Tirilazad

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Tirilazad
Tirilazad.svg
Clinical data
Other names(8S,10S,13S,14S,16R,17S)-17-[2-[4-(2,6-dipyrrolidin-1-ylpyrimidin-4-yl)piperazin-1-yl]acetyl]-10,13,16-trimethyl-6,7,8,12,14,15,16,17-octahydrocyclopenta[a]phenanthren-3-one
ATC code
Identifiers
  • (16α)-21-[4-(2,6-dipyrrolidin-1-ylpyrimidin-4-yl)piperazin-1-yl]-16-methylpregna-1,4,9(11)-triene-3,20-dione
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
Formula C38H52N6O2
Molar mass 624.874 g·mol−1
3D model (JSmol)
  • O=C(CN4CCN(c2nc(nc(N1CCCC1)c2)N3CCCC3)CC4)[C@H]6[C@H](C)C[C@H]5[C@H]8C(=C/C[C@@]56C)\[C@]/7(/C=C\C(=O)\C=C\7CC8)C
  • InChI=1S/C38H52N6O2/c1-26-22-31-29-9-8-27-23-28(45)10-12-37(27,2)30(29)11-13-38(31,3)35(26)32(46)25-41-18-20-43(21-19-41)34-24-33(42-14-4-5-15-42)39-36(40-34)44-16-6-7-17-44/h10-12,23-24,26,29,31,35H,4-9,13-22,25H2,1-3H3/t26-,29-,31+,35-,37+,38+/m1/s1 Yes check.svgY
  • Key:RBKASMJPSJDQKY-RBFSKHHSSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Tirilazad is a drug that has been proposed to treat acute ischaemic stroke. When tested on animal models, tirilazad protects brain tissue, and reduces brain damage. However, the drug fails to treat, and even worsens a stroke when studied on a human being. [1]

Tirilazad is a 21-aminosteroid and belongs to the "Lazaroid" family of agents. The metabolite of tirilazad is called U-89678 [157744-31-5]. Other known lazaroids found in the data base include the following list of agents: U-74389G [153190-29-5], U-74500 [111640-85-8], U-75412E [130590-09-9] & U-87999 [177949-23-4]. The name comes from Lazarus — the biblical figure raised from the dead — because these compounds were thought to “bring cells back to life” after oxidative injury.

More recently Tirilazad has shown some promising results in treating traumatic brain inhury (TBI). [2]

Synthesis

The chemical synthesis has been reported: [3] [4]
Patent (Example 83; S22 page 59, A22 page 47): [5] Precursor patent: [6]

Tirilazad synthesis.svg

N.B The precursor 4-chloro-2,6-di(pyrrolidin-1-yl)pyrimidine [111669-15-9] (6) finds dual use in the synthesis of 2-MAC (U-78517F) [122003-11-6] as well as for U-83836E (aka PNU-83836E or GNF-Pf-3881) [137018-55-4]. These agents show similar antiinflammatory/antioxidant activity to lazaroids but are not related to steroid hormones.

References

  1. ↑ Bath PM, Iddenden R, Bath FJ, Orgogozo JM, et al. (Tirilazad International Steering Committee) (2001). "Tirilazad for acute ischaemic stroke". The Cochrane Database of Systematic Reviews (4) CD002087. doi:10.1002/14651858.CD002087. PMID   11687138.
  2. ↑ Hall ED, Wang JA, Miller DM, Cebak JE, Hill RL (February 2019). "Newer pharmacological approaches for antioxidant neuroprotection in traumatic brain injury". Neuropharmacology. 145 (Pt B): 247–258. doi:10.1016/j.neuropharm.2018.08.005. PMID   30086292.
  3. ↑ Lednicer D, Mitscher LA (1995). The Organic Chemistry of Drug Synthesis. Vol. 5. Wiley. ISBN   978-0-471-58959-4.
  4. ↑ Jacobsen EJ, McCall JM, Ayer DE, Van Doornik FJ, Palmer JR, Belonga KL, et al. (April 1990). "Novel 21-aminosteroids that inhibit iron-dependent lipid peroxidation and protect against central nervous system trauma". Journal of Medicinal Chemistry. 33 (4): 1145–1151. doi:10.1021/jm00166a010. PMID   2319560.
  5. ↑ WO 1987/001706,Mc Call JM, Ayer DE, Jacobsen EJ, Van Doornik FJ, Palmer JR, Karnes HA,"C20 through c26 amino steroids",published 26 March 1987, assigned to The Upjohn Company
  6. ↑ US patent 2864834,Mendelsohn H, Smith LL, Origoni VE,"Pregnatetraenes and method of preparing the same",issued 16 December 1958, assigned to Wyeth Holdings LLC
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