Forasartan

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Forasartan
Forasartan.svg
Systematic (IUPAC) name
5-[(3,5-dibutyl-1H-1,2,4-triazol-1-yl)methyl]-2-[2-(2H-tetrazol-5-yl)phenyl]pyridine
Clinical data
  • Not assigned
Legal status
  • Development halted, never marketed[1]
Routes Oral
Pharmacokinetic data
Half-life 1–2 hours
Identifiers
CAS number 145216-43-9
ATC code C09CA
PubChem CID 132706
DrugBank DB01342
ChemSpider 117146
UNII 065F7WPT0B
KEGG D04243
ChEBI CHEBI:239233
ChEMBL CHEMBL315021
Synonyms SC-52458
Chemical data
Formula C23H28N8 
Molecular mass 416.522 g·mol−1

Forasartan, otherwise known as the compound SC-52458, is a nonpeptide angiotensin II receptor antagonist (ARB, AT1 receptor blocker).[2][3][4][5]

Indications[edit]

Forasartan is indicated for the treatment of hypertension [6] and, similar to other ARBs, it protects the kidneys from kidney blood vessel damage caused by increased kidney blood pressure by blocking renin-angiotensin system activation.[7]

Administration[edit]

Forasartan is administered in the active oral form [6] which means that it must go through first pass metabolism in the liver. The dose administered ranges between 150 mg-200 mg daily.[6] Increasing to more than 200 mg daily does not offer significantly greater AT1 receptor inhibition.[6] Forasartan is absorbed quickly in the GI, and within an hour it becomes significantly biologically active.[6] Peak plasma concentrations of the drug are reached within one hour.[6]

Contraindications[edit]

Negative side effects of Forasartan are similar to other ARBs, and include hypotension and hyperkalemia.[8] There are no drug interactions identified with forasartan.[6]

Pharmacology[edit]

The angiotensin II receptor, type 1[edit]

Angiotensin II binds to AT1 receptors, increases contraction of vascular smooth muscle, and stimulates aldosterone resulting in sodium reabsorption and increase in blood volume.[9] Smooth muscle contraction occurs due to increased calcium influx through the L-type calcium channels in smooth muscle cells during the plateau component, increasing the intracellular calcium and membrane potential which sustain depolarization and contraction.[10]

Effects of forasartan[edit]

Forasartan is a competitive and reversible ARB that competes with the angiotensin II binding site on AT1 [11] and relaxes vascular smooth muscle,[10] resulting in decreased blood pressure. Forasartan has a high affinity for the AT1 receptor (IC50=2.9 +/- 0.1nM).[12] In dogs, it was found to block the pressor response of Angiotensin II with maximal inhibition, 91%.[10] Forasartan administration selectively inhibits L-type calcium channels in the plateau component of the smooth muscle cells, favoring relaxation of the smooth muscle.[10] Forasartan also decreases heart rate by inhibiting the positive chronotropic effect of high frequency preganglionic stimuli.[13]

Scarce use of Forasartan[edit]

Even though experiments have been conducted on rabbits,[6] guinea pigs,[10] dogs [14] and humans,[6][13] forasartan is not a popular drug of choice for hypertension due to its short duration of action; forasartan is less effective than losartan.[6] Research demonstrates that forasartan is also significantly less potent than losartan.[6]

Synthesis[edit]

Forasartan synthesis:[15]

N.B. Same journal issue contains many similar analogs.

