Sarpogrelate hydrochloride

Ki: 8.39 nM

Sarpogrelate (MCI-9042) was shown to have the same affinity as ritanserin for 5-HT2A receptors, [1].

The blockade of 5-HT2A receptors can inhibit thrombus formation suppresses platelet aggregation and inhibits vascular smooth muscle cell proliferation [2].

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].

Clinical trial: Clinical study has been conducted.

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.

The effects of the 5-HT2A receptor antagonist sarpogrelate hydrochloride on chronic hypoxic pulmonary hypertension in rats.[Pubmed:27191897]

Exp Lung Res. 2016 May;42(4):190-8.

PURPOSE OF THE STUDY: This study investigated whether Sarpogrelate hydrochloride (SPG), a 5-HT2A receptor antagonist, alleviates chronic hypoxic pulmonary hypertension (CH-PH) in rats by stimulating apoptosis and inhibiting proliferation in pulmonary artery smooth muscle cells (PASMCs). MATERIALS AND METHODS: Forty male Sprague-Dawley rats were pretreated with SPG (50 mg/kg/day by oral gavage) or saline vehicle and then subjected to chronic hypoxia (CH) (hypobaric chamber set to 380 mmHg, 10% oxygen) or normoxia for 14 days. Mean pulmonary artery pressure (PAP) and right ventricular hypertrophy (RVH) were measured. Hypertensive pulmonary vascular remodeling was assayed by light microscopy. Terminal deoxynucletidyl transferase dUTP nick end ligase (TUNEL) assays, western blotting, and real-time polymerase chain reaction were used to assess apoptosis, proliferation and underlying signaling pathways in PASMCs from lung tissue and isolated pulmonary artery rings. RESULTS: CH increased mean PAP and RVH. CH increased the percentage of muscularized arteries in the peripheral pulmonary vasculature and medial wall thickness in small muscular arteries. CH increased pulmonary protein and mRNA levels of the B-cell lymphoma protein 2 (Bcl-2), pyruvate dehydrogenase kinase (PDK), phosphorylation of extracellular signal-regulated kinases 1 and 2 (pERK1/2), cyclin D1, proliferating cell nuclear antigen (PCNA) and decreased protein and mRNA levels of Bcl-2-associated X protein (BAX), cleaved caspase-3. Pretreatment with SPG, which has been shown previously to inhibit ERK1/2 phosphorylation and PDK, countered all of these effects. Isolated pulmonary artery rings incubated with 5-HT increased pERK1/2, PDK, and Bcl-2 expression, and decreased Bax expression. CONCLUSION: Administration of SPG ameliorated the development of CH-PH by stimulating apoptosis in and inhibiting proliferation of PASMCs.

Application of physiologically based pharmacokinetic modeling in predicting drug-drug interactions for sarpogrelate hydrochloride in humans.[Pubmed:27695293]

Drug Des Devel Ther. 2016 Sep 14;10:2959-2972.

BACKGROUND: Evaluating the potential risk of metabolic drug-drug interactions (DDIs) is clinically important. OBJECTIVE: To develop a physiologically based pharmacokinetic (PBPK) model for Sarpogrelate hydrochloride and its active metabolite, (R,S)-1-{2-[2-(3-methoxyphenyl)ethyl]-phenoxy}-3-(dimethylamino)-2-propanol (M-1), in order to predict DDIs between sarpogrelate and the clinically relevant cytochrome P450 (CYP) 2D6 substrates, metoprolol, desipramine, dextromethorphan, imipramine, and tolterodine. METHODS: The PBPK model was developed, incorporating the physicochemical and pharmacokinetic properties of Sarpogrelate hydrochloride, and M-1 based on the findings from in vitro and in vivo studies. Subsequently, the model was verified by comparing the predicted concentration-time profiles and pharmacokinetic parameters of sarpogrelate and M-1 to the observed clinical data. Finally, the verified model was used to simulate clinical DDIs between Sarpogrelate hydrochloride and sensitive CYP2D6 substrates. The predictive performance of the model was assessed by comparing predicted results to observed data after coadministering Sarpogrelate hydrochloride and metoprolol. RESULTS: The developed PBPK model accurately predicted sarpogrelate and M-1 plasma concentration profiles after single or multiple doses of Sarpogrelate hydrochloride. The simulated ratios of area under the curve and maximum plasma concentration of metoprolol in the presence of Sarpogrelate hydrochloride to baseline were in good agreement with the observed ratios. The predicted fold-increases in the area under the curve ratios of metoprolol, desipramine, imipramine, dextromethorphan, and tolterodine following single and multiple Sarpogrelate hydrochloride oral doses were within the range of >/=1.25, but <2-fold, indicating that Sarpogrelate hydrochloride is a weak inhibitor of CYP2D6 in vivo. Collectively, the predicted low DDIs suggest that Sarpogrelate hydrochloride has limited potential for causing significant DDIs associated with CYP2D6 inhibition. CONCLUSION: This study demonstrated the feasibility of applying the PBPK approach to predicting the DDI potential between Sarpogrelate hydrochloride and drugs metabolized by CYP2D6. Therefore, it would be beneficial in designing and optimizing clinical DDI studies using sarpogrelate as an in vivo CYP2D6 inhibitor.

