Description
Sarpogrelate hydrochloride, a potent and selective serotonin 5-HT2 receptor
antagonist, was launched in Japan as an antithrombotic. It exhibits inhibition of ex vivo
platelet aggregation stimulated by serotonin in combination with collagen and suppression of
blood vessel constriction mediated by 5-HT2 in vitro. Its antithrombotic effects have been
demonstrated in several in vivo experimental models including reduction of the mortality rate in
acute pulmonary thromboembolic disease, arterial thrombosis, and peripheral obstructive
disease. Sarpogrelate has been shown to be especially useful as an antiplatelet agent for
patients with Type 2 diabetes mellitus, in whom 5-HT2mediated amplification of collageninduced
platelet aggregation is significantly increased.
Chemical Properties
White Solid
Originator
Mitsubishi Kasei (Japan
)
Uses
Sarpogrelate hydrochloride is a potent and selective 5-HT2A receptor antagonist
ress-induced hemolysis.
Definition
ChEBI: Sarpogrelate hydrochloride is a stilbenoid.
Biological Activity
Selective 5-HT 2A receptor antagonist (pK i values are 8.52, 7.43 and 6.57 for 5-HT 2A , 5-HT 2C and 5-HT 2B receptors respectively). Displays selectivity over 5-HT 1 , 5-HT 3 , 5-HT 4 H 1 , H 2 , M 3 , α 1 -adrenergic, α 2 -adrenergic and β -adrenergic receptors. Displays cardioprotective activity in vivo .
Synthesis
1. 1-Dimethylamino-3-[2-[2-(3-methoxyphenyl)ethyl]phenoxy]-2-propanol (29.8 g, 0.090 mol) and succinic anhydride (11.3 g, 0.113 mol) were dissolved in acetone (200 ml). 2. The mixture was heated to reflux and maintained for 6 h. 3. Upon completion of the reaction the mixture was cooled in an ice bath to 0~5°C. 4. Dry hydrogen chloride gas was slowly passed into the cooled mixture to adjust the pH to 1~2. 5. Slowly warmed to room temperature and continued to warm to room temperature where a white solid precipitated. 6. The mixture was cooled in an ice bath to 0~5°C. 4. Dry HCl gas was slowly introduced into the cooled mixture and the pH was adjusted to 1~2, when a white solid was precipitated. 5. The temperature was slowly raised to room temperature and stirring was continued for 8 hours to ensure that the reaction was complete. 6. The white solid was collected by filtration and was dried and then recrystallized using acetone. 7. The final product was sagarate hydrochloride as a white solid (38.8 g, 92.5% yield). The purity was tested to be 99.8%.
in vitro
the major metabolite (r,s)-m-1, and m-1 enantiomers of sarpogrelate specifically blocked 5-ht at 5-ht2a receptors. the stereochemical configuration of the ligands does not obviously play a key role at binding to the 5-ht2a receptor [2].
in vivo
pad patients were divided into two groups. one group treated with 100 mg sarpogrelate in oral 3 times one day for 12 weeks (n = 10), while the other group who remained on conventional therapy as control group (n = 11). forearm blood flow (fbf) and leg blood flow (lbf) responses to reactive hyperemia (rh) and sublingual administration of nitroglycerin (ntg) were measured by strain-gauge plethysmography. after twelve weeks of its administration, fbf and lbf responses during rh exhibited significant increases from 13.2 6 1.7 to 18.1 6 2.2 ml/min every 100 ml tissue (p , 0.01) and from 8.2 6 0.9 to 14.2 6 2.1 ml/min every 100 ml tissue (p , 0.05), respectively. augmentation of fbf and lbf induced by sarpogrelate responses to rh was maintained at 24 weeks. the control group had no change observed in at each follow-up time point. the changes in fbf and lbf after sublingual ntg were similar during follow-up periods in the two groups. these findings suggest that longterm oral administration of sarpogrelate improves vascular function in patients with pad [3].
References
[1] nishio h1, inoue a, nakata y. binding affinity of sarpogrelate, a new antiplatelet agent, and its metabolite for serotonin receptor subtypes. arch int pharmacodyn ther. 1996 mar-apr;331(2):189-202.
[2] pertz h1, elz s. in-vitro pharmacology of sarpogrelate and the enantiomers of its major metabolite: 5-ht2a receptor specificity, stereoselectivity and modulation of ritanserin-induced depression of 5-ht contractions in rat tail artery. j pharm pharmacol. 1995 apr;47(4):310-6.
[3] miyazaki m1, higashi y, goto c, chayama k, yoshizumi m, sanada h, orihashi k, sueda t. sarpogrelate hydrochloride, a selective 5-ht2a antagonist, improves vascular function in patients with peripheral arterial disease. j cardiovasc pharmacol. 2007 apr;49(4):221-7.
