Discovery of N-(3-fluorophenyl)-1-[(4-([(35)-3-methyl-1-piperazinyl]methyl) phenyl)acetyl]-4-piperidinamine (GSK962040), the first small molecule motilin receptor agonist clinical candidate

Journal of Medicinal Chemistry

Volumn 52, Issue 4, 2009, Pages 1180-1189

  Westaway, Susan M ^a   Brown, Samantha L ^a   Fell, Stephen C M ^a   Johnson, Christopher N ^a   MacPherson, David T ^a   Mitchell, Darren J ^a   Myatt, James W ^a   Stanway, Steven J ^a   Seal, Jon T ^a   Stemp, Geoffrey ^a   Thompson, Mervyn ^a   Lawless, Kirk ^a   McKay, Fiona ^a   Muir, Alison I ^a   Barford, Jonathan M ^a   Cluff, Chermaine ^a   Mahmood, Sadhia R ^a   Matthews, Kim L ^a   Mohamed, Shiyam ^a   Smith, Beverley ^a   Stevens, Alexander J ^a   Bolton, Victoria J ^a   Jarvie, Emma M ^a   Sanger, Gareth J ^a   more..

^a GLAXOSMITHKLINE   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

GSK 962040; MOTILIN; MOTILIN RECEPTOR AGONIST; N (3 FLUOROPHENYL) 1 [[4 ((3 METHYL 1 PIPERAZINYL)METHYL]PHENYL]ACETYL] 4 PIPERIDINAMINE; UNCLASSIFIED DRUG;

ARTICLE; CONTROLLED STUDY; DOG; DRUG POTENTIATION; DRUG SELECTIVITY; GASTROINTESTINAL TRACT; NONHUMAN; RABBIT; RAT; STOMACH ANTRUM;

ANIMALS; DOGS; DRUG DISCOVERY; GASTROINTESTINAL AGENTS; GASTROINTESTINAL MOTILITY; HUMANS; MUSCLE CONTRACTION; PIPERAZINES; PIPERIDINES; PYLORIC ANTRUM; RABBITS; RATS; RECEPTORS, GASTROINTESTINAL HORMONE; RECEPTORS, NEUROPEPTIDE;

EID: 64349119324     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm801332q     Document Type: Article

References (32)

