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 names	SC-52458
Pregnancy category	Not assigned
Routes of administration	Oral
ATC code	C09CA (WHO)
Legal status
Legal status	Development halted, never marketed[1]
Pharmacokinetic data
Elimination half-life	1–2 hours
Identifiers
IUPAC name 5-[(3,5-Dibutyl-1H-1,2,4-triazol-1-yl)methyl]-2-[2-(2H-tetrazol-5-yl)phenyl]pyridine
CAS Number	145216-43-9
PubChem CID	132706
DrugBank	DB01342
ChemSpider	117146
UNII	065F7WPT0B
KEGG	D04243
ChEBI	CHEBI:141552
ChEMBL	ChEMBL315021
CompTox Dashboard (EPA)	DTXSID70162942
Chemical and physical data
Formula	C23H28N8
Molar mass	416.533 g·mol^−1
3D model (JSmol)	Interactive image
SMILES CCCCC1=NN(C(=N1)CCCC)CC2=CN=C(C=C2)C3=CC=CC=C3C4=NNN=N4
InChI 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

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

• Discovery and development of angiotensin receptor blockers

References

1. Bräse, Stefan; Banert, Klaus (2010). Organic Azides: Syntheses and Applications. New York: Wiley. p. 38. ISBN 978-0-470-51998-1.
2. Knox C, Law V, Jewison T, Liu P, Ly S, Frolkis A, et al. (January 2011). "DrugBank 3.0: a comprehensive resource for 'omics' research on drugs". Nucleic Acids Research. DrugBank. 39 (Database issue): D1035-41. doi:10.1093/nar/gkq1126. PMC 3013709. PMID 21059682.
3. Wishart DS, Knox C, Guo AC, Cheng D, Shrivastava S, Tzur D, et al. (January 2008). "DrugBank: a knowledgebase for drugs, drug actions and drug targets". Nucleic Acids Research. 36 (Database issue): D901-6. doi:10.1093/nar/gkm958. PMC 2238889. PMID 18048412.
4. Wishart DS, Knox C, Guo AC, Shrivastava S, Hassanali M, Stothard P, et al. (January 2006). "DrugBank: a comprehensive resource for in silico drug discovery and exploration". Nucleic Acids Research. 34 (Database issue): D668-72. doi:10.1093/nar/gkj067. PMC 1347430. PMID 16381955.
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): 617–25. doi:10.1097/00005344-199310000-00016. PMID 7505365.
6. 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): 444–50. 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): 8418–56. 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): 656–63. 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): 417–28. doi:10.1042/cs20060342. PMID 17346243.
10. 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): 1179–85. 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): 115–20. 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): 137–52. doi:10.2165/00003088-200241020-00005. PMID 11888333.
13. 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): 110–6. 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): 671–7. doi:10.1016/s0895-7061(96)00500-6. PMID 9194514.