PDGF
Trapidil targets multiple pathways to exert its therapeutic effects. It acts as a non-selective phosphodiesterase (PDE) inhibitor (IC50 ≈275 µM across PDE I-IV) and a competitive antagonist of platelet-derived growth factor (PDGF) receptor binding. It also inhibits thromboxane A2 biosynthesis, counteracts its effects at the receptor level, and promotes prostacyclin synthesis and release. Additionally, trapidil inhibits raf-1/extracellular signal-regulated kinase (ERK) by inhibiting PDGF-induced proliferation of vascular smooth muscle cells (VSMC) through the cAMP/protein kinase A (PKA) pathway. It targets FGFR3 as an inhibitor and has been shown to inhibit the proliferation of PDGF-producing glioma cells.

Trapidil breaks the autocrine loop by acting on PDGF and PDGF receptors.Significant antiproliferative activity has been demonstrated by tramadil[1]. The addition of 100–400 μg/ml trapidil significantly inhibited the growth of cells stimulated by various growth factors (FCS, PDGF-BB, bFGF, and EGF), with PDGF-BB stimulating Mesangial cell (MC) growth being most inhibited. The medication had a dose-dependent, presumably targeted effect. ADP, arachidonic acid, PAF, collagen, calcium ionophore, and other aggregating agents are all targets of the anti-platelet medication tramadil. It works by inhibiting thromboxane A2 biosynthesis, counteracting its effects at the receptor level, and promoting prostacyclin synthesis and release[2]. In co-cultures of bone marrow cells and osteoblasts, tratidil significantly reduced the formation of osteoclasts while having no effect on the expression of osteoprotegerin or receptor activator of NF-κB ligand (RANKL) in osteoblasts. Furthermore, trapidil inhibited the formation of osteoclasts from osteoclast precursors induced by RANKL. Without influencing the expression of c-Fos, which serves as a crucial upstream activator of NFATc1 during osteoclastogenesis, tramadil decreased the RANKL-induced expression of nuclear factor of activated T cells, cytoplasmic 1 (NFATc1), a master transcription factor for osteoclastogenesis. Moreover, it has been documented that rivatimil activates protein kinase A and inhibits phosphodiesterase, thromboxane A2, and CD40 signaling[3].
Trapidil demonstrates significant in vitro antiproliferative activity. The addition of 100–400 μg/ml trapidil significantly inhibited the growth of cells stimulated by various growth factors (FCS, PDGF-BB, bFGF, and EGF), with PDGF-BB-stimulated mesangial cell (MC) growth being most inhibited. The medication had a dose-dependent, presumably targeted effect. ADP, arachidonic acid, PAF, collagen, calcium ionophore, and other aggregating agents are all targets of the anti-platelet medication. In co-cultures of bone marrow cells and osteoblasts, trapidil significantly reduced the formation of osteoclasts while having no effect on the expression of osteoprotegerin or receptor activator of NF-κB ligand (RANKL) in osteoblasts. Furthermore, trapidil inhibited the formation of osteoclasts from osteoclast precursors induced by RANKL.

Trapidil is an antiplatelet medication that specifically antagonizes platelet-derived growth factors and has antiproliferative effects following balloon angioplasty in rat and rabbit models[1]. In an animal model of interleukin-1-induced osteoclast formation and bone resorption, tramadil demonstrated a strong inhibitory effect. Following intraperitoneal injections of trapidil, no abnormal symptoms, including weight changes, diarrhea, elevated fever, and convulsions, were noted[3].
Trapidil is an antiplatelet medication that specifically antagonizes platelet-derived growth factors and has antiproliferative effects following balloon angioplasty in rat and rabbit models. In an animal model of interleukin-1-induced osteoclast formation and bone resorption, trapidil demonstrated a strong inhibitory effect. Following intraperitoneal injections of trapidil, no abnormal symptoms, including weight changes, diarrhea, elevated fever, and convulsions, were noted. It has been documented that trapidil activates protein kinase A and inhibits phosphodiesterase, thromboxane A2, and CD40 signaling. Trapidil also shows preferential large epicardial coronary artery relaxation, which avoids coronary steal, unlike dipyridamole or adenosine.