1. Abell, T. L.; Bernstein, R. K.; Cutts, T.; Farrugia, G.; Forster, J.; Hasler, W. L.; McCallum, R. W.; Olden, K. W.; Parkman, H. P.; Parrish, C. R.; Pasricha, P. J.; Prather, C. M.; Soffer, E. E.; Twillman, R.; Vinik, A. I. Treatment of gastroparesis: a multidisciplinary clinical review. Neurogastroenterol. Motil. 2006, 18, 263.
2. Hiyama, T.; Yoshihara, M.; Matsuo, K.; Kusunoki, H.; Kamada, T.; Ito, M.; Tanaka, S.; Nishi, N.; Chayama, K.; Haruma, K. Meta-analysis of the effects of prokinetic agents in patients with functional dyspepsia. J. Gastroenterol. Hepatol. 2007, 22, 304-310.
3. Chapman, M. J.; Nguyen, N. Q.; Fraser, R. J. L. Gastrointestinal motility and prokinetics in the critically ill. Curr. Opin. Crit. Care 2007, 13, 187.
4. Peeters, T.; Matthijs, G.; Depoortere, I.; Cachet, T.; Hoogmartens, J.; Vantrappen, G. Erythromycin is a motilin receptor agonist. Am. J. Physiol. 1989, 257, G470.
5. Feighner, S. D.; Tan, C. P.; McKee, K. K.; Palyha, O. C.; Hreniuk, D. L.; Pong, S.-S.; Austin, C. P.; Figueroa, D.; MacNeil, D.; Cascieri, M. A.; Nargund, R.; Bakshi, R.; Abramovitz, M.; Stocco, R.; Kargman, S.; O'Neill, G.; Van Der Ploeg, L. H. T.; Evans, J.; Patchett, A. A.; Smith, R. G.; Howard, A. D. Receptor for motilin identified in the human gastrointestinal system. Science 1999, 284, 2184.
6. Xu, L.; Depoortere, I.; Tomasetto, C.; Zandecki, M.; Tang, M.; Timmermans, J.-P.; Peeters, T. L. Evidence for the presence of motilin, ghrelin, and the motilin and ghrelin receptor in neurons of the myenteric plexus. Resul. Pept. 2005, 124, 119.
7. Takeshita, E.; Matsuura, B.; Dong, M.; Miller, L. J.; Matsui, H.; Onji, M. Molecular characterization and distribution of motilin family receptors in the human gastrointestinal tract. J. Gastroenterol. 2006, 41, 223.
8. (a) Itoh, Z. Motilin and clinical application. Peptides 1997, 18, 593.
9. (b) Sanger, G. J.; Lee, K. Hormones of the gut-brain axis as targets for the treatment of upper gastrointestinal disorders. Nat. Rev. Drus Discovery 2008, 7, 241.
10. (a) Christofides, N. D.; Modlin, I. M.; Fitzpatrick, M. L.; Bloom, S. R. Effect of motilin on the rate of gastric emptying and gut hormone release during breakfast. Gastroenterology 1979, 76, 903.
11. (b) Peeters, T. L.; Muls, E.; Janssens, J.; Urbain, J. L.; Bex, M.; Van Cutsem, E.; Depoortere, I.; De Roo, M.; Vantrappen, G.; Bouillon, R. Effect of motilin on gastric emptying in patients with diabetic gastroparesis. Gastroenterology 1992, 102, 97.
12. Mantides, A.; Xynos, E.; Chrysos, E.; Georgopoulos, N.; Vassilakis, J. S. The effect of erythromycin in gastric emptying of solids and hypertonic liquids in healthy subjects. Am. J. Gastroenterol. 1993, 88, 198.
13. Peeters, T. L. New motilin agonists: a long and winding road. Neurogastroenterol.Motil. 2006, 18,1.
14. Sann, H. Discovery and Development of the Motilin Agonist KC 11458: Pharmacological Characteristics. In Functional Disorders of the Gastrointestinal Tract; Krause, G., Ed.; IOS Press: Amsterdam, The Netherlands, 2005. Russo, A.; Stevens, J. E.; Giles, N.; Krause, G.; O'Donovan, D. G.; Horowitz, M.; Jones, K. L. Effect of the motilin agonist KC 11458 on gastric emptying in diabetic gastroparesis. Aliment. Pharmacol. Ther. 2004, 20, 333-338.
15. (a) Verhagen, M. A. M. T.; Samson, M.; Maes, B.; Geypens, B. J.; Ghoos, Y. F.; Smout, A. J. P. M. Effects of a new motilide, ABT-229, on gastric emptying and postprandial antroduodenal motility in healthy volunteers. Aliment. Pharmacol. Ther. 1997, 11, 1077.
16. (b) Talley, N. J.; Verlinden, M.; Snape, W.; Beker, J. A.; Ducrotte, P.; Dettmer, A.; Brinkhoff, H.; Eaker, E.; Ohning, G.; Miner, P. B.; Mathias, J. R.; Fumagalli, I.; Staessen, D.; Mack, R. J. Failure of a motilin receptor agonist (ABT-229) to relieve the symptoms of functional dyspepsia in patients with and without delayed gastric emptying: a randomized double-blind placebo-controlled trial. Aliment. Pharmacol. Ther. 2000, 14, 1653.
17. (c) Talley, N. J.; Verlinden, M.; Geenen, D. J.; Hogan, R. B.; Riff, D.; McCallum, R. W.; Mack, R. J. Effects of a motilin receptor agonist (ABT-229) on upper gastrointestinal symptoms in type 1 diabetes mellitus: a randomised, double blind, placebo controlled trial. Gut 2001, 49, 395.
