Synthesis of orally active small-molecule gonadotropin-releasing hormone antagonists

Current Opinion in Drug Discovery and Development

Volumn 7, Issue 6, 2004, Pages 832-847

  Tucci, Fabio C ^a   Chen, Chen ^a  

^a NEUROCRINE BIOSCIENCES INC   (United States)

Author keywords

Antagonists; GnRH receptor; Gonadotropin releasing hormone; Heterocycle; Orally active; Synthesis

Indexed keywords

2 FUROIC ACID AMIDE; 2 PHENYLIMIDAZO[1,2 A]PYRIMIDIN 5 ONE; 2 PHENYLTHIENO[2,3 B]PYRIDIN 4 ONE; 3 (N BENZYL N METHYLAMINOMETHYL) 7 (2,6 DIFLUOROBENZYL) 4,7 DIHYDRO 2 (4 ISOBUTYRYLAMINOPHENYL) 4 OXOTHIENO[2,3 B]PYRIDINE 5 CARBOXYLIC ACID ISOPROPYL ESTER; 6 PHENYLTHIENO[2,3 D]PYRIMIDINE 2,4 DIONE; A 198401; AG 045572; ARACHIDONIC ACID; CYTOCHROME P450 3A; ERYTHROMYCIN; ESTROGEN; FOLLITROPIN; GONADORELIN ANTAGONIST; GONADORELIN RECEPTOR; LEUPRORELIN; LUTEINIZING HORMONE; MACROLIDE; NBI 42902; PROGESTERONE; QUINOLONE DERIVATIVE; SUFUGOLIX; TESTOSTERONE; THYMIDINE DERIVATIVE; TRYPTAMINE DERIVATIVE; UNCLASSIFIED DRUG;

ANIMAL CELL; ANIMAL EXPERIMENT; ARACHIDONIC ACID METABOLISM; BROMINATION; CHO CELL; CLINICAL TRIAL; CONTROLLED CLINICAL TRIAL; CONTROLLED STUDY; CYCLIZATION; DEBENZYLATION; DESILYLATION; DOSE RESPONSE; DRUG BIOAVAILABILITY; DRUG CLEARANCE; DRUG HALF LIFE; DRUG METABOLISM; DRUG SYNTHESIS; FEMALE; FRIEDEL CRAFTS REACTION; HORMONE RELEASE; HUMAN; MALE; MANNICH REACTION; MITSUNOBU REACTION; MONKEY; MOUSE; NONHUMAN; NUCLEAR OVERHAUSER EFFECT; PHASE 1 CLINICAL TRIAL; RABBIT; REVIEW; STRUCTURE ACTIVITY RELATION; SUZUKI REACTION; SWERN OXIDATION; TRANSESTERIFICATION; X RAY CRYSTALLOGRAPHY;

ADMINISTRATION, ORAL; ANIMALS; GONADOTROPIN-RELEASING HORMONE; HORMONE ANTAGONISTS; HUMANS; INDICATORS AND REAGENTS;

EID: 10444280766     PISSN: 13676733     EISSN: None     Source Type: Journal    
DOI: None     Document Type: Review

References (46)

