Summary
After almost two decades, the research on LHRH antagonists has produced a number of decapeptides that are currently in clinical studies. The structures of these antagonists, unlike the agonists, differ substantially from that of LHRH. Five of the ten amino acids are unnatural and of D configuration. The structural combination of a hydrophobic N-terminus (residues 1, 2, and 3) and a basic/hydrophilic C-terminus (residues 6 and 8) was thought to be responsible for some HR reactions encountered with the second generation of LHRH antagonists. This side effect was greatly reduced by substituting the appropriate combination of amino acids at positions 5, 6, and 8. The next hurdle in the drug development of LHRH antagonists was solubility and aggregation. In the case of A-75998, water solubility was improved by 12- to 25-fold via substitution of NMeTyr at position 5. However, based on DLS analysis, the aqueous solutions still contained some large aggregates that were not visible to the naked eye. This formation of aggregates was eliminated on formulating A-75998 in Encapsin®. In men, a single s.c. dose of 2 mg of A-75998 suppressed T to the castrate levels for over 30 hr. Other LHRH antagonists including ganirelix and cetrorelix are also in phase I/II clinical studies. Clinical studies with cetrorelix in prostate cancer, in vitro fertilization, and benign prostate hypotrophy have been reported.
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References
Bagatell, C. J., McLachlan, R. I., de Krester, D. M, Burger, H. G., Vale, W. W., Rivier, J. E., and Bremner, W. J., 1989, A comparison of the suppressive effects of testosterone and a potent new gonadotropin-releasing hormone antagonist on gonadotropin and inhibin levels in normal men, J. Clin. Endocrinol. Metab. 69:43–48.
Bagatell, C. J., Conn, P. M., and Bremner, W. J., 1993, Single dose administration of the gonadotropin-releasing hormone antagonist, Nal-Lys (antide) to healthy men, Fertil. Steril. 60:680–685.
Bajusz, S., Kovacs, M., Gazdag, M., Bokser, L., Karashima, T., Csernus, V. J., Janaky, T., Gouth, J., and Schally, A. V., 1988, Highly potent antagonists of luteinizing hormone-releasing hormone free of edematogenic effects, Proc. Natl. Acad. Sci. USA 85:1637–1641.
Behre, H. M., Bockers, A., Schlingheider, A., and Nieschlag, E., 1994, Sustained suppression of serum LH, FSH and testosterone and increase of high-density lipoprotein cholesterol by daily injection of GnRH antagonist cetrorelix over 8 days in normal men, Clin. Endocrinol. 40:241–248.
Bush, E. N., Nguyen, A. T., Diaz, G. J., Love, S. K., Mikusa, J. P., Cybulski, V. A., Carlson, R. P., Haviv, F., Fitzpatrick, T. D., Nichols, C. J., Swenson, R. E., Mort, N. A., Johnson, E. S., Dodge, P. W., Knittle, J., and Greer, J., 1993, Effects of A-75998 and other antagonists of gonadotropin-releasing hormone (GnRH) in castrate male rats, Endocr. J. 1:291–297.
Bush, E. N., Leal, J. A., Cybulski, V. A., Rhutasel, N., Diaz, G. J., Bammert, G., Haviv, F., Nichols, C., Swenson, R. E., Mort, N., Matayoshi, E., Krill, S., McChesney-Harris, L., Ruiz, L., Johnson, E. S., Knittle, J,, Dodge, P. W., and Greer, J., 1996, Effect of formulation, concentration, and route of administration of the GnRH antagonist A-75998 on pharmacokinetics and testosterone suppression in male dogs, in: 10th International Congress of Endocrinology, San Francisco, Abstr, P-3-240.
Cannon, J. B., Krill, S. L., and Porter, W, R., 1995, Physicochemical properties of A-75998, an antagonist of luteinizing hormone releasing hormone, J. Pharm. Sci. 84:953–958.
Chan, R. L., Hsieh, S. C., Haroldsen, P. E., Ho, W., and Nestor, J. J., 1991, Disposition of RS-26306, a potent luteinizing hormone antagonist, in monkeys and rats after single intravenous and subcutaneous administration, Drug Metab. Dispos. 19:858–864.
Conn, P. M., and Crowley, W. F., 1994, Gonadotropin-releasing hormone and its analogs, Annu. Rev. Med. 45:391–405.
Coy, D. H., Labrie, F., Savary, M., Coy, E. J., and Schally, A. V., 1975, LH-releasing activity of potent LH-RH analogs in vitro, Biochem. Biophys. Res. Commun. 67:576–582.
Coy, D. H., Vilchez-Martines, J. A., Coy, E. J., and Schally, A. V, 1976, Analogs of luteinizing hormone releasing hormone (LHRH) with increased biological activity produced by D-amino acid substitutions in position six, J. Med. Chem. 19:423–425.
