Forasartan

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

Forasartan
Clinical data
Other namesSC-52458
Pregnancy
category
  • Not assigned
Routes of
administration		Oral
ATC code
Legal status
Legal status
  • Development halted, never marketed[1]
Pharmacokinetic data
Elimination half-life1–2 hours
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC23H28N8
Molar mass416.522 g·mol−1 g·mol−1
3D model (JSmol)

Indications

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

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

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

The angiotensin II receptor, type 1

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

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

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]

See also

References
  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. 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. PMID 17346243.
  10. 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. 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.
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