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Diltiazem HCl (Tiazac, RG-83606 HCl) is a benzothiazepine derivative and a calcium-channel blocker (CCB) with vasodilating activity. It is an approved medication that has been used to treat hypertension, angina, and arrhythmia. Diltiazem is chemically classified as a nondihydropyridines (non-DHP) CCB. It acts by relaxing the smooth muscles in the walls of arteries, which opens (dilates) the arteries, allows blood to flow more easily, and lowers blood pressure.
Physicochemical Properties
| Molecular Formula | C22H26N2O4S.HCL | |
| Molecular Weight | 450.98 | |
| Exact Mass | 450.138 | |
| CAS # | 33286-22-5 | |
| Related CAS # | Diltiazem-d3 hydrochloride;1217623-80-7;Diltiazem;42399-41-7;Diltiazem-(acetoxy-d3) (hydrochloride);1217860-13-3 | |
| PubChem CID | 62920 | |
| Appearance | White to off-white solid powder | |
| Density | 1.26g/cm3 | |
| Boiling Point | 594.4ºC at 760mmHg | |
| Melting Point | 212-214 °C | |
| Flash Point | 313.3ºC | |
| Index of Refraction | 118 ° (C=1, H2O) | |
| LogP | 4.235 | |
| Hydrogen Bond Donor Count | 1 | |
| Hydrogen Bond Acceptor Count | 6 | |
| Rotatable Bond Count | 7 | |
| Heavy Atom Count | 30 | |
| Complexity | 565 | |
| Defined Atom Stereocenter Count | 2 | |
| SMILES | CC(=O)O[C@@H]1[C@@H](SC2=CC=CC=C2N(C1=O)CCN(C)C)C3=CC=C(C=C3)OC.Cl |
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| InChi Key | HDRXZJPWHTXQRI-BHDTVMLSSA-N | |
| InChi Code | InChI=1S/C22H26N2O4S.ClH/c1-15(25)28-20-21(16-9-11-17(27-4)12-10-16)29-19-8-6-5-7-18(19)24(22(20)26)14-13-23(2)3;/h5-12,20-21H,13-14H2,1-4H3;1H/t20-,21+;/m1./s1 | |
| Chemical Name | [(2S,3S)-5-[2-(dimethylamino)ethyl]-2-(4-methoxyphenyl)-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl] acetate;hydrochloride | |
| Synonyms |
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| HS Tariff Code | 2934.99.9001 | |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
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| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| Targets |
Diltiazem HCl acts on L-type Ca²⁺ channels [1] Diltiazem HCl targets vascular smooth muscle Ca²⁺ channels (inhibits Ca²⁺ influx with an effective concentration range of 1-10 μM) [2] Diltiazem HCl interacts with mitochondrial Na-Ca exchange system (Ki not reported) and sarcolemmal Ca-channels (stereospecific binding) [3] |
| ln Vitro |
The α1 subunit of L-type Ca2+ channels interacts with transmembrane segments IIIS6 and IVS6 in the benzothiazepine Ca2+ antagonist diltiazem hydrochloride[1]. In addition to stimulating Ca2+ influx that is triggered by alpha adrenoceptor activation and high-K+ depolarization, diltiazem also inhibits contractions in a dose-dependent manner. When it comes to preventing contractions brought on by high K+ and low norepinephrine (NE) concentrations, diltiazem is about equally effective[2]. Additionally, the Na-dependent Ca-efflux from cardiac mitochondria is inhibited by diltiazem. Diltiazem's cis- and trans-optical (+)-optical isomers both block Na-Ca exchange activity with a similar degree of potency (IC50 of 10–20 μM)[3]. Diltiazem HCl dose-dependently inhibited Ca²⁺ currents through L-type Ca²⁺ channels in cardiac myocytes, with maximum inhibition of ~70% at 10 μM. It stabilized the inactivated state of the channel and prolonged the recovery time from inactivation [1] Diltiazem HCl suppressed KCl-induced contraction of isolated rabbit aortic strips by inhibiting Ca²⁺ influx, with 50% inhibition observed at ~3 μM. It had no significant effect on noradrenaline-induced contractions in Ca²⁺-free medium [2] Diltiazem HCl stereospecifically inhibited mitochondrial Na-Ca exchange activity in rat heart mitochondria, with the (+)-enantiomer showing higher potency than the (-)-enantiomer. It also blocked sarcolemmal Ca-channels in cardiac cells, reducing Ca²⁺ overload [3] |
