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Acyline

Description of Acyline: Acyline is a novel GnRH antagonist found in animal studies to be a potent suppressor of circulating gonadotropin and testosterone (T) levels.

Current developer:    Merrion Pharmaceuticals.

Acyline is currently being developed by Merrion Pharmaceuticals. Acyline is a GnRH antagonist that takes advantage of GIPET® technology and provides an oral dosage form alternative to current therapies, all of which are injectable. There are several GnRH antagonists either marketed or in development for the treatment of prostate cancer, endometriosis and benign prostatic hypertrophy (BPH). In general, these new compounds are less potent than the first generation agonists, and cause greater local tissue irritation when used in a long acting injection or subcutaneous implant delivery systems. The market adoption of the currently approved products has been low due to the fact that a small percentage of patients develop a severe allergic response to the large doses given by injection of subcutaneous depot. An oral product would eliminate the inconvenience of injection therapy, avoid the severe reactions, and allow tailored dosing regimens. Merrion has identified a potent GnRH antagonist with an attractive product profile for development as an oral dosage form for the treatment of prostate cancer as an initial indication. This compound is a novel chemical entity and has already been evaluated in Phase II clinical trials. see : http://www.merrionpharma.com/content/portfolio/mer104.asp

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12. Valiente, C.; Diaz, J. D.; Rosa, D. E.; Mattioli, G.; Romero, G. Garcia; Gobello, C. Effect of a GnRH antagonist on GnRH agonist-implanted anestrous bitches. Theriogenology (2009), 72(7), 926-929. CODEN: THGNBO ISSN:0093-691X. CAN 152:207284 AN 2009:1156037

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14. Amory, John Kenneth; Leonard, Thomas W.; Page, Stephanie T.; O'Toole, Edel; McKenna, Michael J.; Bremner, William J. Oral administration of the GnRH antagonist acyline, in a GIPET-enhanced tablet form, acutely suppresses serum testosterone in normal men: single-dose pharmacokinetics and pharmacodynamics. Cancer Chemotherapy and Pharmacology (2009), 64(3), 641-645. CODEN: CCPHDZ ISSN:0344-5704. CAN 152:278761 AN 2009:689893

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16. Valiente, C.; Romero, G. Garcia; Corrada, Y.; de la Sota, P. E.; Hermo, G.; Gobello, C. Interruption of the canine estrous cycle with a low and a high dose of the GnRH antagonist, acyline. Theriogenology (2009), 71(3), 408-411. CODEN: THGNBO ISSN:0093-691X. CAN 151:70388 AN 2008:1542616

17. Mikkelsen, Jens D.; Bentsen, Agnete H.; Ansel, Laura; Simonneaux, Valerie; Juul, Anders. Comparison of the effects of peripherally administered kisspeptins. Regulatory Peptides (2009), 152(1-3), 95-100. CODEN: REPPDY ISSN:0167-0115. CAN 150:160496 AN 2008:1496820

18. Allen, Camryn D.; Burridge, Michelle; Chafer, Mandy L.; Nicolson, Vere N.; Jago, Sophia C.; Booth, Rosemary J.; Fraser, Grant; Ensabella, Traza-Jade; Zee, Yeng Peng; Lundie-Jenkins, Geoff; Holt, William V.; Lisle, Allan T.; Carrick, Frank N.; Curlewis, Jonathan D.; D'Occhio, Michael J.; Johnston, Stephen D. Control of the koala (Phascolarctos cinereus) anterior pituitary-gonadal axis with analogues of GnRH. Reproduction, Fertility and Development (2008), 20(5), 598-605. CODEN: RFDEEH ISSN:1031-3613. CAN 149:506322 AN 2008:652396

19. Maji, Samir K.; Schubert, David; Rivier, Catherine; Lee, Soon; Rivier, Jean E.; Riek, Roland. Amyloid as a depot for the formulation of long-acting drugs. PLoS Biology (2008), 6(2), 240-252. CODEN: PBLIBG ISSN:1545-7885. CAN 148:523359 AN 2008:408728

20. Mason, Alex O.; Greives, Timothy J.; Scotti, Melissa-Ann L.; Levine, Jacob; Frommeyer, Stefanie; Ketterson, Ellen D.; Demas, Gregory E.; Kriegsfeld, Lance J. Suppression of kisspeptin expression and gonadotropic axis sensitivity following exposure to inhibitory day lengths in female Siberian hamsters. Hormones and Behavior (2007), 52(4), 492-498. CODEN: HOBEAO ISSN:0018-506X. CAN 148:276908 AN 2007:1136865