In vitro enzyme/receptor binding assays for trapidil typically involve evaluating its inhibitory activity against phosphodiesterases (PDE) and its binding affinity to the platelet-derived growth factor (PDGF) receptor. For PDE inhibition assays, the compound is incubated with purified PDE enzyme isoforms in the presence of a substrate, and the enzymatic activity is measured, allowing for the determination of IC50 values. For PDGF receptor binding assays, radiolabeled PDGF is used to compete with trapidil for binding to the receptor, and the displacement is measured to determine binding affinity. Cell viability is assessed using the Trypan blue dye exclusion test and the LDH assay. Cells are seeded in serum-free medium after being exposed to various mitogens and drugs, and the supernatants are obtained, centrifuged, and the concentration of LDH is measured.

The Trypan blue dye exclusion test and the LDH assay were used to assess cell viability. After being exposed to various mitogens and drugs, cells were seeded in serum-free medium. The cells' supernatants were obtained, centrifuged, and the concentration of LDH was measured. As a positive control, supernatants from cells that had been sonicated were employed. In order to completely rule out Trapidil having a cytotoxic effect on human MC, cells that had been cultured for four days both with and without the medication were challenged with new medium containing 10% FBS, and the rate of cell division was assessed.
For in vitro cell-based assays, trapidil is dissolved in DMSO (36 mg/mL; 175.38 mM) and applied to cultured cells such as mesangial cells, vascular smooth muscle cells, or osteoclast precursors at concentrations ranging from 100-400 μg/ml. Cells are typically seeded in serum-free medium and exposed to various mitogens and drugs. Cell viability is assessed using the Trypan blue dye exclusion test and the LDH assay. After treatment, cell supernatants are obtained and centrifuged, and the concentration of LDH is measured as an indicator of cell damage. The effects on cell proliferation, osteoclast formation, and signaling pathways such as cAMP/PKA are evaluated after specific treatment periods.

ICR mice
5 or 20 mg/kg
i.p.
In vivo animal studies for trapidil are commonly conducted in rat and rabbit models of restenosis following balloon angioplasty. The compound is typically administered orally or intraperitoneally at doses ranging from 1-100 mg/kg. Efficacy is evaluated by measuring the reduction in neointimal hyperplasia, restenosis rates, and the inhibition of smooth muscle cell proliferation. In animal models of interleukin-1-induced osteoclast formation and bone resorption, trapidil demonstrates a strong inhibitory effect. Following intraperitoneal injections of trapidil, no abnormal symptoms, including weight changes, diarrhea, elevated fever, and convulsions, are noted, indicating a favorable tolerability profile.

Absorption, Distribution and Excretion
The time to peak concentration (Tmax) of tropidil is 1 hour. The apparent clearance after a single dose is 179 mL/min, and the apparent clearance after steady-state administration is 273 mL/min. Biological Half-Life The elimination half-life after a single dose is 1.31 hours, and the elimination half-life after steady-state administration is 1.14 hours.
Trapidil has a molecular weight of 205.26 g/mol and a molecular formula of C10H15N5. It demonstrates complete oral bioavailability (96%) with a plasma elimination half-life of 3 hours in healthy subjects. The compound is soluble in DMSO (36 mg/mL; 175.38 mM) and water (≥ 50 mg/mL). It is typically stored as a solid powder at 0-4°C for short-term storage or at -20°C for long-term storage. Trapidil is supplied with a purity of ≥98% (HPLC).