Deckers, G. H. J., Kloosterboer, H. J., and Loozen, H. J. J., 1989, Properties of a new LHRH antagonist (Org 30850), in: 71st Annual Meeting of the Endocrine Society, Seattle, Abstr. 923.
Deghenghi, R., Boutignon, F., Wuthrich, P., and Lenaerts, V., 1993, Antarelix (EP 24332) a novel water soluble LHRH antagonist, Biomed. Pharmacother. 47:107–110.
Diedrich, K., Diedrich, C., Santos, E., Zoll, C., Al-Hasani, S., Reissmann, T., Krebs, T., and Klingmuller, D., 1994, Suppression of the endogenous luteinizing hormone surge by the gonadotrophin-releasing hormone antagonist cetrorelix during ovarian stimulation, Hum. Reprod. 9:788–791.
Dlugi, M. A., Miller, J. D., Knittle, J., and Lupron Study Group, 1990, Lupron Depot (luprolide acetate for depot suspension) in the treatment of endometriosis: A randomized, placebo-controlled double-blind study, Fertil. Steril. 54:419–127.
Dutta, A. S., 1988, Luteinizing hormone-releasing hormone (LHRH) agonists, Drugs Future 13:43–57.
Edelstein, M. C., Gordon, K., Williams, R. F, Danforth, D. R., and Hodgen, G. D., 1990, Single dose long-term suppression of testosterone secretion by a gonadotropin-releasing hormone antagonist (antide) in male monkeys, Contraception 42:209–214.
Filicori, M., and Flamigni, C., 1988, GnRH agonists and antagonists: Current clinical status, Drugs 35:63–82.
Fujino, M., Shinagawa, S., Yamazaki, I., Kobayashi, S., Obayashi, M., Fukuda, T., Nakayama, R., White, W. F., and Rippel, R. H., 1973, [DesGlyNH 102 , Pro-ethylamide9]LHRH A highly potent analog of luteinizing hormone releasing hormone, Arch. Biochem. Biophys. 154:488–489.
Garnick, M. B., Glode, M., and Lupron Study Group, 1984, Leuprolide versus diethylstilbestrol for metastatic prostate cancer, N. Engl. J. Med. 311:1281–1286.
Gonzalez-Barcena, D., Vadillo-Buenfil, M., Gomez-Orta, F., Fuentes-Garcia, M., Cardenas-Cornejo, I., Graef-Sanchez, A., Comaru-Schally, A. M., and Schally, A. V., 1994, Responses to the antagonist analog of LH-RH (SB-75, cetrorelix) in patients with benign prostatic hyperplasia and prostatic cancer, Prostate 24:84–92.
Gordon, K., Williams, R. F., Greer, J,, Bush, E. N., Haviv, R, Herrin, M., and Hodgen, G. D., 1994a, A-75998: A fourth generation GnRH antagonist: I. Preclinical studies in male primates, Endocrine 2:1133–1139.
Gordon, K., Williams, R. F., Greer, J., Bush, E. N., Haviv, F., Herrin, M., and Hodgen, G. D., 1994b, A-75998: A fourth generation GnRH antagonist: II. Preclinical studies in female primates, Endocrine 2:1141–1144.
Haviv, F., Palabrica, C. A., Bush, E. N., Diaz, G., Johnson, E. S., Love, S., and Greer, J., 1989, Active reduced-size hexapeptide analogues of luteinizing hormone-releasing hormone, J. Med. Chem. 32:2340–2344.
Haviv, F, Fitzpatrick, T. D., Nichols, C. J., Swenson, R. E., Mort, N. A., Bush, E. N., Diaz, G., Nguyen, A., Holst, M. R., Cybulski, V. A., Leal, J. A., Bammert, G., Rhutasel, N. S., Dodge, P. W., Johnson, E. S., Cannon, J. B., Knittle, J., and Greer, J., 1993a, The effect of NMeTyr5 substitution in luteinizing hormone-releasing hormone antagonists, J. Med. Chem. 36:928–933.
Haviv, F., Fitzpatrick, T. D., Swenson, R. E., Nichols, C. J., Mort, N. A., Bush, E. N., Diaz, G., Bammert, G., Nguyen, A., Rhutasel, N. S., Nellans, H. N., Hoffman, D. J., Johnson, E. S., and Greer, J., 1993b, Effect of N-methyl substitution of the peptide bonds in luteinizing hormone-releasing hormone agonists, J. Med. Chem. 36:363–369.