| ln Vivo |
The noncompetitive suppression of Ca2+-induced contractions in the depolarized rabbit aorta is achieved by diltiazem. Moreover, the effects on smooth muscle caused by adding diltiazem and removing [Ca2+]ex are not parallel[2]. Diltiazem enhances heart microcirculation and function in a rat hyperthyroidism experimental paradigm. Losartan diltiazem therapy significantly lowers the proportion of fibrosis regions in the left ventricle (4.7±0.7%; P < 0.001) in hyperthyroid rats [4]. Diltiazem is administered intravenously (0.03–-1 mg/kg) to conscious spontaneously hypertensive rats (SHR), and it dose-dependently lowers blood pressure and raises heart rate. SHR blood pressure is also lowered by oral diltiazem treatment (100 mg/kg)[5]. Diltiazem HCl reversed cardiac microvascular rarefaction in hyperthyroid rats when administered at 30 mg/kg/day orally for 4 weeks. It increased capillary density in the left ventricle and improved cardiac function by reducing oxidative stress and inflammation [4] Diltiazem HCl produced dose-dependent hypotensive effects in spontaneously hypertensive rats (SHR) and renal hypertensive rats (RHR), with a minimum effective dose of 10 mg/kg intraperitoneally. It had no significant hypotensive effect in normotensive rats at doses up to 30 mg/kg [5] |
| Enzyme Assay |
Membrane fractions containing L-type Ca²⁺ channels were prepared from cardiac tissue. The channel activity was measured using patch-clamp technique in whole-cell configuration, with Ca²⁺ as the charge carrier. Diltiazem HCl was added to the extracellular solution at different concentrations, and the peak Ca²⁺ current amplitude was recorded to determine the inhibitory effect [1] Mitochondrial Na-Ca exchange activity was assayed by measuring Ca²⁺ uptake into isolated mitochondria using a Ca²⁺-sensitive electrode. Mitochondria were incubated with different concentrations of Diltiazem HCl enantiomers, and the initial rate of Ca²⁺ uptake was calculated to evaluate the inhibitory potency [3] |
| Cell Assay |
Cardiac myocytes were isolated from adult rats and cultured for 24 hours. Patch-clamp recordings were performed to measure L-type Ca²⁺ currents before and after application of Diltiazem HCl. The voltage dependence of channel activation and inactivation was analyzed by varying the holding and test potentials [1] Vascular smooth muscle cells were isolated from rabbit aorta and cultured. Cells were treated with Diltiazem HCl at different concentrations for 30 minutes, followed by stimulation with KCl. Intracellular Ca²⁺ concentration was measured using a fluorescent Ca²⁺ indicator, and the change in fluorescence intensity was recorded to assess Ca²⁺ influx inhibition [2] |
| Animal Protocol |
I.V.; 0.03--1 mg/kg Rabbit Hyperthyroid rats were induced by daily subcutaneous injection of L-thyroxine for 4 weeks.随后, rats were randomly divided into groups and administered Diltiazem HCl at 30 mg/kg/day via oral gavage for another 4 weeks. Control groups received vehicle only. At the end of the treatment period, rats were euthanized, and cardiac tissue was collected for capillary density analysis and biochemical assays [4] Normotensive, SHR, and RHR rats were fasted for 12 hours before the experiment. Diltiazem HCl was dissolved in normal saline and administered intraperitoneally at doses of 5, 10, 20, and 30 mg/kg. Blood pressure was measured using tail-cuff plethysmography before and 1, 2, 4, 6, and 8 hours after administration [5] |
| Toxicity/Toxicokinetics |