1. Burgus R, Butcher M, Amoss M, Ling N, Monahan M, Rivier J, Fellows R, Blackwell R, Vale W, Guillemin R: Primary structure of the ovine hypothalamic luteinizing hormone-releasing factor (LRF) (LH-hypothalamus-LRF-gas chromatography-mass spectrometry-decapeptide-Edman degradation). Proc Natl Acad Sci USA (1972) 69(1):278-282.
2. Matsuo H, Baba Y, Nair RM, Arimura A, Schally AV: Structure of the porcine LH- and FSH-releasing hormone. I. The proposed amino acid sequence. Biochem Biophys Res Commun (1971) 43(6):1334-1339.
3. Huirne JA, Lambalk CB: Gonadotropin-releasing-hormone-receptor antagonists. Lancet (2001) 358(9295):1793-1803.
4. Barbieri RL: Endometriosis and the estrogen threshold theory. Relation to surgical and medical treatment. J Reprod Med (1998) 43(3 Suppl):287-292.
5. Cho N, Harada M, Imaeda T, Imada T, Matsumoto H, Hayase Y, Sasaki S, Furuya S, Suzuki N, Okubo S, Ogi K et al: Discovery of a novel, potent and orally active nonpeptide antagonist of the human luteinizing hormone-releasing hormone (LHRH) receptor. J Med Chem (1998) 41 (22):4190-4195. First report of the design and synthesis of a small-molecule GnRH antagonist.
6. Sasaki S, Cho N, Nara Y, Harada M, Endo S, Suzuki N, Furuya S, Fujino M: Discovery of a thieno[2,3-d]pyrimidine-2,4-dione bearing a p-methoxyureidophenyl moiety at the 6-position: A highly potent and orally bioavailable non-peptide antagonist of the human luteinizing hormone-releasing hormone receptor. J Med Chem (2003) 46(1):113-124. This paper describes the synthesis, SAR and in vivo pharmacological activity of TAK-013, the first small-molecule GnRH antagonist to enter clinical trials.
7. Hara T, Araki H, Kusaka M, Harada M, Cho N, Suzuki N, Furuya S, Fujino M: Suppression of a pituitary-ovarian axis by chronic oral administration of a novel nonpeptide gonadotropin-releasing hormone antagonist, TAK-013, in cynomolgus monkeys. J Clin Endocrinol Metab (2003) 88(4):1697-1704. Results from chronic administration of TAK-013 to female cynomolgus monkeys suggest that the compound is a selective and efficacious GnRH antagonist, and that its effects are reversible upon discontinuation of treatment.
8. Clark E, Boyce M, Warrington S, Johnston A, Suzuki N, Cho N, Dote N, Nishizawa A, Furuya S: Effects of single doses of TAK-013, a new non-peptide orally active gonadotropin-releasing hormone antagonists, in healthy young men. Proc Br Pharmacol Soc Clin Pharmacol Section, Br J Clin Pharmacol (2003) 55:443. First disclosure of data from clinical trials of TAK-013.
9. Guo Z, Chen Y, Wu D, Zhu YF, Struthers RS, Saunders J, Xie Q, Chen C: Synthesis and structure-activity relationships of thieno[2,3-d]pyrimidine-2,4- dione derivatives as potent GnRH receptor antagonists. Bioorg Med Chem Lett (2003) 13(20):3617-3622.
10. Sasaki S, Imaeda T, Hayase Y, Shimizu Y, Kasai S, Cho N, Harada M, Suzuki N, Furuya S, Fujino M: A new class of potent nonpeptide luteinizing hormone-releasing hormone (LHRH) antagonists: Design and synthesis of 2-phenylimidazo[1,2-a]pyrimidin-5-ones. Bioorg Med Chem Lett (2002) 12(16):2073-2077.
11. Wilcoxen K, Zhu YF, Connors PJ, Saunders J, Gross TD, Gao Y, Reinhart GJ, Struthers RS, Chen C: Synthesis and initial structure-activity relationships of a novel series of imidazolo[1,2-a]pyrimid-5-ones as potent GnRH receptor antagonists. Bioorg Med Chem Lett (2002) 12(16):2179-2183.
12. Gross TD, Zhu YF, Saunders J, Wilcoxen KM, Gao Y, Connors PJ Jr, Guo Z, Struthers RS, Reinhart GJ, Chen C: Design, synthesis and structure-activity relationships of a novel series of imidazolo[1,2-a]pyrimid-5-ones as potent GnRH receptor antagonists. Bioorg Med Chem Lett (2002) 12(16):2185-2187. Replacement of the ester group by substituted phenyls at the 6-position led to an imidazolo[1,2-a]pyrimid-5-one series with up to 50-fold improved binding.
