The design of orally bioavailable 2,5-diketopiperazine oxytocin antagonists: From concept to clinical candidate for premature labor

Medicinal Research Reviews

Volumn 31, Issue 4, 2011, Pages 576-604

  Borthwick, Alan D ^a   Liddle, John ^a  

^a GLAXOSMITHKLINE   (United Kingdom)

Author keywords

Diketopiperazines; GSK221149A; Oxytocin antagonist; Preterm labor; Retosiban

Indexed keywords

2, 5 DIKETOPIPERAZINE; ATOSIBAN; CYTOCHROME P450; OXYTOCIN; OXYTOCIN ANTAGONIST; OXYTOCIN RECEPTOR; PIPERAZINEDIONE; RETOSIBAN; UNCLASSIFIED DRUG; VASOPRESSIN RECEPTOR;

ARTICLE; CRYSTAL STRUCTURE; DRUG ABSORPTION; DRUG ACTIVITY; DRUG BIOAVAILABILITY; DRUG DESIGN; DRUG PROTEIN BINDING; DRUG SOLUBILITY; DRUG STRUCTURE; DRUG SYNTHESIS; HUMAN; IN VIVO STUDY; NONHUMAN; PREMATURE LABOR; STEREOCHEMISTRY;

ADMINISTRATION, ORAL; BIOLOGICAL AVAILABILITY; DIKETOPIPERAZINES; DRUG DESIGN; FEMALE; HUMANS; OBSTETRIC LABOR, PREMATURE; OXYTOCIN; PREGNANCY;

EID: 79959539577     PISSN: 01986325     EISSN: 10981128     Source Type: Journal    
DOI: 10.1002/med.20193     Document Type: Article

References (45)