18. (a) Tack, J; Peeters, T. What comes after macrolides and other motilin stimulants? Gut 2001, 49, 317.
19. (b) Poitras, P.; Peeters, T. L. Motilin. Curr. Opin. Endocrinol., Diabetes Obes. 2008, 15, 54.
20. (c) Sanger, G. J.; Alpers, D. H. Development of drugs for gastrointestinal motor disorders: translating science to clinical need. Neurosastroenterol. Motil. 2008, 20, 177.
21. (d) Sanger, G. J. Motilin, ghrelin and related neuropeptides as targets for the treatment of GI diseases. Drus Discovery Today 2008, 13, 234.
22. Mccallum, R. W.; Cynshi, O. Efficacy of mitemcinal, a motilin agonist, on gastrointestinal symptoms in patients with symptoms suggesting diabetic gastropathy: a randomized, multi-center, placebo-controlled trial. Aliment. Pharmacol. Ther. 2007, 26, 107.
23. Jasserand, D.; Antel, J.; Preuschoff, U.; Brueckner, R.; Sann, H.; Wurl, M.; Eickelmann, P. PCT Int. Appl. WO 2002092592, CAN 137: 384755, 2002.
24. Li, J. J.; Chao, H.-G.; Wang, H.; Tino, J. A.; Lawrence, R. M.; Ewing, W. R.; Ma, Z.; Yan, M.; Slusarchyk, D.; Seethala, R.; Sun, H.; Li, D.; Burford, N. T.; Stoffel, R. H.; Salyan, M. E.; Li, C. Y.; Witkus, M.; Zhao, N.; Rich, A.; Gordon, D. A. Discovery of a potent and novel motilin agonist. J. Med. Chem. 2004, 47, 1704.
25. Heightman, T. D.; Conway, E.; Corbett, D. F.; Macdonald, G. J.; Stemp, G.; Westaway, S. M.; Celestini, P.; Gagliardi, S.; Riccaboni, M.; Ronzoni, S.; Vaidya, K.; Butler, S.; McKay, F.; Muir, A.; Powney, B.; Winborn, K.; Wise, A.; Jarvie, E. M.; Sanger, G. J. Identification of novel small molecule agonists of the motilin receptor. Bioors. Med. Chem. Lett. 2008, 18, 6423-6428.
26. Westaway, S. M.; Brown, S. L.; Conway, E.; Heightman, T. D.; Johnson, C. N.; Lapsley, K.; Macdonald, G. J.; MacPherson, D. T.; Mitchell, D. J.; Myatt, J. W.; Seal, J. T.; Stanway, S. J.; Stemp, G.; Thompson, M.; Colombo, A.; Consonni, A.; Gagliardi, S.; Roccaboni, M.; Ronzoni, S.; Briggs, M. A.; Matthews, K. L.; Stevens, A. J.; Bolton, V. J.; Jarvie, E. M.; Stratton, S. C.; Sanger, G. J. The discovery of biaryl carboxamides as novel small molecule agonists of the motilin receptor. Bioors. Med. Chem. Lett. 2008, 18, 6429-6436.
27. Johnson, C. N.; Macpherson, D. T.; Stanway, S. J.; Stemp, G.; Thompson, M.; Westaway, S. M. Preparation of Benzylpiperazine Derivatives as Agonists of GPR38 Receptors. PCT Int. Appl. WO 2007012479, 2007.
28. The potency data quoted for compound 6 (and all other compounds) in this paper are those obtained using the recombinant human motilin receptor expressed in a CHO cell line (see Experimental Section for details), whereas that given previously19 was obtained using a HEK293 cell line. There is a shift in potency between the two assay formats, but the rank order of potency remains consistent; see ref 19 for a comparison of potency data for standard compounds. In addition, the CYP inhibition data given in this paper were obtained using enzyme sourced from Cypex whereas those given previously were obtained using enzyme sourced from Gentest; hence, there is some variation in the data quoted in this publication and in ref 19.
29. 50 data quoted are the mean of at least three values with SEM ≤ 0.3 in all cases except for compounds 7 and 8, where n = 2.
30. See Experimental Section for the method used to assess time dependent inhibition (TDI) of CYP3A4.
31. Jarvie, E. M.; North Laidler, V. J.; Corcoran, S.; Bassil, A.; Sanger, G. J. Differences between the abilities of tegaserod and motilin receptor agonists to stimulate gastric motility in vitro. Br. J. Pharmacol. 2007, 150, 455-462.
32. Sanger, G. J.; Westaway, S. M.; Barnes, A. A.; MacPherson, D. T.; Muir, A. I.; Jarvie, E. M.; Bolton, V. N.; Cellek, S.; Naslund, E.; Hellstrom, P. M.; Borman, R. A.; Unsworth, W. P.; Matthews, K. L.; Lee, K. GSK96 2040: a small molecule, selective motilin receptor agonist, effective as a stimulant of human and rabbit gastrointestinal motility. Neurosastroenterol. Motil., in press.