Repositioning Candidate Details

Candidate ID: R0231
Source ID: DB00661
Source Type: approved
Compound Type: small molecule
Compound Name: Verapamil
Synonyms: Iproveratril; Verapamil
Molecular Formula: C27H38N2O4
SMILES: COC1=C(OC)C=C(CCN(C)CCCC(C#N)(C(C)C)C2=CC(OC)=C(OC)C=C2)C=C1
Structure:
DrugBank Description: Verapamil is a phenylalkylamine calcium channel blocker used in the treatment of high blood pressure, heart arrhythmias, and angina, and was the first calcium channel antagonist to be introduced into therapy in the early 1960s. It is a member of the non-dihydropyridine class of calcium channel blockers, which includes drugs like and , but is chemically unrelated to other cardioactive medications. Verapamil is administered as a racemic mixture containing equal amounts of the S- and R-enantiomer, each of which is pharmacologically distinct - the S-enantiomer carries approximately 20-fold greater potency than the R-enantiomer, but is metabolized at a higher rate.
CAS Number: 52-53-9
Molecular Weight: 454.6016
DrugBank Indication: Verapamil is indicated in the treatment of vasopastic (i.e. Prinzmetal's) angina, unstable angina, and chronic stable angina. It is also indicated to treat hypertension, for the prophylaxis of repetitive paroxysmal supraventricular tachycardia, and in combination with digoxin to control ventricular rate in patients with atrial fibrillation or atrial flutter. Given intravenously, it is indicated for the treatment of various supraventricular tachyarrhythmias, including rapid conversion to sinus rhythm in patients with supraventricular tachycardia and for temporary control of ventricular rate in patients with atrial fibrillation or atrial flutter. Verapamil is commonly used off-label for prophylaxis of cluster headaches.
DrugBank Pharmacology: Verapamil is an L-type calcium channel blocker with antiarrhythmic, antianginal, and antihypertensive activity. Immediate-release verapamil has a relatively short duration of action, requiring dosing 3 to 4 times daily, but extended-release formulations are available that allow for once-daily dosing. As verapamil is a negative inotropic medication (i.e. it decreases the strength of myocardial contraction), it should not be used in patients with severe left ventricular dysfunction or hypertrophic cardiomyopathy as the decrease in contractility caused by verapamil may increase the risk of exacerbating these pre-existing conditions.
DrugBank MoA: Verapamil inhibits L-type calcium channels by binding to a specific area of their alpha-1 subunit,Cav1.2, which is highly expressed on L-type calcium channels in vascular smooth muscle and myocardial tissue where these channels are responsible for the control of peripheral vascular resistance and heart contractility. Calcium influx through these channels allows for the propagation of action potentials necessary for the contraction of muscle tissue and the heart's electrical pacemaker activity. Verapamil binds to these channels in a voltage- and frequency-dependent manner, meaning affinity is increased 1) as vascular smooth muscle membrane potential is reduced, and 2) with excessive depolarizing stimulus. Verapamil's mechanism of action in the treatment of angina and hypertension is likely due to the mechanism described above. Inhibition of calcium influx prevents the contraction of vascular smooth muscle, causing relaxation/dilation of blood vessels throughout the peripheral circulation - this lowers systemic vascular resistance (i.e. afterload) and thus blood pressure. This reduction in vascular resistance also reduces the force against which the heart must push, decreasing myocardial energy consumption and oxygen requirements and thus alleviating angina. Electrical activity through the AV node is responsible for determining heart rate, and this activity is dependent upon calcium influx through L-type calcium channels. By inhibiting these channels and decreasing the influx of calcium, verapamil prolongs the refractory period of the AV node and slows conduction, thereby slowing and controlling the heart rate in patients with arrhythmia. Verapamil's mechanism of action in the treatment of cluster headaches is unclear, but is thought to result from an effect on other calcium channels (e.g. N-, P-, Q-, or T-type). Verapamil is known to interact with other targets, including other calcium channels, potassium channels, and adrenergic receptors.
Targets: Voltage-dependent L-type calcium channel subunit alpha-1C inhibitor; Voltage-dependent N-type calcium channel subunit alpha-1B inhibitor; Voltage-dependent P/Q-type calcium channel subunit alpha-1A inhibitor; ATP-sensitive inward rectifier potassium channel 11 inhibitor; Voltage-dependent T-type calcium channel subunit alpha-1G inhibitor; Voltage-dependent T-type calcium channel subunit alpha-1H inhibitor; Potassium voltage-gated channel subfamily H member 2 inhibitor; Sodium-dependent serotonin transporter unknown; Alpha-1A adrenergic receptor antagonist; Alpha-1B adrenergic receptor antagonist; Alpha-1D adrenergic receptor antagonist
Inclusion Criteria: Therapeutic strategy associated

Strategy ID Strategy Synonyms Related Targets Related Drugs

Target ID Target Name GENE Action Class UniProtKB ID Entry Name

Diseases ID DO ID Disease Name Definition Class
I08 114 Cardiovascular system disease A disease of anatomical entity which occurs in the blood, heart, blood vessels or the lymphatic system that passes nutrients (such as amino acids and electrolytes), gases, hormones, blood cells or lymph to and from cells in the body to help fight diseases and help stabilize body temperature and pH to maintain homeostasis. http://en.wikipedia.org/wiki/Circulatory_system disease of anatomical entity Details
I12 10763 Hypertension An artery disease characterized by chronic elevated blood pressure in the arteries. https://en.wikipedia.org/wiki/Hypertension, https://www.ncbi.nlm.nih.gov/pubmed/24352797 disease of anatomical entity/ cardiovascular system disease/vascular disease/ artery disease Details