Haviv, F., Fitzpatrick, T. D., Nichols, C. J. Bush, E. N., Diaz, G., Bammert, G., Nguyen, A., Johnson, E. S., Knittle, J., and Greer, J., 1994, In vitro and in vivo activities of educed-size antagonists of luteinizing hormone-releasing hormone, J. Med. Chem. 37:701–705.
Karten, M. J., 1992, An overview of GnRH antagonist development: Two decades of progress, in: Modes of Actions of GnRH and GnRH Analogs (W. F. Crowley and P. M. Conn, eds.), pp. 277–297, Elsevier, Amsterdam.
Karten, M., and Rivier, J. E., 1986, Gonadotropin-releasing hormone analog design. Structure-function studies toward the development of agonists and antagonists: Rationale and perspective, Endocr. Rev. 7:44–66.
Karten, M. J., Hook, W. A., Siraganian, R. P., Coy, D. H., Folkers, K., Rivier, J. E., and Roeskc, R. W., 1987, In vitro histamine release with LHRH analogs, in: LHRH and its Analogs: Contraception and Therapeutic Applications, Part 2 (B. H. Vickery and J. J. J. Nestor, eds.), pp. 179–190, MTP Press, Lancaster.
Klingmuller, D., Schepke, M., Enzweiler, C., and Bidlingmaier, F., 1993, Hormonal responses to the new potent GnRH antagonist cetrorelix, Acta Endocrinol. 128:15–18.
Koch, Y., Baram, T., Chobsieng, P., and Fridkin, M., 1974, Enzymatic degradation of luteinizing hormone-releasing hormone (LHRH) by hypothalamic tissue, Biochem. Biophys. Res. Commun. 61:95–103.
Leal, J. A., Williams, R. F., Danforth, D. R., Gordon, K., and Hodgen, G. D., 1988, Prolonged duration of gonadotropin inhibition by a third generation GnRH antagonist, J. Clin. Endocrinol. Metab. 67:1325–1327.
Leal, J. A., Bush, E. N., Hoist, M. R., Cybulski, V. A., Nguyen, A. T., Rhutasel, N. S., Diaz, G. J., Haviv, F., Fitzpatrick, T. D., Nichols, C. J., Swenson, R. E., Mort, N. A., Carlson, R. P., Dodge, P. W., Knittle, J., and Greer, J., 1994, A-75998 and other GnRH antagonists suppress testosterone in male beagle dogs. A comparison of single injection, multiple injections and infusion administration, Endocrine 2:921–927.
Lee, C. H., VanAntwerp, D., Hedley, L., Nestor, J. J. J., and Vickery, B. H., 1989, Comparative studies on the hypotensive effect of LHRH antagonists in anesthetized rats, Life Sci. 45:697–702.
Ljungqvist, A., Feng, D. M., Tang, P. F., Kubota, M., Okamoto, T, Zhang, Y. W., Bowers, C. Y, Hook, W. A., and Folkers, K., 1987, Design, synthesis and bioassays of antagonists of LHRH which have high antiovulatory activity and release negligible histamine, Biochem. Biophys. Res. Commun. 148:849–856.
Ljungqvist, A., Feng, D. M., Hook, W., Shen, Z. X., Bowers, C., and Folkers, K., 1988, Antide and related antagonists of luteinizing hormone release with long action and oral activity, Proc. Natl. Acad. Sci. USA 85:8236–8240.
Matayoshi, E., and Krill, S., 1998, Manuscript in preparation.
Monahan, M. W., Amoss, M. S., Anderson, H. A., and Vale, W., 1973, Synthetic analogs of the hypothalamic lutenizing hormone releasing factor with increased agonist or antagonist properties. Biochemistry 12:4616–4620.
Nelson, L. R., Fujimoto, V. Y, Jaffe, R. B., and Monroe, S. E., 1995, Suppression of follicular phase pituitary-gonadal function by a potent new gonadotropin-releasing hormone antagonist with reduced histamine-releasing properties (ganirelix), Fertil. Steril. 63:963–969.
Nestor, J. J., Tahilramani, R., Ho, T. L., McRae, G. I., and Vickery, B. H., 1988, Potent, long-acting luteinizing hormone releasing hormone antagonists containing new synthetic amino acids: N,N & dialkyl-D-homoarginines, J. Med. Chem. 31:65–72.
Nestor, J. J., Tahilramani, R., Ho, T. L., Goodpasture, J. C., Vickery, B. H., and Ferrandon, P., 1992, Potent gonadotropin releasing hormone antagonists with low histamine-releasing activity, J. Med. Chem. 35:3942–3948.