13. Zhu YF, Guo Z, Gross TD, Gao Y, Connors PJ Jr, Struthers RS, Xie Q, Tucci FC, Reinhart GJ, Wu D, Saunders J et al: Design and structure-activity relationships of 2-alkyl-3-aminomethyl-6-(3-methoxyphenyl-7-methyl-8-(2- fluorobenzyl)imidazolo[1,2-a]pyrimid-5-ones as potent GnRH receptor antagonists. J Med Chem (2003) 46(9):1769-1772. This paper reports on a reduction in molecular size of imidazolo[1,2-a]pyrimid-5-ones by replacement of the aromatic ring at the 2-postion by a simple alkyl group.
14. Zhu YF, Struthers RS, Connors PJ Jr, Gao Y, Gross TD, Saunders J, Wilcoxen K, Reinhart GJ, Ling N, Chen C: Initial structure-activity relationship studies of a novel series of pyrrolo[1,2-a]pyrimid-7-ones as GnRH receptor antagonists. Bioorg Med Chem Lett (2002) 12(3):339-402.
15. Zhu YF, Wilcoxen K, Saunders J, Guo Z, Gao Y, Connors PJ Jr, Gross TD, Tucci FC, Struthers RS, Reinhart GJ, Xie Q et al: A novel synthesis of 2-arylpyrrolo[1,2-a]pyrimid-7-ones and their structure-activity relationships as potent GnRH receptor antagonists. Bioorg Med Chem Lett (2002) 12(3):403-406.
16. Tucci FC, Zhu YF, Guo Z, Gross TD, Connors PJ Jr, Struthers RS, Reinhart GJ, Wang X, Saunders J, Chen C: A novel synthesis of 7-aryl-8-fluoro-pyrrolo[1, 2-a]pyrimid-4-ones as potent, stable GnRH receptor antagonists. Bioorg Med Chem Lett (2002) 12(23):3491-3495.
17. Lin C, Hutchins JE, Weber AE, Lo JL, Yang YT, Cheng K, Smith RG, Fisher MH, Wyvratt MJ, Goulet MT: Initial structure-activity relationship of a novel class of nonpeptidyl GnRH receptor antagonists: 2-Arylindoles. Bioorg Med Chem Lett (2001) 11(4):509-513.
18. Young JR, Huang SX, Walsh TF, Wyvratt MJ, Yang YT, Yudkovitz JB, Cui J, Mount GR, Ren RN, Wu TJ, Shen X et al: 2-Arylindoles as gonadotropin releasing hormone (GnRH) antagonists: Optimization of the tryptamine side chain. Bioorg Med Chem Lett (2002) 12(5):827-832.
19. Simeone JP, Bugianesi RL, Ponpipom MM, Yang YT, Lo JL, Yudkovitz JB, Cui J, Mount GR, Ren RN, Creighton M, Mao AH et al: Modification of the pyridine moiety of non-peptidyl indole GnRH receptor antagonists. Bioorg Med Chem Lett (2002) 12(22):3329-3332.
20. Walsh TF, Toupence RB, Ujjainwalla F, Young JR, Goulet MT: A convergent synthesis of (S)-β-methyl-2-aryltryptamine based gonadotropin releasing hormone antagonists. Tetrahedron (2001) 57(24):5233-5241. The convergent asymmetric synthesis of a 2-aryltryptamine GnRH antagonist is reported, in which a palladium-catalyzed Larock indole synthesis is successfully utilized in the key step.
21. Simeone JP, Bugianesi RL, Ponpipom MM, Goulet MT, Levorse MS, Desai RC: Synthesis of chiral β-methyl tryptamin-derived GnRH antagonists. Tetrahedron Lett (2001) 42(37):6459-6461.
22. DeVita RJ, Holling DD, Goulet MT, Wyvratt MJ, Fisher MH, Lo JL, Yang YT, Cheng K, Smith RG: Identification and initial structure-activity relationships of a novel non-peptide quinolone GnRH receptor antagonist. Bioorg Med Chem Lett (1999) 9(17):2615-2620.
23. DeVita RJ, Walsh TF, Young JR, Jiang JL, Ujjainwalla F, Toupence RB, Parkh M, Huang SX, Fair JA, Goulet MT, Wyvratt MJ et al: A potent, nonpeptidyl 1H-quinolone antagonist for the gonadotropin-releasing hormone receptor. J Med Chem (2001) 44(6):917-922. Results from a study in which intravenous administration of a 3-arylquinolone small-molecule GnRH antagonist to rhesus monkeys demonstrate its effectiveness in suppressing plasma LH and testosterone levels.