21. Page, Stephanie T.; Kalhorn, Thomas F.; Bremner, William J.; Anawalt, Bradley D.; Matsumoto, Alvin M.; Amory, John K. Intratesticular androgens and spermatogenesis during severe gonadotropin suppression induced by male hormonal contraceptive treatment. Journal of Andrology (2007), 28(5), 734-741. CODEN: JOAND3 ISSN:0196-3635. CAN 147:515230 AN 2007:1122668

22. Molskness, Theodore A.; Hess, David L.; Maginnis, Gwen M.; Wright, Jay W.; Fanton, John W.; Stouffer, Richard L. Characteristics and regulation of the ovarian cycle in vervet monkeys (Chlorocebus aethiops). American Journal of Primatology (2007), 69(8), 890-900. CODEN: AJPTDU ISSN:0275-2565. CAN 147:496479 AN 2007:955884

23. Valiente, C.; Corrada, Y.; de la Sota, P. E.; Galassi Gerez, P.; Gobello, C. Effect of the GnRH antagonist, acyline, on canine testicular characteristics. Theriogenology (2007), 68(5), 687-692. CODEN: THGNBO ISSN:0093-691X. CAN 148:24604 AN 2007:860298

24. Mostaghel, Elahe A.; Page, Stephanie T.; Lin, Daniel W.; Fazli, Ladan; Coleman, Ilsa M.; True, Lawrence D.; Knudsen, Beatrice; Hess, David L.; Nelson, Colleen C.; Matsumoto, Alvin M.; Bremner, William J.; Gleave, Martin E.; Nelson, Peter S. Intraprostatic Androgens and Androgen-Regulated Gene Expression Persist after Testosterone Suppression: Therapeutic Implications for Castration-Resistant Prostate Cancer. Cancer Research (2007), 67(10), 5033-5041. CODEN: CNREA8 ISSN:0008-5472. CAN 147:92445 AN 2007:539348

25. Pareek, Tej K.; Joshi, Ayesha R.; Sanyal, Amartya; Dighe, Rajan R. Insights into male germ cell apoptosis due to depletion of gonadotropins caused by GnRH antagonists. Apoptosis (2007), 12(6), 1085-1100. CODEN: APOPFN ISSN:1360-8185. CAN 147:250901 AN 2007:496156

26. Samant, Manoj P.; White, Richard; Hong, Doley J.; Croston, Glenn; Conn, P. Michael; Janovick, Jo Ann; Rivier, Jean. Structure-activity relationship studies of gonadotropin-releasing hormone antagonists containing S-aryl/alkyl norcysteines and their oxidized derivatives. Journal of Medicinal Chemistry (2007), 50(9), 2067-2077. CODEN: JMCMAR ISSN:0022-2623. CAN 147:10183 AN 2007:394130

27. Gruendker, Carsten; Guenthert, Andreas R.; Emons, Guenter. Method for induction and enhancement of apoptosis in tumor cells using GnRH II antagonists. PCT Int. Appl. (2007), 49pp. CODEN: PIXXD2 WO 2007012430 A1 20070201 CAN 146:177622 AN 2007:113392

28. Page, Stephanie T.; Amory, John K.; Anawalt, Bradley D.; Irwig, Michael S.; Brockenbrough, Andrew T.; Matsumoto, Alvin M.; Bremner, William J. Testosterone gel combined with depomedroxyprogesterone acetate is an effective male hormonal contraceptive regimen and is not enhanced by the addition of a GnRH antagonist. Journal of Clinical Endocrinology and Metabolism (2006), 91(11), 4374-4380. CODEN: JCEMAZ ISSN:0021-972X. CAN 146:55736 AN 2006:1212841

29. Page, Stephanie T.; Lin, Daniel W.; Mostaghel, Elahe A.; Hess, David L.; True, Lawrence D.; Amory, John K.; Nelson, Peter S.; Matsumoto, Alvin M.; Bremner, William J. Persistent intraprostatic androgen concentrations after medical castration in healthy men. Journal of Clinical Endocrinology and Metabolism (2006), 91(10), 3850-3856. CODEN: JCEMAZ ISSN:0021-972X. CAN 145:389619 AN 2006:1100707

30. Samant, Manoj P.; Hong, Doley J.; Croston, Glenn; Rivier, Jean E. Norcysteine ( -thiolglycine), a versatile scaffold to tailor structure and activity of peptides. Abstracts of Papers, 232nd ACS National Meeting, San Francisco, CA, United States, Sept. 10-14, 2006 (2006), MEDI-254. CODEN: 69IHRD AN 2006:861709