Pavlou, S. N., Wakefield, G. B., Schlechter, N. L., Lindner, J., Souza, K. H., Kamilaris, T. C., Konidaris, S., Rivier, J. E., Vale, W. W., and Toglia, M., 1989, Mode of suppression of pituitary and gonadal function after acute or prolonged administration of a luteinizing hormone-releasing hormone antagonist in normal men, J. Clin. Endocrinol. Metab. 68:446–454
Rabinovici, J., Rothman, P., Monroe, S. E., Nerenberg, C., and Jaffe, R. B., 1992, Endocrine effects and pharmacokinetic characteristics of a potent new gonadotropin-releasing hormone antagonist (ganirelix) with minimal histamine-releasing properties: Studies in postmenopausal women, J. Clin. Endocrinol. Metab. 75:1220–1225.
Redding, T. W., Kastin, A. J., Gonzales-Barcena, D., Coy, D. H., Coy, E. J., Schalch, D. S., and Schally, A. V., 1973, The half-life, metabolism and excretion of tritiated luteinizing hormone-releasing hormone (LH-RH) in man, J. Clin. Endocrinol. Metab. 37:626–631.
Reissmann, T., Engel, J., Kutscher, B., Bernd, M., Hilgard, P., Peukert, M., Szelenyi, I., Reichert, S., Gonzales-Barcena, D., Nieschlag, E., Comaru-Schally, A. M., and Schally, A. V., 1994, Cetrorelix, Drugs Future 19:228–237.
Reissmann, T., Klenner, T., Deger, W., Hilgard, P., McGregor, G. P., and Voigt, K., 1996, Pharmacological studies with cetrorelix (SB-75), a potent antagonist of luteinizing hormone-releasing hormone, Eur. J. Cancer 32A:1574–1579.
Rivier, J., Rivier, C., Perrin, M., Porter, J., and Vale, W. W., 1981, GnRH analogs: Structure activity relationships, in: LHRH Peptidex as Female and Male Contraceptives (G. I. Zatuchni, J. D. Shelton, and J. J. Sciarra, eds.), pp. 13–23, Harper & Row, New York.
Rivier, J., Rivier, C., Perrin, M., Porter, J., and Vale, W., 1984, LHRH analogs as antiovulatory agents, in: LHRH and its Analogs (B. H. Vickery, J. J. J. Nestor, and E. S. E. Hafez, eds.), pp. 11–22, MTP Press, Lancaster.
Rivier, J. E., Porter, J., Rivier, C. L., Perrin, M., Corrigan, A., Hook, W. A., Siraganian, R. P., and Vale, W. W., 1986, New effective gonadotropin releasing hormone antagonists with minimal potency for histamine release in vitro, J. Med. Chem. 29:1846–1851.
Rivier, J., Porter, J., Hoeger, C., Theobald, P., Craig, A. G., Dykert, J., Corrigan, A., Perrin, M., Hook, W. A., Siraganian, R. P., Vale, W., and Rivier, C., 1992a, Gonadotropin-releasing hormone antagonists with N omega-triazolylornithine,-lysine, or-p-aminophenylalanine residues at positions 5 and 6, J. Med. Chem. 35:4270–4278.
Rivier, J. E., Theobald, P., Hoeger, C., Craig, A. G., Perrin, M., Porter, J., Corrigan, A., Koerber, S., Hagler, A., Vale, W., and Rivier, C., 1992b, GnRH antagonists: A synopsis, Contraception 46:109–112.
Scott, R. T. J., Gordon, K., Williams, R. F., and Hodgen, G. D., 1989, New long-acting GnRH antagonist: Accelerated GnRH test response in primates, in: 71st Annual Meeting of the Endocrine Society, Seattle, Abstr. 216.
Simon, A., Birkenfeld, A., and Schenker, J. G., 1990, Gonadotropin releasing hormone (GnRH): Mode of action and clinical applications. A review, Int. J. Fertil. 35:350–362.
Sommer, L., Zanger, K., Dyong, T, Dorn, C., Luckhaus, T, Diedrich, K., and Klingmuller, D., 1994, Seven-day administration of the gonadotropin-releasing hormone antagonist cetrorelix in normal cycling women, Eur. J. Endocrinol. 131:280–285.
Vickery, B. H., McRae, G., Lee, C. H., Nerenberg, C. A., Ferrandon, P., and Nestor, J. J. A., 1990, A new highly potent LHRH antagonist with low histamine releasing activity has unusually high oral bioavailability, in: 72nd Annual Meeting of the Endocrine Society, Atlanta, Abstr. 1375.
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Haviv, F., Bush, E.N., Knittle, J., Greer, J. (2002). LHRH Antagonists. In: Borchardt, R.T., Freidinger, R.M., Sawyer, T.K., Smith, P.L. (eds) Integration of Pharmaceutical Discovery and Development. Pharmaceutical Biotechnology, vol 11. Springer, Boston, MA. https://doi.org/10.1007/0-306-47384-4_7
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