorders. Recent studies in women and in nonhuman primates also indicate that PR antagonists may have potential applications in contraception and for the treatment of reproductive disorders such as fibroids and endometriosis. Currently, all clinically available PR agonists and antagonists are steroidal compounds. They often cause various side effects due to their functional interactions with other steroid receptors or because of effects associated with their steroidal metabolites. In an effort to identify more receptor-selective and structurally diverse compounds that may render clinical advantages over steroidal PR ligands, numerous receptor-selective novel nonsteroidal PR agonists and antagonists have been discovered. This review focuses on the structure activity relationships and the biological profile of the nonsteroidal PR modulators discovered in the last decade.

KEYWORDS

Progesterone receptor (PR) - PR agonists - PR antagonists - contraception - endometriosis - hormone therapy - uterine fibroids

REFERENCES

  • 1 Edgren R A, Sturtevant F M. Potencies of oral contraceptives.  Am J Obstet Gynecol. 1976;  125 1029-1038
    PubMedSearch in Google Scholar
  • 2 Keating N L, Cleary P D, Rossi A S, Zaslavsky A M, Ayanian J Z. Use of hormone replacement therapy by postmenopausal women in the United States.  Ann Intern Med. 1999;  130 545-553
    PubMedSearch in Google Scholar
  • 3 Utian W H, Shoupe D, Bachmann G, Pinkerton J V, Pickar J H. Relief of vasomotor symptoms and vaginal atrophy with lower doses of conjugated equine estrogens and medroxyprogesterone acetate.  Fertil Steril. 2001;  75 1065-1079
    CrossrefPubMedSearch in Google Scholar
  • 4 Torgerson D J, Bell-Syer S EM. Hormone replacement therapy and prevention of nonvertebral fractures: a meta-analysis of randomized trials.  JAMA. 2001;  285 2891-2897
    CrossrefPubMedSearch in Google Scholar
  • 5 Vercellini P, De Giorgi O, Oldani S et al.. Depot medroxyprogesterone acetate versus an oral contraceptive combined with very-low-dose danazol for long-term treatment of pelvic pain associated with endometriosis.  Am J Obstet Gynecol. 1996;  175 396-401
    CrossrefPubMedSearch in Google Scholar
  • 6 Glasier A, Baird D. The effects of self-administering emergency contraception.  N Engl J Med. 1998;  339 1-4
    CrossrefPubMedSearch in Google Scholar
  • 7 Brogden R N, Goa K L, Faulds D. Mifepristone: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential.  Drugs. 1993;  45 384-409
    PubMedSearch in Google Scholar
  • 8 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
    CrossrefPubMedSearch in Google Scholar
  • 9 Zelinski-Wooten M B, Slayden O D, Chwalisz K et al.. Chronic treatment of female rhesus monkeys with low doses of the antiprogestin ZK 137 316: establishment of a regimen that permits normal menstrual cyclicity.  Hum Reprod. 1998;  13 259-267
    CrossrefPubMedSearch in Google Scholar
  • 10 Kettel L M, Murphy A A, Morales A J, Yen S S. Clinical efficacy of the antiprogesterone RU486 in the treatment of endometriosis and uterine fibroids.  Hum Reprod. 1994;  9(suppl 1) 116-120
    PubMedSearch in Google Scholar
  • 11 Kettel L M, Murphy A A, Morales A J, Yen S S. Preliminary report on the treatment of endometriosis with low-dose mifepristone (RU 486).  Am J Obstet Gynecol. 1998;  178 1151-1156
    CrossrefPubMedSearch in Google Scholar
  • 12 Murphy A A, Kettel L M, Morales A J, Roberts V J, Yen S S. Regression of uterine leiomyomata in response to the antiprogesterone RU 486.  J Clin Endocrinol Metab. 1993;  76 513-517
    CrossrefPubMedSearch in Google Scholar
  • 13 Brenner R M, Slayden O D, Critchley H OD. Anti-proliferative effects of progesterone antagonists in the primate endometrium: a potential role for the androgen receptor.  Reproduction. 2002;  124 167-172
    CrossrefPubMedSearch in Google Scholar