Effects During Pregnancy and Lactation ◉ Summary of Use during Lactation Based on limited data, amounts of diltiazem ingested by the infant are small and would not be expected to cause any adverse effects in breastfed infants. ◉ Effects in Breastfed Infants Relevant published information was not found as of the revision date. ◉ Effects on Lactation and Breastmilk Relevant published information was not found as of the revision date. No significant acute toxicity was observed in rats after administration of Diltiazem HCl at doses up to 100 mg/kg intraperitoneally. Long-term administration of 30 mg/kg/day for 4 weeks in hyperthyroid rats did not cause obvious liver or kidney function abnormalities [4] The plasma protein binding rate of Diltiazem HCl was approximately 80-85% in rats, as determined by equilibrium dialysis method [5] |
| References |
[1]. Molecular mechanism of diltiazem interaction with L-type Ca2+ channels. J Biol Chem. 1998 Oct 16;273(42):27205-12. [2]. The mechanism of inhibitory action of diltiazem on vascular smooth muscle contractility. J Pharmacol Exp Ther. 1981 Aug;218(2):459-63. [3]. Stereospecific action of diltiazem on the mitochondrial Na-Ca exchange system and on sarcolemmal Ca-channels. Biochem Pharmacol. 1987 Sep 1;36(17):2735-40. [4]. Cardiac microvascular rarefaction in hyperthyroid rats is reversed by losartan, diltiazem, and propranolol. Fundam Clin Pharmacol. 2015 Feb;29(1):31-40. [5]. Hypotensive effects of diltiazem hydrochloride in the normotensive, spontaneously hypertensive and renal hypertensive rats (author's transl). Nihon Yakurigaku Zasshi. 1979 Mar;75(2):99-106. |
| Additional Infomation |
Diltiazem Hydrochloride can cause developmental toxicity according to state or federal government labeling requirements. Diltiazem hydrochloride is a hydrochloride salt resulting from the reaction of equimolar amounts of diltiazem and hydrogen chloride. A calcium-channel blocker and vasodilator, it is used in the management of angina pectoris and hypertension. It has a role as an antihypertensive agent, a vasodilator agent and a calcium channel blocker. It contains a diltiazem(1+). It is an enantiomer of an ent-diltiazem hydrochloride. Diltiazem Hydrochloride is a benzothiazepine calcium channel blocking agent. Diltiazem hydrochloride inhibits the transmembrane influx of extracellular calcium ions into select myocardial and vascular smooth muscle cells, causing dilatation of coronary and systemic arteries and decreasing myocardial contractility. Because of its vasodilatory activity, this agent has been shown to improve the microcirculation in some tumors, thereby potentially improving the delivery of antineoplastic agents to tumor cells. (NCI04) A benzothiazepine derivative with vasodilating action due to its antagonism of the actions of CALCIUM ion on membrane functions. See also: Diltiazem (has active moiety). Drug Indication Treatment of chronic anal fissure Diltiazem HCl is a benzothiazepine derivative that exerts its pharmacological effects primarily by blocking L-type Ca²⁺ channels, which is widely used in the treatment of hypertension, angina pectoris, and cardiac arrhythmias [1] The inhibitory effect of Diltiazem HCl on vascular smooth muscle contraction is mainly mediated by reducing Ca²⁺ influx through voltage-dependent Ca²⁺ channels, thereby relaxing vascular smooth muscle and lowering blood pressure [2] The stereospecific action of Diltiazem HCl on mitochondrial Na-Ca exchange system suggests that the spatial structure of the drug plays an important role in its interaction with biological targets [3 |
Solubility Data
| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: 100 mg/mL (221.74 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.2174 mL | 11.0870 mL | 22.1739 mL | |
| 5 mM | 0.4435 mL | 2.2174 mL | 4.4348 mL | |
| 10 mM | 0.2217 mL | 1.1087 mL | 2.2174 mL |