Discovery process and pharmacological characterization of 2-(S)-(4-fluoro-2-methylphenyl)piperazine-1-carboxylic acid [1-(R)-(3,5-bis- trifluoromethylphenyl)ethyl]methylamide (vestipitant) as a potent, selective, and orally active NK1 receptor antagonist

Journal of Medicinal Chemistry

Volumn 52, Issue 10, 2009, Pages 3238-3247

  Di Fabio, Romano ^a   Griffante, Cristiana ^a   Alvaro, Giuseppe ^a   Pentassuglia, Giorgio ^a,b   Pizzi, Domenica A ^a   Donati, Daniele ^a,c   Rossi, Tino ^a   Guercio, Giuseppe ^a   Mattioli, Mario ^a   Cimarosti, Zadeo ^a   Marchioro, Carla ^a   Provera, Stefano ^a   Zonzini, Laura ^a   Montanari, Dino ^a   Melotto, Sergio ^a   Gerrard, Philip A ^a   Trist, David G ^a   Ratti, Emiliangelo ^a   Corsi, Mauro ^a  

^a GSK   (Italy)

^b E Pharma Trento SpA   (Italy)

^c NERVIANO MEDICAL SCIENCES   (Italy)

Author keywords

[No Author keywords available]

Indexed keywords

(2R) N [(3,5 BIS (TRIFLUOROMETHYL)PHENYL)METHYL] 2 (4 FLUORO 2 METHYLPHENYL) N METHYL 1 PIPERAZINECARBOXAMIDE; (2S) N [(3,5 BIS (TRIFLUOROMETHYL)PHENYL)METHYL] 2 (4 FLUORO 2 METHYLPHENYL) N METHYL 1 PIPERAZINECARBOXAMIDE; 2 (R) (4 FLUORO 2 METHYLPHENYL)PIPERAZINE 1 CARBOXYLIC ACID [1 (R) (3,5 BIS TRIFLUOROMETHYLPHENYL)ETHYL]METHYLAMIDE ACETATE; 2 (R) (4 FLUORO 2 METHYLPHENYL)PIPERAZINE 1 CARBOXYLIC ACID [1 (S) (3,5 BIS TRIFLUOROMETHYLPHENYL)ETHYL]METHYLAMIDE ACETATE; 2 (S) (4 FLUORO 2 METHYLPHENYL)PIPERAZINE 1 CARBOXYLIC ACID [1 (R) (3,5 BIS TRIFLUOROMETHYLPHENYL)ETHYL]METHYLAMIDE ACETATE; 2 (S) (4 FLUORO 2 METHYLPHENYL)PIPERAZINE 1 CARBOXYLIC ACID [1 (S) (3,5 BIS TRIFLUOROMETHYLPHENYL)ETHYL]METHYLAMIDE ACETATE; 3 [3,5 BIS(TRIFLUOROMETHYL)BENZYLOXY] 2 PHENYLPIPERIDINE; [(3,5 BIS (TRIFLUOROMETHYL)PHENYL)METHYL] 2 (4 FLUORO 2 METHYLPHENYL) N METHYL 1 PIPERAZINECARBOXAMIDE; NEUROKININ 1 RECEPTOR; NEUROKININ 1 RECEPTOR ANTAGONIST; PHENYLPIPERAZINE DERIVATIVE; PIPERAZINE DERIVATIVE; UNCLASSIFIED DRUG; VESTIPITANT;

ANIMAL CELL; ANIMAL EXPERIMENT; ARTICLE; BINDING AFFINITY; CONCENTRATION RESPONSE; CONTROLLED STUDY; DOSE RESPONSE; DRUG ANTAGONISM; DRUG CLEARANCE; DRUG HALF LIFE; DRUG MECHANISM; DRUG SYNTHESIS; NONHUMAN; STRUCTURE ACTIVITY RELATION;

ADMINISTRATION, ORAL; ANIMALS; CHO CELLS; CRICETINAE; CRICETULUS; DRUG DISCOVERY; DRUG EVALUATION, PRECLINICAL; GERBILLINAE; PHARMACOKINETICS; PIPERAZINES; PIPERIDINES; RECEPTORS, NEUROKININ-1; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 66249126788     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm900023b     Document Type: Article

References (27)

