Saturday, August 27, 2016

Telmisartan | Angiotensin II Type 1 Receptor Antagonist | Treatment for Hypertension

Telmisartan [4’-[(1,4’-dimethyl-2’-propyl[2,6’-bi-1H-benzimidazol]-1'-yl)methyl]-[1,1’-biphenyl]-2-carboxylic acid] is a potent, long-lasting, nonpeptide antagonist of the angiotensin II type-1 (AT1) receptor that is indicated for the treatment of essential hypertension. Telmisartan chemically is a non-peptide amphiphilic molecule with a benzimidazole structure with heteroaromatic substituents which possesses one acidic and two basic centers.
It selectively and insurmountably inhibits stimulation of the AT1 receptor by angiotensin II without affecting other receptor systems involved in cardiovascular regulation. Very high lipophilicity, a unique feature of Telmisartan, coupled with a high volume of distribution; indicate that the compound offers the clinically important advantage of good tissue penetration.

Telmisartan: 2D and 3D Structures

Telmisartan is not a prodrug and has a longer terminal elimination half-life than other commercially available sartans (~24 h), making it suitable for once-daily dosing. The compound is not metabolized by cytochrome P450 isoenzymes and has a low risk for P450-based drug interactions. 

Telmisartan exerts potent and sustained antagonism of AII-mediated pressor responses in vivo, and effectively lowers blood pressure in animal models of hypertension as well as in humans. The hypotensive effects are of long duration. The drug was licensed for treatment of hypertension on 10 November 1998 in the USA, and on 11 December 1998 in the EU.

Later studies suggest that Telmisartan may also have PPAR-gamma agonistic properties that could potentially confer beneficial metabolic effects.

Telmisartan Synthesis

J Med Chem 1993, 36(25), 4040-4051: This is the oldest reported synthetic procedure. Telmisartan was produced in 21% overall yield and with eight steps as the longest sequence.

Intermediate 1:

Intermediate 2:

Final Synthesis:


1H NMR (Estimated) for Telmisartan

Experimental: 1H NMR (400 MHz, CDCl3) (δ ppm): 12.8 (1H, s, -COOH), 8.42 (1H, d, J = 8.0 Hz, ArH), 8.02 (1H, d, J = 8.0 Hz, ArH), 7.50-7.26 (8H, m, ArH), 7.20 (2H, d, J = 8.0 Hz, ArH), 7.05 (1H, s, ArH), 6.96 (1H, s, ArH), 5.42 (2H, s, -CH2), 3.82 (3H, s, -CH3), 2.97 (2H, t, J = 7.6 Hz, -CH2), 2.74 (3H, s, -CH3), 1.92 (2H, m, J = 7.6 Hz, -CH2), 1.04 (3H, t, J = 7.6 Hz, -CH3).

13C-NMR (Estimated) for Telmisartan

Experimental: 13C NMR (100 MHz, DMSO-d6) (δ ppm): 13.5, 16.7, 20.6, 27.6, 32.7, 47.1, 51.7, 112.0, 112.7, 114.7, 118.6, 125.3, 125.7, 125.8, 127.0, 127.4, 128.6, 129.3, 130.4, 130.6, 131.5, 132.3, 133.1, 133.2, 133.7, 134.5, 140.2, 140.5, 150.2, 157.3, 168.1.

Sideeffects: The overall incidence of adverse events (AEs) reported with Telmisartan (41.4%) was usually comparable to placebo (43.9%) in controlled trials in patients treated either for hypertension or for reduction of cardiovascular morbidity.
On the basis of safety data, Telmisartan, like the other ARBs, is contraindicated in patients with severe hepatic impairment or biliary obstructive disorders, and in second and third trimesters of pregnancy (animal studies indicate no teratogenic effect, but showed foetotoxicity). Laboratory examinations may also be altered, and in particular the following have been observed: increase of uric acid, hepatic enzymes, creatine phosphokinase; reduction of hemoglobin and red cells parameter.
The incidence of adverse events was not dose related and showed no correlation with gender, age or race of the patients.


1. Wienen, W.; et. al. A Review on Telmisartan: A Novel, Long-Acting Angiotensin II-Receptor Antagonist. Cardiovascular Drug Reviews 2000, 18(2), 127-154. (FMO only)
2. Destro, M.; et. al. Telmisartan: just an antihypertensive agent? A literature review. Expert Opin Pharmacother 2011, 12(17), 2719-2735. (FMO only)
3. Ries, U. J.; et. al. 6-Substituted benzimidazoles as new nonpeptide angiotensin II receptor antagonists: synthesis, biological activity, and structure-activity relationships. J Med Chem 1993, 36(25), 4040-4051. (FMO only)