MedKoo product information:

Vestipitant

Vestipitant is a drug developed by GlaxoSmithKline which acts as a selective antagonist for the NK1 receptor. It is under development as a potential antiemetic and anxiolytic drug, and as a treatment for tinnitus.

Vestipitant possessed high affinity for human NK(1) receptors (pK(i), 9.4), and potently blocked Substance P-mediated phosphorylation of Extracellular-Regulated-Kinase. In vivo, it occupied central NK(1) receptors in gerbils (Inhibitory Dose(50), 0.11 mg/kg). At similar doses, it abrogated nociception elicited by formalin in gerbils, and blocked foot-tapping and locomotion elicited by the NK(1) agonist, GR73632, in gerbils and guinea pigs, respectively. Further, vestipitant attenuated fear-induced foot-tapping in gerbils, separation-induced distress-vocalizations in guinea pigs, marble-burying behaviour in mice, and displayed anxiolytic actions in Vogel conflict and fear-induced ultrasonic vocalization procedures in rats. These actions were mimicked by CP99,994, L733,060 and GR205,171 which acted stereoselectively vs its less active isomer, GR226,206. In conclusion, vestipitant is a potent NK(1) receptor antagonist: its actions support the utility of NK(1) receptor blockade in the alleviation of anxiety and, possibly, depression. [source: Eur Neuropsychopharmacol. 2008 Oct;18(10):729-50. Epub 2008 Jul 26. Cellular and behavioural profile of the novel, selective neurokinin1 receptor antagonist, vestipitant: a comparison to other agents. Brocco M, Dekeyne A, Mannoury la Cour C, Touzard M, Girardon S, Veiga S, de Nanteuil G, deJong TR, Olivier B, Millan MJ. Psychopharmacology Department, Institut de Recherches Servier, Centre de Recherches de Croissy, 125 chemin de Ronde, Croissy/Seine, Paris, France.]

Current developer:    GlaxoSmithKline.

Synthetic Process of Vestipitant

The following synthetic route was reported by Giuseppe Guercio et al from GlaxoSmithKline:

The initial chemical development synthetic route, derived from the one used by medicinal chemistry, involved several hazardous reagents, gave low yields and produced high levels of waste. Through a targeted process of research and development, application of novel techniques and extensive route scouting, a new synthetic route for GW597599 was developed. This paper reports the optimisation work of the third and last stage in the chemical synthesis of GW597599 and the development of a pilot-plant-suitable process for the manufacturing of optically pure arylpiperazine derivative 1. In particular, the process eliminated the use of triphosgene in the synthesis of an intermediate carbamoyl chloride, substantially enhancing safety, overall yield, and throughput.

source:

1. Giuseppe Guercio*†, Sergio Bacchi*†, Alcide Perboni†, Corinne Leroi§, Francesco Tinazzi†, Ilaria Bientinesi†, Marie Hourdin, Michael Goodyear†, Stefano Curti†, Stefano Provera‡ and Zadeo Cimarosti†. Synthesis of the NK1 Receptor Antagonist GW597599. Part 3: Development of a Scalable Route to a Key Chirally Pure Arylpiperazine Urea, A Happy End. Org. Process Res. Dev., 2009, 13 (6), pp 1100–1110. DOI: 10.1021/op9002032,

2. Giuseppe Guercio*†, Angelo Maria Manzo†, Michael Goodyear†, Sergio Bacchi†, Stefano Curti† and Stefano Provera‡
Synthesis of the NK1 Receptor Antagonist GW597599. Part 2: Development of a Scalable Route to a Key Chirally Pure Arylpiperazine, Org. Process Res. Dev., 2009, 13 (3), pp 489–493. DOI: 10.1021/op8002823

3. Giuseppe Guercio*, Sergio Bacchi*, Michael Goodyear, Antonella Carangio, Francesco Tinazzi and Stefano Curti Synthesis of the NK1 Receptor Antagonist GW597599. Part 1: Development of a Scalable Route to a Key Chirally Pure Arylpiperazine. Org. Process Res. Dev., 2008, 12 (6), pp 1188–1194. DOI: 10.1021/op800146d

1: Di Fabio R, Alvaro G, Griffante C, Pizzi DA, Donati D, Mattioli M, Cimarosti Z, Guercio G, Marchioro C, Provera S, Zonzini L, Montanari D, Melotto S, Gerrard PA, Trist DG, Ratti E, Corsi M. Discovery and biological characterization of (2R,4S)-1'-acetyl-N-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-2-(4-fluoro-2- methylphenyl)-N-methyl-4,4'-bipiperidine-1-carboxamide as a new potent and selective neurokinin 1 (NK1) receptor antagonist clinical candidate. J Med Chem. 2011 Feb 24;54(4):1071-9. Epub 2011 Jan 13. PubMed PMID: 21229983.