1. Benntt PR. Preterm labour. In: Edmonds DK, Dewhurst J, editors. Dewhurst's textbook of obstetrics and gynaecology, 7th ed. Malden, MA: Blackwell; 2007. pp 177-191.
2. Steer P. The epidemiology of preterm labour. Br J Obstet Gynaecol 2005;112(Supplement 1):1-3.
3. Goldenberg RL, Culhane JF, Iams JD, Romero R. Epidemiology and causes of preterm birth. Lancet 2008;371:75-84.
4. Bryce J, Boschi-Pinto C, Shibuya K, Black RE, the WHO Child Health Epidemiology Reference Group. WHO estimates of the causes of death in children. Lancet 2005;365:1147-1152.
5. Ezzati M, Lopez AD, Rodgers A, Vander Hoorn S, Murray CJ. Comparative Risk Assessment Collaborating Group. Selected major risk factors and global and regional burden of disease. Lancet 2002;360:1347-1360.
6. Behrman RE, Butler AS. Preterm birth: Causes, consequences, and prevention. Washington, DC: National Academic Press; 2007.
7. Slattery MM, Morrison JJ. Preterm delivery. Lancet 2002;360:1489-1497.
8. Hall MH, Danielian P, Lamont RF. Importance of preterm birth. In: Elder MG, Romero R, Lamont RF, editors. Preterm labour. New York: Churchill Livingstone; 1997. pp 1-28.
9. Coomarasamy A, Knox EM, Gee H, Khan KS. Oxytocin antagonists for tocolysis in preterm labour-a systematic review. Med Sci Monit 2002;8:RA268-RA273.
10. Tsatsaris V, Carbonne B, Cabrol D. Atosiban for Preterm Labour. Drugs 2004;64:375-382.
11. Bossmar T. Treatment of preterm labor with the oxytocin and vasopressin antagonist atosiban. J Perinat Med 1998;26:458-465.
12. Nilsson L, Reinheimer T, Steinwall M, Akerlund M. FE 200 440: A selective oxytocin antagonist on the term-pregnant human uterus. Br J Obstet Gynaecol 2003;110:1025-1028.
13. Freidinger RM, Pettibone DJ. Small molecule ligands for oxytocin and vasopressin receptors. Med Res Rev 1997;17:1-16.
14. Allen MJ, Livermore DGH, Mordaunt JE. Oxytocin antagonists as potential therapeutic agents for the treatment of preterm labour. Prog Med Chem 2006;44:335-373.
15. Schwarz MK, Page P. Preterm labour: An overview of current and emerging therapeutics. Curr Med Chem 2003;10:1441-1468.
16. Borthwick AD. Oxytocin antagonists and agonists. Annu Rep Med Chem 2006;41:413-422.
17. Gimpl G, Fahrenholz F. The oxytocin receptor system: Structure, function, and regulation. Physiol Rev 2001;81:629-683.
18. Zingg HH, Laporte SA. The oxytocin receptor. Trends Endocrinol Metab 2003;14:222-227.
19. Lee HJ, Macbeth AH, Pagani JH, Young III, WS. Oxytocin: The great facilitator of life. Prog Neurobiol 2009;88:127-151.
20. Lippert TH, Mueck AO, Seeger H, Pfaff A. Effects of Oxytocin Outside Pregnancy. Horm Res 2003;60:262-271.
21. Uvnas-Moberg K. The oxytocin factor. Cambridge, MA: Da Capo Press, 2003.
22. Horton DA, Bourne GT, Smythe ML. Exploring privileged structures: The combinatorial synthesis of cyclic peptides. Mol Div 2002;5:289-304.
23. Wyatt PG, Allen MJ, Borthwick AD, Davies DE, Exall AM, Hatley RJD, Irving WR, Livermore DG, Miller ND, Nerozzi F, Sollis SL, Szardenings AK. 2, 5-Diketopiperazines as potent and selective oxytocin antagonists 1: Identification, stereochemistry and initial SAR. Bioorg Med Chem Lett 2005;15:2579-2582.
24. Borthwick AD, Davies DE, Exall AM, Livermore DG, Sollis SL, Nerozzi F, Allen MJ, Perren M, Shabbir SS, Woollard PM, Wyatt PG. 2, 5-Diketopiperazines as potent, selective and orally bioavailable oxytocin antagonists 2: Synthesis, chirality and pharmacokinetics. J Med Chem 2005;48:6956-6969.
25. Havass J, Bakos K, Marki A, Gaspar R, Gera L, Stewart JM, Fulop F, Toth GK, Zupko I, Falkay G. Noncompetitive nature of oxytocin antagonists with general structure Mpa1Xxx2Sar7Arg8. Peptides 2002;23:1419-1425.
26. Melin P, Vilhardt H, Lindeberg G, Larsson LE, Akerlund M. Inhibitory effect of O-alkylated analogues of oxytocin and vasopressin on human and rat myometrial activity. J Endocrinol 1981;88:173-180.
27. Borthwick AD, Davies DE, Exall AM, Hatley RJD, Hughes JA, Irving WR, Livermore DG, Sollis SL, Nerozzi F, Valko KL, Allen MJ, Perren M, Shabbir SS, Woollard PM, Price MA. 2, 5-Diketopiperazines as potent, selective and orally bioavailable oxytocin antagonists 3: Synthesis, pharmacokinetics and in vivo potency. J Med Chem 2006;49:4159-4970.
28. Wyatt PG, Allen MJ, Chilcott J, Gardner CJ, Livermore DG, Mordaunt JE, Nerozzi F, Patel M, Perren MJ, Weingarten GG, Shabbir SS, Woollard PM, Zhou P. Identification of potent and selective oxytocin antagonists. Part 2: Further investigation of benzofuran derivatives. Bioorg Med Chem Lett 2002;12:1405-1411.
29. Van De Waterbeemd H, Jones BC. Predicting oral absorption and bioavailability. Prog Med Chem 2003;41:1-59.
30. Lajiness MS, Vieth M, Erickson J. Molecular properties that influence oral drug-like behaviour. Curr Opin Drug Dis Dev 2004;7:470-477.
31. Lipinski CA, Lombardo F, Dominy BW, Feeny P. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Delivery Rev 1997;23:3-25.
32. Clark DE. Rapid calculation of polar molecular surface area and its application to the prediction of transport phenomena. 1. Prediction of intestinal absorption. J Pharm Sci 1999;88:807-814.
33. Abraham MH, Zhao YH, Le J, Hersey A, Eddershaw PJ, Luscombe CN, Reynolds DP, Beck G, Sherborne B, Cooper I. On the mechanism of human intestinal absorption. Eur J Med Chem 2002;37:595-605.
34. Zhao YH, Le J, Abraham MH, Hersey A, Eddershaw PJ, Luscombe CN, Butina D, Beck G, Sherborne B, Cooper I, Platts JA. Evaluation of human intestinal absorption data and subsequent derivation of a quantitative structure-activity relationship (QSAR) with the Abraham descriptors. J Pharm Sci 2001;90:749-784.
35. Zhao YH, Abraham MH, Le J, Hersey A, Luscombe CN, Beck G, Sherborne B, Cooper I. Rate-limited steps of human oral absorption and QSAR studies. Pharm Res 2002;19:1446-1457.
36. 2 -Benzyloxyphenylisocynanide isonitrile was prepared by the method of Obrecht R, Herrmann R, Ugi I. Isocyanide synthesis with phosphoryl chloride and diisopropylamine. Synthesis 1985;4:400-402.
37. Microsomes, from human lymphoblastoid cell lines transfected with cDNA for specific cytochrome P450 enzymes, were obtained from Gentest Corporation (Woburn, MA). Reaction progress was monitored using fluorescent substrates. Each test compound was dissolved in methanol at 5mM and serially diluted to determine IC50 values. A positive control was included for each isozyme.
38. 50 values. A positive control was included for each isozyme.
39. Liddle J, Allen MJ, Borthwick AD, Brooks DP, Davies DE, Edwards RM, Exall AM, Hamlett C, Irving WR, Mason AM, McCafferty GP, Nerozzi F, Peace S, Philp J, Pollard D, Pullen MA, Shabbir SS, Sollis SL, Westfall TD, Woollard PM, Wu C, Hickey DMB. The discovery of GSK221149A: A potent and selective oxytocin antagonist. Bioorg Med Chem Lett 2008;18:90-94.
40. Dimethyl, tert-butyl and isopropyl amides are generally equipotent in the binding assay.
41. McCafferty GP, Pullen MA, Wu C, Edwards RM, Allen MJ, Woollard PM, Borthwick AD, Liddle J, Hickey DMB, Brooks DP, Westfall TD. Use of a novel and highly selective oxytocin receptor antagonist to characterize uterine contractions in the rat. Am J Physiol 2007;293:R299-R305.
42. Reprinted from reference 16 Copyright 2003, (with permission from Elsevier and Dr. Hans H. Zingg).
43. The in-silico predictions (with high levels of confidence) for CNS-penetration of this class of compounds (and in particular Retosiban) have always been low and therefore it was not considered a significant risk.
44. The Safety, Tolerability And Metabolism Of GSK221149A, In Pregnant Women (34-36 Weeks), In Pre-Term Labor. Dr. Jill G. Mauldin. Medical University of South Carolina Newsletter 08 Winter/Spring.
45. GSK's Product Development Pipeline February 2009 (221149 oxytocin antagonist for threatened pre-term labour-Phase ll Clinical trial) [].