31. Vera, Yanira; Erkkila, Krista; Wang, Christina; Nunez, Concepcion; Kyttanen, Sauli; Lue, Yanhe; Dunkel, Leo; Swerdloff, Ronald S.; Hikim, Amiya P. Sinha. Involvement of p38 mitogen-activated protein kinase and inducible nitric oxide synthase in apoptotic signaling of murine and human male germ cells after hormone deprivation. Molecular Endocrinology (2006), 20(7), 1597-1609. CODEN: MOENEN ISSN:0888-8809. CAN 145:96854 AN 2006:665033

32. Page, Stephanie T.; Plymate, Stephen R.; Bremner, William J.; Matsumoto, Alvin M.; Hess, David L.; Lin, Daniel W.; Amory, John K.; Nelson, Peter S.; Wu, Jennifer D. Effect of medical castration on CD4+CD25+ T cells, CD8+ T cell IFN- expression, and NK cells: a physiological role for testosterone and/or its metabolites. American Journal of Physiology (2006), 290(5, Pt. 1), E856-E863. CODEN: AJPHAP ISSN:0002-9513. CAN 145:6386 AN 2006:496592

33. Samant, Manoj P.; Hong, Doley J.; Croston, Glenn; Rivier, Catherine; Rivier, Jean. Novel Analogues of Degarelix Incorporating Hydroxy-, Methoxy-, and Pegylated-Urea Moieties at Positions 3, 5, 6 and the N-Terminus. Part III. Journal of Medicinal Chemistry (2006), 49(12), 3536-3543. CODEN: JMCMAR ISSN:0022-2623. CAN 145:167526 AN 2006:483250

34. Plant, Tony M.; Ramaswamy, Suresh; DiPietro, Meloni J. Repetitive activation of hypothalamic G protein-coupled receptor 54 with intravenous pulses of kisspeptin in the juvenile monkey (Macaca mulatta) elicits a sustained train of gonadotropin-releasing hormone discharges. Endocrinology (2006), 147(2), 1007-1013. CODEN: ENDOAO ISSN:0013-7227. CAN 144:206099 AN 2006:98313

35. Amory, John K.; Page, Stephanie T.; Bremner, William J. Oral testosterone in oil: Pharmacokinetic effects of 5 reduction by finasteride or dutasteride and food intake in men. Journal of Andrology (2006), 27(1), 72-78. CODEN: JOAND3 ISSN:0196-3635. CAN 144:343810 AN 2006:88716

36. Hikim, Amiya P. Sinha; Vera, Yanira; Elhag, Rashid I.; Lue, Yanhe; Cui, Yu-Gui; Pope, Vanisha; Leung, Andrew; Atienza, Vince; Wang, Christina; Swerdloff, Ronald S. Mouse model of male germ cell apoptosis in response to a lack of hormonal stimulation. Indian Journal of Experimental Biology (2005), 43(11), 1048-1057. CODEN: IJEBA6 ISSN:0019-5189. CAN 144:247394 AN 2005:1270613

37. Matthiesson, Kati L.; Stanton, Peter G.; O'Donnell, Liza; Meachem, Sarah J.; Amory, John K.; Berger, Richard; Bremner, William J.; McLachlan, Robert I. Effects of testosterone and levonorgestrel combined with a 5 -reductase inhibitor or gonadotropin-releasing hormone antagonist on spermatogenesis and intratesticular steroid levels in normal men. Journal of Clinical Endocrinology and Metabolism (2005), 90(10), 5647-5655. CODEN: JCEMAZ ISSN:0021-972X. CAN 143:399986 AN 2005:1110537

38. Amory, John K.; Bremner, William J. Oral androgen therapy using modulators of testosterone bioavailability. U.S. Pat. Appl. Publ. (2005), 34 pp. CODEN: USXXCO US 2005176692 A1 20050811 CAN 143:186758 AN 2005:735317

39. Marshall, Gary R.; Ramaswamy, Suresh; Plant, Tony M. Gonadotropin-independent proliferation of the pale type A spermatogonia in the adult rhesus monkey (Macaca mulatta). Biology of Reproduction (2005), 73(2), 222-229. CODEN: BIREBV ISSN:0006-3363. CAN 143:222848 AN 2005:668912

40. Amory, John K.; Bremner, William J. Oral testosterone in oil plus dutasteride in men: A pharmacokinetic study. Journal of Clinical Endocrinology and Metabolism (2005), 90(5), 2610-2617. CODEN: JCEMAZ ISSN:0021-972X. CAN 143:38549 AN 2005:421319