2: Gannon RL, Lungwitz E, Batista N, Hester I, Huntley C, Peacock A, Delagrange P, Millan MJ. The benzodiazepine diazepam demonstrates the usefulness of Syrian hamsters as a model for anxiety testing: evaluation of other classes of anxiolytics in comparison to diazepam. Behav Brain Res. 2011 Mar 17;218(1):8-14. Epub 2010 Nov 20. PubMed PMID: 21094664.

3: Provera S, Guercio G, Turco L, Curcuruto O, Alvaro G, Rossi T, Marchioro C. Application of LC-NMR to the identification of bulk drug impurities in NK1 antagonist GW597599 (vestipitant). Magn Reson Chem. 2010 Jul;48(7):523-30. PubMed PMID: 20535779.

4: Provera S, Martini L, Guercio G, Turco L, Costa L, Marchioro C. Application of LC-NMR and HR-NMR to the characterization of biphenyl impurities in the synthetic route development for vestipitant, a novel NK1 antagonist. J Pharm Biomed Anal. 2010 Nov 2;53(3):389-95. Epub 2010 Apr 29. PubMed PMID: 20478677.

5: Sabbatini FM, Di Fabio R, Griffante C, Pentassuglia G, Zonzini L, Melotto S, Alvaro G, Capelli AM, Pippo L, Perdona' E, St Denis Y, Costa S, Corsi M. Synthesis and pharmacological characterization of constrained analogues of Vestipitant as in vitro potent and orally active NK(1) receptor antagonists. Bioorg Med Chem Lett. 2010 Jan 15;20(2):623-7. Epub 2009 Nov 20. PubMed PMID: 19963378.

6: Di Fabio R, Griffante C, Alvaro G, Pentassuglia G, Pizzi DA, Donati D, Rossi T, Guercio G, Mattioli M, Cimarosti Z, Marchioro C, Provera S, Zonzini L, Montanari D, Melotto S, Gerrard PA, Trist DG, Ratti E, Corsi M. 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. J Med Chem. 2009 May 28;52(10):3238-47. PubMed PMID: 19388677.

7: Brocco M, Dekeyne A, Mannoury la Cour C, Touzard M, Girardon S, Veiga S, de Nanteuil G, deJong TR, Olivier B, Millan MJ. Cellular and behavioural profile of the novel, selective neurokinin1 receptor antagonist, vestipitant: a comparison to other agents. Eur Neuropsychopharmacol. 2008 Oct;18(10):729-50. Epub 2008 Jul 26. PubMed PMID: 18657401.

8: Reddy GK, Gralla RJ, Hesketh PJ. Novel neurokinin-1 antagonists as antiemetics for the treatment of chemotherapy-induced emesis. Support Cancer Ther. 2006 Apr 1;3(3):140-2. PubMed PMID: 18632487.

9. Giuseppe Guercio*†, Sergio Bacchi*†, Alcide Perboni†, Corinne Leroi§, Francesco Tinazzi†, Ilaria Bientinesi†, Marie Hourdin, Michael Goodyear†, Stefano Curti†, Stefano Provera‡ and Zadeo Cimarosti†. Synthesis of the NK1 Receptor Antagonist GW597599. Part 3: Development of a Scalable Route to a Key Chirally Pure Arylpiperazine Urea, A Happy End. Org. Process Res. Dev., 2009, 13 (6), pp 1100–1110. DOI: 10.1021/op9002032,

10. Giuseppe Guercio*†, Angelo Maria Manzo†, Michael Goodyear†, Sergio Bacchi†, Stefano Curti† and Stefano Provera‡
Synthesis of the NK1 Receptor Antagonist GW597599. Part 2: Development of a Scalable Route to a Key Chirally Pure Arylpiperazine, Org. Process Res. Dev., 2009, 13 (3), pp 489–493. DOI: 10.1021/op8002823

11. Giuseppe Guercio*, Sergio Bacchi*, Michael Goodyear, Antonella Carangio, Francesco Tinazzi and Stefano Curti Synthesis of the NK1 Receptor Antagonist GW597599. Part 1: Development of a Scalable Route to a Key Chirally Pure Arylpiperazine. Org. Process Res. Dev., 2008, 12 (6), pp 1188–1194. DOI: 10.1021/op800146d