In preclinical studies, trapidil has demonstrated a favorable safety profile with no significant toxicity reported at therapeutic doses. Following intraperitoneal injections of trapidil, no abnormal symptoms, including weight changes, diarrhea, elevated fever, and convulsions, were noted. Common side effects associated with trapidil use are generally mild and may include gastrointestinal disturbances, headache, and flushing. No significant hepatotoxicity or nephrotoxicity has been reported. The compound's safety profile is supported by its clinical use as a vasodilator and antiplatelet agent.

[1]. Circulation . 1994 Dec;90(6):2710-5.

[2]. Kidney Int . 1994 Oct;46(4):1002-9.

[3]. Biochem Pharmacol . 2013 Sep 15;86(6):782-90.

Trapidil belongs to the triazolopyrimidine class of drugs. Trapidil is a platelet-derived growth factor antagonist, initially developed as a vasodilator and antiplatelet drug for the treatment of patients with ischemic coronary artery disease, liver disease, and kidney disease. It is a coronary vasodilator. Drug Indications: Used to treat chronic stable angina. Mechanism of Action: Trapidil is believed to inhibit cyclic adenosine monophosphate (cAMP) phosphodiesterase. The resulting increase in cAMP levels enhances the inhibitory effect of adenosine on platelets. Decreased platelet activation may be the reason why Trapidil reduces thromboxane A2 production. Increased cAMP levels may also be the reason for Trapidil's vasodilatory effect. Increased cAMP in the heart activates L-type calcium channels, leading to enhanced protein kinase A (PKA) activity, which in turn causes enhanced depolarization and positive inotropic effects. Furthermore, PKA inactivates Raf-1, the activator of mitogen-activated protein kinase (MAPK), thereby reducing MAPK activation. The reduction in MAPK inhibits the binding of PDGF to its receptor, thus preventing cell division.

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Pharmacodynamics
Trapidil has vasodilatory and antiplatelet aggregation effects and can inhibit the activity of platelet-derived growth factor (PDGF).

Trapidil (AR-12008) is a triazolopyrimidine derivative originally developed as a coronary vasodilator and antianginal agent. It functions as a dual-mechanism therapeutic via non-selective phosphodiesterase (PDE) inhibition (IC50 ≈275 µM across PDE I-IV) and competitive antagonism of platelet-derived growth factor (PDGF) receptor binding. Trapidil demonstrates complete oral bioavailability (96%) with a plasma elimination half-life of 3 hours in healthy subjects. In the STARC trial, it achieved a 39% relative risk reduction in 6-month restenosis versus aspirin (24.2% vs. 39.7%, P<0.01). It also shows a 67% reduction in ST-segment depression vs. 23% with ISDN at 12 weeks. Trapidil is an antiplatelet agent that specifically antagonizes platelet-derived growth factor and has antiproliferative effects following balloon angioplasty in rat and rabbit models.

C10H15N5

205.2596

205.132

C, 58.51; H, 7.37; N, 34.12

15421-84-8

15421-84-8

5531

White to off-white solid powder

1.2±0.1 g/cm3

98-99.4° (Pfeifer); 102-104° from heptane (Tenor)

1.626

1.45

0

4

3

15

206

0

N(C([H])([H])C([H])([H])[H])(C([H])([H])C([H])([H])[H])C1=C([H])C(C([H])([H])[H])=NC2=NC([H])=NN12

GSNOZLZNQMLSKJ-UHFFFAOYSA-N

InChI=1S/C10H15N5/c1-4-14(5-2)9-6-8(3)13-10-11-7-12-15(9)10/h6-7H,4-5H2,1-3H3

N,N-diethyl-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine

AR 12008; AR-12008; AR12008

2934.99.03.00

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO: ~41 mg/mL (~199.8 mM)
Ethanol: ~41 mg/mL (~199.8 mM)
Water: ~41 mg/mL (~199.8 mM)

Solubility in Formulation 1: 100 mg/mL (487.19 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication.

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 (Please use freshly prepared in vivo formulations for optimal results.)