Forasartan

Forasartan
Clinical data
Other namesSC-52458
Pregnancy
category
  • Not assigned
Routes of
administration		Oral
ATC code
Legal status
Legal status
  • Development halted, never marketed
Pharmacokinetic data
Elimination half-life1–2 hours
Identifiers
  • 5-[(3,5-Dibutyl-1H-1,2,4-triazol-1-yl)methyl]-2-[2-(2H-tetrazol-5-yl)phenyl]pyridine
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC23H28N8
Molar mass416.533 g·mol−1
3D model (JSmol)
  • CCCCC1=NN(C(=N1)CCCC)CC2=CN=C(C=C2)C3=CC=CC=C3C4=NNN=N4
  • InChI=1S/C23H28N8/c1-3-5-11-21-25-22(12-6-4-2)31(28-21)16-17-13-14-20(24-15-17)18-9-7-8-10-19(18)23-26-29-30-27-23/h7-10,13-15H,3-6,11-12,16H2,1-2H3,(H,26,27,29,30)
  • Key:YONOBYIBNBCDSJ-UHFFFAOYSA-N

Forasartan, otherwise known as the compound SC-52458, is a nonpeptide angiotensin II receptor antagonist (ARB, AT1 receptor blocker).

Indications

Forasartan is indicated for the treatment of hypertension 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.

Administration

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

Contraindications

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

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. 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.

Effects

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

Scarce use

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

See also

References

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  5. ↑ Olins GM, Corpus VM, Chen ST, McMahon EG, Palomo MA, McGraw DE, et al. (October 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. PMID 7505365. S2CID 93468.
  6. 1 2 3 4 5 6 7 8 9 10 11 Hagmann M, Nussberger J, Naudin RB, Burns TS, Karim A, Waeber B, Brunner HR (April 1997). "SC-52458, 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. PMID 9156352.
  7. ↑ Naik P, Murumkar P, Giridhar R, Yadav MR (December 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. PMID 21071232.
  8. ↑ Ram CV (August 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. PMID 18691475.
  9. ↑ Higuchi S, Ohtsu H, Suzuki H, Shirai H, Frank GD, Eguchi S (April 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. S2CID 27624282.
  10. 1 2 3 4 5 Usune S, Furukawa T (October 1996). "Effects of SC-52458, a new nonpeptide angiotensin II receptor antagonist, on increase in cytoplasmic Ca2+ 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. PMID 8981065.
  11. ↑ Olins GM, Chen ST, McMahon EG, Palomo MA, Reitz DB (January 1995). "Elucidation of the insurmountable nature of an angiotensin receptor antagonist, SC-54629". Molecular Pharmacology. 47 (1): 115–120. PMID 7838120.
  12. ↑ Csajka C, Buclin T, Fattinger K, Brunner HR, Biollaz J (2002). "Population pharmacokinetic-pharmacodynamic modelling of angiotensin receptor blockade in healthy volunteers". Clinical Pharmacokinetics. 41 (2): 137–152. doi:10.2165/00003088-200241020-00005. PMID 11888333. S2CID 13185772.
  13. 1 2 Kushiku K, Yamada H, Shibata K, Tokunaga R, Katsuragi T, Furukawa T (January 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. PMID 11139482.
  14. ↑ McMahon EG, Yang PC, Babler MA, Suleymanov OD, Palomo MA, Olins GM, Cook CS (June 1997). "Effects of SC-52458, an angiotensin AT1 receptor antagonist, in the dog". American Journal of Hypertension. 10 (6): 671–677. doi:10.1016/s0895-7061(96)00500-6. PMID 9194514.