Sarpogrelate hydrochloride, a serotonin 5HT2A receptor antagonist, ameliorates the development of chronic hypoxic pulmonary hypertension in rats.[Pubmed:25931318]

J Anesth. 2015 Oct;29(5):715-23.

PURPOSE: The purpose of the present study was to determine if Sarpogrelate hydrochloride (SPG), a serotonin 5HT2A receptor antagonist, prevented the development of chronic hypoxia-induced pulmonary hypertension (PH) and hypertensive pulmonary vascular remodeling. METHODS: Forty-one male Sprague-Dawley rats were exposed to hypobaric hypoxia (380 mmHg, 10 % oxygen) or room air and administered 50 mg/kg SPG or vehicle by gavage once daily from day -2 to day 14. The mean pulmonary artery pressure (PAP) and right ventricular hypertrophy (RVH) were measured. Hypertensive pulmonary vascular remodelings were assessed morphometrically by light microscopy. Serotonin-induced contraction was determined in isolated pulmonary artery rings from 24 rats. In another set of rats, Western blotting, real-time polymerase chain reaction and immunofluorescent staining (n = 9) for lung tissue were performed. RESULTS: Chronic hypoxia induced a rise in mean PAP and RVH, increased the percentage of muscularized arteries in peripheral pulmonary arteries and medial wall thickness in small muscular arteries, and potentiated serotonin-induced contraction, each of which was significantly (p < 0.05) ameliorated by SPG. Chronic hypoxia significantly increased the expression of endothelial nitric oxide synthase (eNOS) and phosphorylated eNOS (peNOS) protein levels, cyclic guanosine monophosphate, and matrix metalloproteinase-13 (MMP-13) mRNA levels in whole lung tissues. SPG increased peNOS expression in the immunofluorescent staining of peripheral pulmonary arteries from chronic hypoxic rats and decreased the MMP-13 mRNA in lung tissue in chronic hypoxic rats. CONCLUSIONS: The administration of SPG ameliorated the development of chronic hypoxic PH and hypertensive pulmonary vascular changes.

Acute effects of sarpogrelate, a 5-HT2A receptor antagonist on cytokine production in endotoxin shock model of rats.[Pubmed:19318092]

Eur J Pharmacol. 2009 Jul 1;614(1-3):122-7.

Serotonin (5-HT)(2A) receptors are involved in cytokine production in infection or sepsis. Therefore, 5-HT(2A) receptor antagonist might be useful to treat sepsis. The present study investigates the effects of a 5-HT(2A) receptor antagonist, sarpogrelate on endotoxin shock. Catheters were inserted into the femoral artery and vein of Sprague-Dawley rats. First, sarpogrelate 0 (control), 3, or 10 mg/kg dissolved in 0.5 ml of distilled water has been given, followed by endotoxin 10 mg/kg in saline 0.5 ml 5 min later. Blood pressure, pulse rate and survival rate were monitored in 20 rats per dose. Blood gas and plasma cytokine concentrations were measured in 8 rats per dose. In four rats each of sarpogrelate 0, 3, or 10 mg/kg, and sham operation, the lung histology was examined. Zero, 15, and 12 rats survived for 8 h in the control, 3 mg/kg, and 10 mg/kg groups, respectively. The control group had the lowest blood pressure, pulse rate, pH and arterial oxygen tension, and the highest arterial carbon dioxide tension and plasma IL-1beta concentration. The increase of TNF-alpha was significantly lower in 3 mg/kg group than in the control group. Pathological changes of the lung were inhibited in 3 and 10 mg/kg groups. In conclusion, sarpogrelate might be effective to decrease production of pro-inflammatory cytokines, to keep hemodynamics, to inhibit lung damage, and to decrease mortality in endotoxin shock.

Blockade of 5-HT(2A) receptors by sarpogrelate protects the heart against myocardial infarction in rats.[Pubmed:12000979]

J Cardiovasc Pharmacol Ther. 2002 Jan;7(1):53-9.

BACKGROUND: It has been shown that serotonin (5-hydroxytryptamine, 5-HT) is involved in exacerbating vascular abnormalities; however, its role in mediating changes in cardiac function due to myocardial injury has yet to be established. This study examined the effect of sarpogrelate, a 5-HT(2A) receptor blocker, in preventing cardiac dysfunction due to myocardial infarction (MI). METHODS AND RESULTS: Rats were treated 3 days before surgery with or without 5 mg x kg(-1) x day(-1) sarpogrelate, and the left coronary artery was ligated for 3 weeks to induce MI. Sarpogrelate reduced the mortality from 40% to 30%, infarct size from 35% to 25%, and left ventricular end diastolic pressure from 15 mm Hg to 10 mm Hg in MI rats. Electrocardiographic (ECG) tracings showed a marked deviation in the ST-segment and prolongation of the QTc interval in MI rats during the 3 weeks; these changes were attenuated by sarpogrelate pretreatment. In another set of experiments, MI rats were treated with 5 mg x kg(-1) x day(-1) sarpogrelate 1 hour after the surgery, and the hemodynamic and electrocardiograph changes were assessed at 3 weeks. This posttreatment was also found to reduce infarct size, improve cardiac function, and attenuate ECG changes. CONCLUSIONS: Sarpogrelate attenuates cardiac dysfunction, infarct size, and changes in the ECG due to MI. These results also support the view that serotonin and 5-HT(2A) may contribute to the deleterious effects of ischemic injury in the heart.