24. Jiang J, DeVita RJ, Goulet MT, Wyvratt MJ, Lo J-L, Ren N, Yudkovitz JB, Cui J, Yang YT, Cheng K, Rohrer SP: Syntheses and structure-activity relationship studies of piperidine-substituted quinolones as nonpeptide gonadotropin releasing hormone antagonists. Bioorg Med Chem Lett (2004) 14(7):1795-1798. First report of an orally bioavailable compound from the 3-arylquinolone series describing the asymmetric synthesis of the piperidine side chains using a methodology developed at Merck.
25. Iatsimirskaia EA, Gregory ML, Anderes KL, Castillo R, Milgram KE, Luthin DR, Pathak VP, Christie LC, Vazir H, Anderson MB, May JM: Effect of testosterone suppression on the pharmacokinetics of a potent GnRH receptor antagonist. Pharm Res (2002) 19(2):202-208. First report of a 2-furancarboxamide as a small-molecule GnRH antagonist and its effects on testosterone suppression in intact male rats. The authors investigated the differences in pharmacokinetics between male and female rats and correlated them with the suppression of testosterone.
26. Anderes KL, Luthin DR, Castillo R, Kraynov EA, Castro M, Nared-Hood K, Gregory ML, Pathak VP, Christie LC, Paderes G, Vazir H et al: Biological characterization of a novel, orally active small molecule gonadotropin-releasing hormone (GnRH) antagonist using castrated and intact rats. J Pharmacol Exp Ther (2003) 305(2):688-695.
27. Luthin DR, Hong Y, Pathak V, Paderes G, Nared-Hood KD, Castro MA, Vazir H, Li H, Tompkins E, Christie L, May JM et al: The discovery of novel small molecule non-peptide gonadotropin releasing hormone (GnRH) receptor antagonists. Bioorg Med Chem Lett (2002) 12(23):3467-3470.
28. Luthin DR, Hong Y, Tompkins E, Anderes KL, Paderes G, Kraynov EA, Castro MA, Nared-Hood KD, Castillo R, Gregory M, Vazir H et al: Characterization of mono- and diaminopyrimidine derivatives as novel, nonpeptide gonadotropin releasing hormone (GnRH) receptor antagonists. Bioorg Med Chem Lett (2002) 12(24):3635-3639.
29. Zhu YF, Gross TD, Guo Z, Connors PJ Jr, Gao Y, Tucci FC, Struthers RS, Reinhart GJ, Saunders J, Chen TK, Bonneville AL et al: Identification of 1-arylmethyl-3-(2-aminoethyl)-5-aryluracil as novel gonadotropin-releasing hormone receptor antagonists. J Med Chem (2003) 46(11):2023-2026. Details the discovery of 6-methyluracils as GnRH antagonists, including the synthesis, initial SAR trends and preliminary pharmacokinetics.
30. Guo Z, Zhu YF, Tucci FC, Gao Y, Struthers RS, Saunders J, Gross TD, Xie Q, Reinhart GJ, Chen C: Synthesis and structure-activity relationships of 1-arylmethyl-3-(2-aminopropyl)-5-aryl-6-methyl uracils as potent GnRH receptor antagonists. Bioorg Med Chem Lett (2003) 13(19):3311-3315. Introduction of a methyl group in an R-configuration at the β-position of the N(3) side chain of a 6-methyluracil core resulted in compounds with superior binding affinity.
31. Tucci FC, Zhu YF, Guo Z, Gross TD, Connors PJ Jr, Struthers RS, Reinhart GJ, Saunders J, Chen C: Synthesis and structure-activity relationships of 1-arylmethyl-3-(1-methyl-2-amino)ethyl-5-aryl-6-methyluracils as antagonists of the human GnRH receptor. Bioorg Med Chem Lett (2003) 13(19):3317-3322. In the 6-methyluracil series, a pyridine-containing side chain on the basic nitrogen is not required for good potency as long as a methyl group of R-configuration at the α-position of the N(3) side chain is present.
32. Guo Z, Zhu YF, Gross TD, Tucci FC, Gao Y, Moorjani M, Connors PJ Jr, Rowbottom MR, Chen Y, Struthers RS, Xie Q et al: Synthesis and structure-activity relationships of 1-arylmethyl-5-aryl-6-methyl uracils as potent gonadotropin-releasing hormone receptor antagonists. J Med Chem (2004) 47(5):1259-1271.