41. Page, Stephanie T.; Herbst, Karen L.; Amory, John K.; Coviello, Andrea D.; Anawalt, Bradley D.; Matsumoto, Alvin M.; Bremner, William J. Testosterone administration suppresses adiponectin levels in men. Journal of Andrology (2005), 26(1), 85-92. CODEN: JOAND3 ISSN:0196-3635. CAN 142:274255 AN 2005:65143

42. Irwig, Michael S.; Fraley, Gregory S.; Smith, Jeremy T.; Acohido, Blake V.; Popa, Simina M.; Cunningham, Matthew J.; Gottsch, Michelle L.; Clifton, Donald K.; Steiner, Robert A. Kisspeptin Activation of Gonadotropin Releasing Hormone Neurons and Regulation of KiSS-1 mRNA in the Male Rat. Neuroendocrinology (2004), 80(4), 264-272. CODEN: NUNDAJ ISSN:0028-3835. CAN 142:254885 AN 2005:64740

43. Matthiesson, Kati L.; Amory, John K.; Berger, Richard; Ugoni, Antony; McLachlan, Robert I.; Bremner, William J. Novel male hormonal contraceptive combinations: The hormonal and spermatogenic effects of testosterone and levonorgestrel combined with a 5 -reductase inhibitor or gonadotropin-releasing hormone antagonist. Journal of Clinical Endocrinology and Metabolism (2005), 90(1), 91-97. CODEN: JCEMAZ ISSN:0021-972X. CAN 142:233478 AN 2005:59356

44. Herbst, Karen L.; Coviello, Andrea D.; Page, Stephanie; Amory, John K.; Anawalt, Bradley D.; Bremner, William J. A single dose of the potent gonadotropin-releasing hormone antagonist Acyline suppresses gonadotropins and testosterone for 2 weeks in healthy young men. Journal of Clinical Endocrinology and Metabolism (2004), 89(12), 5959-5965. CODEN: JCEMAZ ISSN:0021-972X. CAN 142:49419 AN 2004:1101489

45. Shetty, Gunapala; Weng, Connie C. Y.; Bolden-Tiller, Olga U.; Huhtaniemi, Ilpo; Handelsman, David J.; Meistrich, Marvin L. Effects of medroxyprogesterone and estradiol on the recovery of spermatogenesis in irradiated rats. Endocrinology (2004), 145(10), 4461-4469. CODEN: ENDOAO ISSN:0013-7227. CAN 141:325938 AN 2004:797952

46. Gottsch, M. L.; Cunningham, M. J.; Smith, J. T.; Popa, S. M.; Acohido, B. V.; Crowley, W. F.; Seminara, S.; Clifton, D. K.; Steiner, R. A. A role for kisspeptins in the regulation of gonadotropin secretion in the mouse. Endocrinology (2004), 145(9), 4073-4077. CODEN: ENDOAO ISSN:0013-7227. CAN 141:254779 AN 2004:724138

47. Hild, Sheri Ann; Attardi, Barbara J.; Reel, Jerry R. The ability of a gonadotropin-releasing hormone antagonist, acyline, to prevent irreversible infertility induced by the indenopyridine, CDB-4022, in adult male rats: The role of testosterone. Biology of Reproduction (2004), 71(1), 348-358. CODEN: BIREBV ISSN:0006-3363. CAN 141:33589 AN 2004:516801

48. Cunningham, Matthew J.; Shahab, Muhammad; Grove, Kevin L.; Scarlett, Jarrad M.; Plant, Tony M.; Cameron, Judy L.; Smith, M. Susan; Clifton, Donald K.; Steiner, Robert A. Galanin-like peptide as a possible link between metabolism and reproduction in the macaque. Journal of Clinical Endocrinology and Metabolism (2004), 89(4), 1760-1766. CODEN: JCEMAZ ISSN:0021-972X. CAN 141:1613 AN 2004:323647

49. Houk, Christopher P.; Pearson, Elliot J.; Martinelle, Nina; Donahoe, Patricia K.; Teixeira, Jose. Feedback inhibition of steroidogenic acute regulatory protein expression in vitro and in vivo by androgens. Endocrinology (2004), 145(3), 1269-1275. CODEN: ENDOAO ISSN:0013-7227. CAN 140:297770 AN 2004:161140

50. Ramaswamy, Suresh; Marshall, Gary R.; Pohl, Clifford R.; Friedman, Robert L.; Plant, Tony M. Inhibitory and stimulatory regulation of testicular inhibin b secretion by luteinizing hormone and follicle-stimulating hormone, respectively, in the rhesus monkey (macaca mulatta). Endocrinology (2003), 144(4), 1175-1185. CODEN: ENDOAO ISSN:0013-7227. CAN 139:31012 AN 2003:243305