1. Chahl, L. A. Tackykinins and neuropsychiatric disorders. Curr. Drug Targets 2006, 7, 993-1103
2. Ebner, K.; Singewald, N. The role of substance P in stress and anxiety responses. Amino Acids 2006, 31, 251-272. (Pubitemid 44537051)
3. 1 receptor have a role in depression and anxiety? Curr. Pharm. Des. 2005, 11, 1529-1547.
4. Nemeroff, C. B. Recent advances in the neurobiology of depression. Psychopharmacol. Bull. 2002, 36, 6-23.
5. Mantyh, P. W. Neurobiology of substance P and NK1 receptor. J. Clin. Psychiatry 2002, 63, 6-10.
6. Wong, M. L.; Licinio, J. From monoamine to genomic targets: a paradigm shift for drug discovery in depression. Nat. Rev. Drug Discovery 2004, 3, 136-151.
7. Holtzheimer, P. E.; Nemeroff, C. B. Novel targets for antidepressant therapies. Curr. Psychiatry Rep. 2008, 10, 465-473.
8. Patacchini, R.; Maggi, C. A. Peripheral tachikinin receptors as targets for new drugs. Eur. J. Pharmacol. 2001, 429, 13-21.
9. 1) antagonists. TIPS 1999, 20, 485-490.
10. Kramer, M. S.; Cutler, N.; Feighner, J.; Shrivastava, R.; Carman, J.; Sramek, J. J.; Reines, S. A.; Liu, G.; Snavely, D.; Wyatt-Knowles, E.; Hale, J. J.; Mills, S. G.; MacCoss, M.; Swain, C. J.; Harrison, T.; Hill, R. G.; Hefti, F.; Scolnick, E. M.; Cascieri, M. A.; Chicchi, G. G.; Sadowski, S.; Williams, A. R.; Hewson, L.; Smith, D.; Carlson, E. J.; Hargreaves, R. J.; Rupniak, N. M. J. Distinct mechanism for antidepressant activity by blockade of central substance P receptors. Science 1998, 281, 1640-1645. (Pubitemid 28435572)
11. Kramer, M. S.; Winokur, A.; Kelsey, J.; Preskorn, S. H.; Rothschild, A. J.; Snavely, D.; Ghosh, K.; Ball, W. A.; Reines, S. A; Munjack, D.; Apter, J. T; Cunningham, L.; Kling, M.; Bari, M.; Getson, A.; Lee, Y. Demonstration of the efficacy and safety of a novel substance P (NK1) receptor antagonist in major depression. Neuropsychopharmacology 2004, 29, 385-392. (Pubitemid 38180456)
12. 1 Receptor Antagonist in Patients with Major Depression. Presented at the 42nd Annual Meeting of the New Clinical Drug Evaluation Unit (NCDEU), Boca Raton, FL, Jun 12, 2002.
13. In a phase II trial in 300 social anxiety disorder patients, NKP-608 at 0.1 and 1.0 mg for 8 weeks improved the Liebowitz social anxiety scale of placebo with no adverse events (Company Web Page, Novartis, Jan 16, 2001).
14. Furmark, T.; Appel, L.; Michelgård, A.; Wahlstedt, K.; Åhs, F.; Zancan, S.; Jacobsson, E.; Flyckt, K.; Grohp, M.; Bergström, M.; Merlo-Pich, E.; Nilsson, L. G.; Bani, M.; Långström, B.; Fredrikson, M. Cerebral blood flow changes after treatment of social phobia with the neurokinin-1 antagonist GR205171, citalopram, or placebo. Biol. Psychiatry 2005, 58, 132-142. (Pubitemid 41008130)
15. Ranka, K.; Krishnan, R. Clinical experience with substance P receptor (NK1) antagonists in depression. J. Clin. Psychiatry 2002, 63, 25-29.
16. Herpfer, I.; Lieb, K. Substance P receptor antagonists in psychiatry: rationale for development and therapeutic potential. CNS Drugs 2005, 19, 275-293. (Pubitemid 40593599)
17. 1 receptor antagonists: the identification of an exceptionally potent orally active antiemetic compound. Bioorg. Med. Chem. Lett. 1996, 6, 1015-1020.
18. 1 receptor binding profile in gerbil and human brain. Br. J. Pharmacol. 2006, 148, 39-45.
19. 1 receptors by use of the nonpeptide antagonist CP-96,345. Br. J. Pharmacol. 1991, 104, 292-293.
20. A preliminary part of this work was reported at the ECNP meeting (Amsterdam) in 2005: P.4.027, P.4.052, P.4.053.
21. B estimates for a series of muscarinic and histamine H2-receptor antagonists. Br. J. Pharmacol. 1988, 94, 264-274.
22. i mobilisation, cardiovascular and dural extravasation assays. Eur. J. Pharmacol. 1996, 317, 129-135.
23. Vauquelin, G.; Van Liefde, I. V. Slow antagonist dissociation and long-lasting in vivo receptor protection. TIPS 2006, 27, 355-359. (Pubitemid 43963183)
24. Beattie, D. T.; Beresford, I. J.; Connor, H. E.; Marshall, F. H.; Hawcock, A. B.; Hagan, R. M.; Bowers, J.; Birch, P. J.; Ward, P. The pharmacology of GR203040, a novel, potent and selective non-peptide tachykinin NK1 receptor antagonist. Br. J. Pharmacol. 1995, 116, 3149-3157.
25. Rupniak, N. M. J.; Williams, A. R. Differential inhibition of foot tapping and chromodacryorrhoea in gerbils by CNS penetrant and non-penetrant tachykinin NK-1 receptor antagonists. Eur. J. Pharmacol. 1994, 265, 179-183.
26. Cheng, Y.; Prusoff, W. H. Relationship between the inhibition constant (K1) and the concentration of inhibitor which causes 50% inhibition (I50) of an enzymatic reaction. Biochem. Pharmacol. 1973, 22, 3099-3108.
27. Arunlakshana, O.; Schild, H. O. Some quantitative uses of drug antagonists. Br. J. Pharmacol. 1959, 14, 48-58.