33. Tucci FC, Zhu YF, Guo Z, Gross TD, Connors PJ Jr, Gao Y, Rowbottom R, Struthers RS, Reinhart GJ, Xie Q, Chen TK et al: 3-(2-(Aminoalkyl)-1-(2,6- difluorobenzyl)-5-(2-fluoro-3-methoxyphenyl)-6-methyluracils as orally bioavailable antagonists of the human gonadotropin-releasing hormone receptor. J Med Chem (2004) 47(14):3483-3486. The medicinal chemistry strategy, as well as the synthesis, SAR and pharmacokinetics in mice and cynomolgus monkeys, is presented for a series of novel 6-methyluracil GnRH antagonists.
34. Rowbottom MR, Tucci FC, Zhu YF, Guo Z, Gross TD, Reinhart GJ, Xie Q, Struthers RS, Saunders J, Chen C: Synthesis and structure-activity relationships of (R)-1-alkyl-3-[2-(2-amino)phenethyl]-5-(2-fluorophenyl)-6-methyluracils as human GnRH receptor antagonists. Bioorg Med Chem Lett (2004) 14(9):2269-2274.
35. Tucci FC, Zhu YF, Struthers RS, Guo Z, Gross TD, Rowbottom MW, Acevedo O, Gao Y, Saunders J, Xie Q, Chen C et al: 3-[(2R)-Amino-2-phenylethyl]-1-(2,6- difluorobenzyl)-5-(2-fluoro-3-methoxyphenyl)-6-methylpyrimidin-2,4-dione (NBI 42902) as a potent and orally active antagonist of the human gonadotropin-releasing hormone receptor - design, synthesis and in vitro and in vivo characterization. J Med Chem (2005): manuscript submitted. First disclosure of the structure, in vivo profile and clinical trial data for NBI-42902.
36. Besecke LM, Diaz GJ, Segreti JA, Mohning KM, Cybulski VA, Rao M, Bush EN, Randolph JT, Waid PL, Haviv F, Wegner CD et al: Pharmacological and endocrine characterization of A-198401, an orally active GnRH antagonist, in intact and castrate male rat models. Drug Dev Res (2001) 52(3):485-491. An account describing the discovery and SAR of macrolides as GnRH antagonists.
37. Randolph JT, Waid P, Nichols C, Sauer D, Haviv F, Diaz G, Bammert G, Besecke LM, Segreti JA, Mohning KM, Bush EN et al: Nonpeptide luteinizing hormone-releasing hormone antagonists derived from erythromycin A: Design, synthesis, and biological activity of cladinose replacement analogues. J Med Chem (2004) 47(5):1085-1097.
38. Randolph JT, Sauer DR, Haviv F, Nilius AM, Greer J: Elimination of antibacterial activities of non-peptide luteinizing hormone-releasing hormone (LHRH) antagonists derived from erythromycin A. Bioorg Med Chem Lett (2004) 14(6):1599-1602.
39. Zhu F, Chen C: Recent advances in small molecule gonadotropin-releasing hormone receptor antagonists Expert Opin Ther Pat (2004) 14(2)1187-199.
40. Millar RP, Lu ZL, Pawson AJ, Flanagan CA, Morgan K, Maudeley SA: Gonadotropin-releasing hormone receptors. Endocr Rev (2004) 25(2):235-275. A comprehensive review of the GnRH receptors of different species, as well as the peptide agonists and antagonists. Information regarding the solution structure of GnRH and suggested binding modes to the receptor are discussed.
41. 313 of the gonadotropin-releasing hormone (GnRH) receptor as a site critical for the binding of nonpeptide GnRH antagonists. Mol Endocrinol (2000) 14(5)1671-681.
42. Reinhart GJ, Xie Q, Liu XJ, Zhu YF, Fan J, Chen C, Struthers RS: Species selectivity of nonpeptide antagonists of the gonadotropin-releasing hormone receptor is determined by residues in extracellular loops II and III and the amino terminus. J Biol Chem (2004) 279(33):34115-34122.
43. ASTRAZENECA AB (Foote KM, Matusiak Z, Dossetter AG, Arnould JC, Lamorlette MA, Delouvrie B, Hamon A): 6H-Thieno[2,3-b]pyrrole derivatives as antagonists of gonadotropin-releasing hormone (GnRH). WO-2004018480 (2004).
44. FERRING BV (Roe MB, Batt AR, Evans DM, Pitt GR, Rooker DP): Non-peptide GnRH antagonists. WO-2003078398 (2003).
45. ASTRAZENECA AB (Bird TG, Maudet ML): Pyrazole derivatives as GnRH inhibitors. WO-2004018459 (2004).
46. NEUROCRINE BIOSCIENCES INC (Pontillo J, Chen C): Gonadotropin-releasing hormone receptor antagonists. WO-2003011870 (2003).