  • 14 Zhang P, Terefenko E A, Fensome A et al.. Novel 6-aryl-1,4-dihydrobenzo[d]oxazine-2-thiones as potent, selective, and orally active nonsteroidal progesterone receptor agonists.  Bioorg Med Chem Lett. 2003;  13 1313-1316
    CrossrefPubMedSearch in Google Scholar
  • 15 Zhang Z, Lundeen S G, Zhu Y, Carver J M, Winneker R C. In vitro characterization of trimegestone: a new potent and selective progestin.  Steroids. 2000;  65 637-643
    CrossrefPubMedSearch in Google Scholar
  • 16 Pathirana C, Stein R B, Berger T S et al.. Nonsteroidal human progesterone receptor modulators from the marine alga Cymopolia barbata .  Mol Pharmacol. 1995;  47 630-635
    PubMedSearch in Google Scholar
  • 17 Zhi L, Tegley C M, Kallel E A et al.. Aryl-1,2-dihydrochromeno[3,4-f]quinolines: a novel class of nonsteroidal human progesterone receptor agonists.  J Med Chem. 1998;  41 291-302
    CrossrefPubMedSearch in Google Scholar
  • 18 Palmer S, Campen C A, Allan G F et al.. Nonsteroidal progesterone receptor ligands with unprecedented receptor selectivity.  J Steroid Biochem Mol Biol. 2000;  75 33-42
    CrossrefPubMedSearch in Google Scholar
  • 19 Conti C J, Gimenez-Conti I B, Zerbe G O, Gerschenson L E. Differential effects of estradiol-17b and progesterone on the proliferation of glandular and luminal cells of rabbit uterine epithelium.  Biol Reprod. 1981;  24 643-648
    PubMedSearch in Google Scholar
  • 20 McPhail M K. The assay of progestin.  J Physiol London. 1934;  83 145-156
    PubMedSearch in Google Scholar
  • 21 Zhang Z, Funk C, Glasser S R, Mulholland J. Progesterone regulation of heparin-binding epidermal growth factor-like growth factor gene expression during sensitization and decidualization in the rat uterus: effects of the antiprogestin, ZK 98. 99.  Endocrinology. 1994;  135 1256-1263
    CrossrefPubMedSearch in Google Scholar
  • 22 Lundeen S G, Zhang Z, Zhu Y, Carver J M, Winneker R C. Rat uterine complement C3 expression as a model for progesterone receptor modulators: characterization of the new progestin trimegestone.  J Steroid Biochem Mol Biol. 2001;  78 137-143
    CrossrefPubMedSearch in Google Scholar
  • 23 Van Uem J FHM, Hsiu J G, Chillik C F et al.. Contraceptive potential of RU 486 by ovulation inhibition: I. Pituitary versus ovarian action with blockade of estrogen-induced endometrial proliferation.  Contraception. 1989;  40 171-184
    CrossrefPubMedSearch in Google Scholar
  • 24 Kloosterboer H J, Deckers G H, de Gooyer M E et al.. Pharmacological properties of a new selective antiprogestagen: Org 33628.  Ann N Y Acad Sci. 1995;  761 192-201
    PubMedSearch in Google Scholar
  • 25 Kloosterboer H J, Deckers G H, Schoonen W GEJ et al.. Preclinical experience with two selective progesterone receptor modulators on breast and endometrium.  Steroids. 2000;  65 733-740
    CrossrefPubMedSearch in Google Scholar
  • 26 Zhang P, Fensome A, Wrobel J, Winneker R, Zhang Z. Non-steroidal progesterone receptor modulators.  Expert Opin Ther Pat. 2003;  13 1839-1847
    PubMedSearch in Google Scholar
  • 27 Zhi L, Tegley C M, Pio B et al.. Nonsteroidal progesterone receptor antagonists based on 6-thiophenylhydroquinolines.  Bioorg Med Chem Lett. 2000;  10 415-418
    CrossrefPubMedSearch in Google Scholar
  • 28 Zhang P, Terefenko E A, Fensome A et al.. Potent nonsteroidal progesterone receptor agonists: synthesis and SAR study of 6-aryl benzoxazines.  Bioorg Med Chem Lett. 2002;  12 787-790
    CrossrefPubMedSearch in Google Scholar
  • 29 Beck C A, Weigel N L, Moyer M L, Nordeen S K, Edwards D P. The progesterone antagonist RU486 acquires agonist activity upon stimulation of cAMP signaling pathways.  Proc Natl Acad Sci USA. 1993;  90 4441-4445
    PubMedSearch in Google Scholar
  • 30 Fensome A, Koko M, Wrobel J et al.. Novel 5-aryl-1,3-dihydro-indole-2-thiones: potent, orally active progesterone receptor agonists.  Bioorg Med Chem Lett. 2003;  13 1317-1320
    CrossrefPubMedSearch in Google Scholar
