Zaurazrast

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Structural formula
Structure of Zaurategrast
General
Non-proprietary name Zaurazrast
other names
  • (2 S ) -2 - [(2-Bromo-3-oxospiro [3.5] non-1-en-1-yl) amino] -3- {4 - [(2,7-naphthyridin-1-yl) amino ] phenyl} propanoic acid ( IUPAC )
  • CDP323
Molecular formula C 26 H 25 BrN 4 O 3
External identifiers / databases
CAS number 455264-31-0
EC number 630-608-7
ECHA InfoCard 100.158.922
PubChem 10186367
ChemSpider 8361869
Wikidata Q166806
Drug information
Drug class

α4 integrin inhibitors

properties
Molar mass 521.41 g mol −1
safety instructions
GHS labeling of hazardous substances
08 - Dangerous to health

Caution

H and P phrases H: 361
P: ?
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Zaurategrast (CDP323) is an experimental drug that has been studied for its suitability for the treatment of multiple sclerosis (MS). It is an α4 integrin inhibitor. Zaurategrast is a small chemical molecule that is used as a prodrug .

Mechanism of action

Inflammation leads to the migration of white blood cells ( leukocytes ) into the affected tissue. In immune diseases such as MS, the otherwise useful cells often have a destructive effect through excessive reactions. Zaurategrast inhibits the directed migration of these white blood cells through the vessel wall into the inflamed tissue. Therefore, it was suggested that Zaurategrast could potentially protect nerve cells from attack by misdirected destructive white blood cells. The monoclonal antibody natalizumab also shows this mode of action.

Effectiveness in animal models

Zaurategrast was investigated in chronic experimental autoimmune encephalomyelitis (EAE) of the house mouse . Both when given prophylactically (before the onset of the disease) and when given therapeutically (after the onset of the disease), the drug significantly reduced the severity of the disease.

Clinical examinations

The safety and tolerability of Zaurategrast and its pharmacokinetic properties were investigated in 75 healthy male and female volunteers in three studies. At oral doses up to 1000 mg twice daily, administered for seven days, no significant differences were for the administration of placebo found. There was no influence of the subjects' gender on the results. The inhibition of the α4 integrin function could be sustained over a dosage interval of 12 to 24 hours.

In June 2007, a study in MS patients began in Europe and the USA. The aim in this study was to treat more than 200 MS patients who previously had insufficient treatment success with beta interferons . Two different dosages of Zaurategrast and placebo were used in the study. The study was discontinued in mid-2009 after an interim evaluation.

History

Zaurategrast was originally synthesized by the British biotech company Celltech (now UCB SA ) and initially operated under its development code CDP323 .

In October 2006, UCB agreed to collaborate with Biogen Idec for development in MS as well as other potential applications . In mid-2009, UCB and Biogen announced that the Phase II study had been discontinued and further development was discontinued. The international non-proprietary name Zaurategrast was awarded in 2010 by the WHO.

Individual evidence

  1. ↑ Template: CL Inventory / not harmonized There is not yet a harmonized classification for this substance . A labeling of Ct-7758 in the Classification and Labeling Inventory of the European Chemicals Agency (ECHA), accessed on December 21, 2018, is reproduced from a self-classification by the distributor .
  2. ↑ A. Schülé, C. Ates, M. Palacio et al: Monitoring and Control of Genotoxic Impurity Acetamide in the Synthesis of Zaurategrast Sulfate. In: Org Process Res Dev . 2010; Epub February 11, 2010. doi: 10.1021 / op900330e
  3. ↑ G. Watt, V. Gauden, K. McNeil et al.: Effect of CDP323, a small molecule VLA-4 antagonist, on chronic experimental allergic encephalomyelitis in C57Bl / 6 mice . ( Memento of October 7, 2007 in the Internet Archive ) ECTRIMS 2005; accessed September 11, 2007.
  4. ↑ M. Baker, A. Shock, T. Parton et al .: Pharmacokinetic and pharmacodynamic properties of the VLA-4 inhibitor CDP323 . ( Memento of October 7, 2007 in the Internet Archive ) ECTRIMS 2006; accessed September 11, 2007.
  5. ↑ C. Polman, J. Bowen, F. Barkhof et al .: Double-Blind, Placebo-Controlled Randomized Phase II Serial MRI, Safety and Tolerability Study of Two Doses of CDP323 in Subjects with Relapsing Forms of Multiple Sclerosis over 24 Weeks. , AAN Annual Meeting Toronto 2010. Presentation S21.002. Accessed March 21, 2020.
  6. ^ RJ Davenport, JR Munday: Alpha4-integrin antagonism - an effective approach for the treatment of inflammatory diseases? In: Drug Discov Today . 12, 2007, pp. 569-576. PMID 17631252
  7. ↑ Press release UCB SA (PDF, English ; 101 kB) October 2, 2006; accessed September 11, 2007.
  8. ↑ UCB and Biogen Idec discontinuation phase II clinical trial of CDP323. In: Hospital Pharmacy Europe. July 1, 2009, accessed on March 21, 2020 (English, press release).
  9. ^ World Health Organization: Recommended International Nonproprietary Names: Pre-publication. List 63 (PDF, English ; 270 kB). 2010. Accessed March 10, 2010.

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