See also[edit]

References[edit]

  1. ^ Bräse, Stefan; Banert, Klaus (2010). Organic Azides: Syntheses and Applications. New York: Wiley. p. 38. ISBN 0-470-51998-3. 
  2. ^ Knox, C; Law V (2011). "a comprehensive resource for 'omics' research on drugs". Nucleic Acids Res. DrugBank 39: D1035–41. doi:10.1093/nar/gkq1126. PMC 3013709. PMID 21059682. 
  3. ^ Wishart, DS; Knox C (2008). "a knowledgebase for drugs, drug actions and drug targets". Nucleic Acids Res 36: D901–6. doi:10.1093/nar/gkm958. PMC 2238889. PMID 18048412. 
  4. ^ Wishart, DS; Knox C (2006). "a comprehensive resource for in silico drug discovery and exploration". Nucleic Acids Res 34: D668–72. doi:10.1093/nar/gkj067. PMC 1347430. PMID 16381955. 
  5. ^ Olins, GM; Corpus VM (1993). "Pharmacology of SC-52458, an orally active, nonpeptide angiotensin AT1 receptor antagonist". Journal of Cardiovascular Pharmacology 22 (4): 617–625. doi:10.1097/00005344-199310000-00016. 
  6. ^ a b c d e f g h i j k Hagmann, M; Nussberger J (1997). "an Orally Active Angiotensin II-Receptor Antagonist: Inhibition of Blood Pressure Response to Angiotensin II Challenges and Pharmacokinetics in Normal Volunteers". Journal of Cardiovascular Pharmacology 29 (4): 444–450. doi:10.1097/00005344-199704000-00003. 
  7. ^ Naik, P; Murumkar P (2010). "Angiotensin II receptor type 1 (AT1) selective nonpeptidic antagonists—A perspective". Bioorganic & Medicinal Chemistry 18 (24): 8418–8456. doi:10.1016/j.bmc.2010.10.043. 
  8. ^ Venkata, S; Ram MD (2008). "Angiotensin Receptor Blockers: Current Status and Future Prospects". The American Journal of Medicine 121 (8): 656–663. doi:10.1016/j.amjmed.2008.02.038. 
  9. ^ Higuchi, S; Ohtsu H (2007). "Angiotensin II signal transduction through the AT1 receptor: novel insights into mechanisms and pathophysiology". Clinical Science 112 (8): 417–428. doi:10.1042/cs20060342. 
  10. ^ a b c d e Usune, S; Furukawa T (1996). "Effects of SC-52458, a New Nonpeptide Angiotensin II Receptor Antagonist, on Increase in Cytoplasmic Ca 2+ Concentrations and Contraction Induced by Angiotensin II and K+-Depolarization in Guinea-Pig Taenia Coli". General Pharmacology 27 (7): 1179–1185. doi:10.1016/s0306-3623(96)00058-4. 
  11. ^ Olins, GM; Chen ST (1995). "Elucidation of the Insurmountable Nature of an Angiotensin Receptor". Molecular Pharmacology 47 (1): 115–120. 
  12. ^ Csajka, C; Buclin T (2002). "Population Pharmacokinetic-Pharmacodynamic Modelling of Angiotensin Receptor Blockade in Healthy Volunteers". Clinical Pharmacokinetics 41 (2): 137–152. doi:10.2165/00003088-200241020-00005. 
  13. ^ a b Kushiki, K; Yamada H (2001). "Upregulation of Immunoreactive Angiotensin II Release and Angiotensinogen mRNA Expression by High-Frequency Preganglionic Stimulation at the Canine Cardiac Sympathetic Ganglia". Circulation Research 88 (1): 110–116. doi:10.1161/01.res.88.1.110. 
  14. ^ McMahon, EG; Yang PC (1997). "Effects of SC-52458, an Angiotensin AT1 Receptor Antagonist, in the Dog". American Journal of Hypertension 10 (6): 671–677. 
  15. ^ Glinka, T. W.; De Laszlo, S. E.; Siegl, P. K. S.; Chang, R. S.; Kivlighn, S. D.; Schorn, T. S.; Faust, K. A.; Chen, T. B.; Zingaro, G. J.; Lotti, V. J.; Greenlee, W. J. (1994). "A new class of balanced AT1/AT2 angiotensin II antagonists: Quinazolinone AII antagonists with acylsulfonamide and sulfonylcarbamate acidic functionalities". Bioorganic & Medicinal Chemistry Letters 4: 81. doi:10.1016/S0960-894X(01)81126-4.  edit