  • 31 Collins M A, Hudak V, Bender R et al.. Novel pyrrole-containing progesterone receptor modulators.  Bioorg Med Chem Lett. 2004;  14 2185-2189
    CrossrefPubMedSearch in Google Scholar
  • 32 Zhi L, Tegley C M, Pio B et al.. Benzylidene-1,2-dihydrochromeno[3,4-f]quinolines as selective progesterone receptor modulators.  J Med Chem. 2003;  46 4104-4112
    CrossrefPubMedSearch in Google Scholar
  • 33 Edwards J P, Zhi L, Pooley C LF et al.. Preparation, resolution, and biological evaluation of 5-aryl-1,2-dihydro-5H-chromeno[3,4-f]quinolines: potent, orally active, nonsteroidal progesterone receptor agonists.  J Med Chem. 1998;  41 2779-2785
    CrossrefPubMedSearch in Google Scholar
  • 34 Zhi L, Tegley C M, Edwards J P et al.. Alkyl-1,2-dihydrochromeno[3,4-f]quinolines: a novel class of nonsteroidal progesterone receptor modulators.  Bioorg Med Chem Lett. 1998;  8 3365-3370
    CrossrefPubMedSearch in Google Scholar
  • 35 Zhi L, Tegley C M, Pio B et al.. Synthesis and biological activity of 5-methylidene 1,2-dihydrochromeno[3,4-f]quinoline derivatives as progesterone receptor modulators.  Bioorg Med Chem Lett. 2003;  13 2071-2074
    PubMedSearch in Google Scholar
  • 36 Tabata Y, Miike N, Hatsu M et al.. PF1092A, B and C, new nonsteroidal progesterone receptor ligands produced by Penicillium oblatum. I. Taxonomy of producing strain, fermentation, isolation and biological activities.  J Antibiot. 1997;  50 304-308
    PubMedSearch in Google Scholar
  • 37 Tabata Y, Iizuka Y, Shinei R et al.. CP8668, a novel orally active nonsteroidal progesterone receptor modulator with tetrahydrobenzindolone skeleton.  Eur J Pharmacol. 2003;  461 73-78
    CrossrefPubMedSearch in Google Scholar
  • 38 Dong Y, Roberge J Y, Wang Z et al.. Characterization of a new class of selective nonsteroidal progesterone receptor agonists.  Steroids. 2004;  69 201-217
    CrossrefPubMedSearch in Google Scholar
  • 39 Pooley C LF, Edwards J P, Goldman M E et al.. Discovery and preliminary SAR studies of a novel, nonsteroidal progesterone receptor antagonist pharmacophore.  J Med Chem. 1998;  41 3461-3466
    CrossrefPubMedSearch in Google Scholar
  • 40 Zhi L, Ringgenberg J D, Edwards J P et al.. Development of progesterone receptor antagonists from 1,2-dihydrochromeno[3,4-f]quinoline agonist pharmacophore.  Bioorg Med Chem Lett. 2003;  13 2075-2078
    PubMedSearch in Google Scholar
  • 41 Hamann L G, Winn D T, Pooley C LF et al.. Nonsteroidal progesterone receptor antagonists based on a conformationally-restricted subseries of 6-aryl-1,2-dihydro-2,2,4-trimethylquinolines.  Bioorg Med Chem Lett. 1998;  8 2731-2736
    CrossrefPubMedSearch in Google Scholar
  • 42 Zhang P, Terefenko E A, Wrobel J et al.. Synthesis and progesterone receptor antagonist activities of 6-aryl benzimidazolones and benzothiazolones.  Bioorg Med Chem Lett. 2001;  11 2747-2750
    CrossrefPubMedSearch in Google Scholar
  • 43 Fensome A, Bender R, Cohen J et al.. New progesterone receptor antagonists: 3,3-disubstituted-5-aryloxindoles.  Bioorg Med Chem Lett. 2002;  12 3487-3490
    CrossrefPubMedSearch in Google Scholar
  • 44 Zhang P, Terefenko E A, Fensome A et al.. Aryl-1,4-dihydro-benzo[d][1,3]oxazin-2-ones: a novel class of potent, selective, and orally active nonsteroidal progesterone receptor antagonists.  J Med Chem. 2002;  45 4379-4382
    CrossrefPubMedSearch in Google Scholar
  • 45 Winneker R C, Bitran D, Zhang Z. The preclinical biology of a new potent and selective progestin: trimegestone.  Steroids. 2003;  68 915-920
    CrossrefPubMedSearch in Google Scholar
  • 46 Bitran D, Shiekh M, McLeod M. Anxiolytic effect of progesterone is mediated by the neurosteroid allopregnanolone at brain GABAA receptors.  J Neuroendocrinol. 1995;  7 171-177
    PubMedSearch in Google Scholar

Richard C WinnekerPh.D. 

Women's Health Research Institute, Wyeth Research

500 Arcola Road, Collegeville, PA 19426

Email: winnekr@wyeth.com