Gonadotropin-releasing hormone antagonists

Abarelix is a gonadotropin-releasing hormone antagonist that is associated with life-threatening hypersensitivity reactions. Patients must be observed for 30 minutes after administration. The drug is limited to men who cannot risk tumor flare and refuse orchiectomy. 

Conn, P.M., Rogers, D.C., Stewart, J.M., Niedel, J., and Sheffield, T. (1982a) Conversion of a gonadotropin-releasing hormone antagonist to an agonist. Nature (London) 296, 633-655. 

Debruyne F et al Abarelix for injectable suspension first-in-class gonadotropin-releasing hormone antagonist for prostate cancer. Future Oncol 2006 2 677. [PMID 17155895]... 

Buchter D, Behre HM, Kliesch S, Chirazi A, Nieschlag E, Assmann G, von Eckardstein A. Effects of testosterone suppression in young men by the gonadotropin releasing hormone antagonist cetrorelix on plasma lipids, lipolytic enzymes, lipid transfer proteins, insulin, and leptin. Exp Clin Endocrinol Diabetes 1999 107(8) 522-9. 

DowPharma identified that selective hydrogenation of 179 with Pt-C will reduce the aldehyde moiety to 182, which is an intermediate for a potent nonpeptide gonadotropin-releasing hormone antagonist 183 by Merck (Scheme 12.74). Addition of an acid, either oxalic acid or D-tartaric acid, to the Pt-C hydrogenation will reduce the nitrile to 169, which is isolated as the salt.228,229... 

Category Gonadotropin-releasing hormone antagonist Half-life 13.2 days... 

Indications Inhibition of premature luteinizing hormone surges in women undergoing controlled ovarian stimulation Category Gonadotropin-releasing hormone antagonist Half-life 5 hours... 

Compound 4 is a potent gonadotropin release hormone antagonist, and as such could be useful in treating prostate cancer and endometriosis. This compound, however, showed low oral bioavailability and high clearance in dogs. The clearance was attributed to metabolism at the 6-position of the piperidine, and, as a result, a 6-trifluoromethyl piperidine analog (5) was prepared. This change resulted in a 3-fold increase in oral bioavailability and a 2-fold decrease in clearance rate. 

Jiang, J., DeVita, R. J., Goulet, M. T. et al. Syntheses and structure-activity relationship studies of piperidine-substituted quinolones as nonpeptide gonadotropin releasing hormone antagonists. Bioorg. Med. Chem. Lett. 2004,14, 1795-1798. 

Kettel, L.M., Murphy, A.A., Morales, A.J., Rivier, J., Vale, W. and Yen, S.S. (1993) Rapid regression of uterine leiomyomas in response to daily administration of gonadotropin-releasing hormone antagonist. Fertility and Sterility, 60, 642-646. 

Chem. Soc., 114, 2860 (1992). Conformational Analysis of the Highly Potent Constrained Gonadotropin-Releasing Hormone Antagonist. 2. Molecular Dynamics Simulations. 

Two (5)-P-methyl-2-aryltryptamine-based gonadotropin-releasing hormone antagonists 95 and 96 were synthesized via a consecutive Larock indole synthesis and Suzuki cross-coupling reaction." The key transformation involved the Larock heteroannulation of o-iodoaniline 97 with chiral silyl alkyne 98 in the presence of Pd(OAc)2, PPha, 1 equiv of LiCl, and 2.5 equiv of K2CO3 in DMF at 100 °C to give 99 in 72% yield. 

The other advantage of aminocarbonylation involves the great variety of nucleophiles that can effectively be applied as reactants. Beside the commonly used primary and secondary amines, these include propargylamine in the synthesis of an intermediate of 8-epi-griseoviridin [105], arylamines, and heteroarylamines in the synthesis of gonadotropine-releasing hormone antagonists [104], substituted hydrazine derivatives [97], hydrazides [98], amino crown ethers [99], and amino acids [94,106]. Even sulfonamides were shown to be able to participate as nucleophiles in microwave-accelerated carbonylation in the presence of Mo(CO)g as the carbonyl source [107]. 

---