Description
Telmisartan(cas:144701-48-4) was launched in the US for the treatment of hypertension.
It can be prepared in eight steps starting with methyl 4-amino-3-methyl
benzoate; the first and second cyclization into a benzimidazole ring occur at
steps 4 and 6 respectively. Telmisartan blocks the action of angiotensin II (Ang
II), the primary effector molecule of the renin-angiotensin-aldosterone system
(RAAS). It is the sixth of this class of 《sartans》 to be marketed after the lead
compound Losartan. Its long lasting effect (24h half-life) could be the main
difference with other angiotensin II antagonists. Unlike several other agents in
this category, its activity does not depend upon transformation into an active
metabolite, the 1-O-acylglucuronide being the principal metabolite found in
humans. Telmisartan is a potent competitive antagonist of AT1 receptors that mediate most of the important effects of angiotensin II while lacking affinity for
the AT2 subtypes or other receptors involved in cardiovascular regulation. In
several clinical studies, Telmisartan, at a once daily dosage, produced effective
and sustained blood-pressure lowering effects with a low incidence of side
effects (particularly treatment-related cough associated with ACE inhibitors in
elderly patients).
Originator
Boehringer Ingelheim (Germany)
Uses
Telmisartan is an angiotensin II receptor antagonist that is primarily used for the treatment of hypertension. It can be used alone or in combination with other antihypertensive medications. Additionally, telmisartan is effective in treating diabetic nephropathy in hypertensive patients with type 2 diabetes mellitus. It is also utilized in the treatment of congestive heart conditions.
Definition
ChEBI: A member of the class of benzimidazoles used widely in the treatment of hypertension.
Manufacturing Process
A solution of 2.0 g (6.9 mMol) of 2-n-propyl-5-(1-methylbenzimidazol-2-yl)-
benzimidazole and 0.91 g (7.5 mmol) of potassium tert-butoxide in 50 ml of
dimethylsulfoxide is stirred for 90 min at room temperature, then 2.6 g (7.5
mMol) of tert-butyl 4'-bromomethyl-biphenyl-2-carboxylate are added and the
mixture is stirred for a further 15 h at room temperature. The mixture is then
poured onto 300 ml of water and extracted three times with 50 ml of ethyl
acetate. The crude product obtained after evaporation of the organic phase is
purified by column chromatography (300 g silica gel; eluant:methylene
chloride/methanol = 30:1). In this way, 2.7 g (70%) of an isomer mixture are
obtained (by NMR spectroscopy), contains about 1.18 g of tert-butyl-4'-[(2-npropyl-
5-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl)-methyl]biphenyl-2-
carboxylate and about 1.52 g of tert-butyl 4'-[(2-n-propyl-6-(1-
methylbenzimidazol-2-yl)-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate).
2.70 g of the isomer mixture obtained above are dissolved in 100 ml of
methylene chloride, mixed with 40 ml of trifluoroacetic acid and stirred for 4 h
at room temperature. The mixture is then evaporated to dryness in vacuo, the
residue is dissolved in 100 ml of 2 N sodium hydroxide solution, the solution
is washed with 50 ml of diethylether and the product mixture is precipitated
by acidifying the aqueous phase with acetic acid. By column chromatography
(400 g of silica gel, eluant:methylene chloride/methanol = 15:1) of the solid
thus obtained 0.9 g (74%) of 4'-[[2-n-propyl-6-(1-methylbenzimidazol-2-yl)-
benzimidazol-1-yl]methyl]biphenyl-2-carboxylate, melting point 217°-218°C.
Brand name
Micardis (Boehringer Ingelheim).
Therapeutic Function
Antihypertensive
General Description
Telmisartan, 4'-[(1,4'-dimethyl-2'-propyl[2,6'-bi-1H-benzimidazol]-1'-yl)methyl]-[1,1'-biphenyl]-2-carboxylic acid (Micardis, 144701-48-4), does not appear to bear any structuralrelationship to this class, but there is actually a great dealof overlap in the chemical architecture with other agents. Thefirst, and most significant, difference is the replacement of theacidic tetrazole system with a simple carboxylic acid. Thisacid, like the tetrazole, plays a role in receptor binding. Thesecond difference is the lack of a carboxylic acid near the imidazolenitrogen that also contributes to receptor binding.As with irbesartan, however, there is not a need for this groupto be acidic but, rather, to be one that participates in receptorbinding. The second imidazole ring, much like a purine basein deoxyribonucleic acid (DNA), can hydrogen bond with theangiotensin II receptor.
Biochem/physiol Actions
Telmisartan is a non-peptide AT1 angiotensin receptor antagonist.
Clinical Use
Angiotensin-II antagonist:
Hypertension
Prevention of cardiovascular events
Synthesis
Telmisartan can be prepared in eight steps starting with methyl 4-amino-3-methyl benzoate; the first and second cyclization into a benzimidazole ring occur at steps 4 and 6 respectively.
Drug interactions
Potentially hazardous interactions with other drugs
Anaesthetics: enhanced hypotensive effect.
Analgesics: antagonism of hypotensive effect and
increased risk of renal impairment with NSAIDs;
hyperkalaemia with ketorolac and other NSAIDs.
Antihypertensives: increased risk of hyperkalaemia,
hypotension and renal impairment with ACE-Is and
aliskiren.
Cardiac glycosides: concentration of digoxin
increased.
Ciclosporin: increased risk of hyperkalaemia and
nephrotoxicity.
Diuretics: enhanced hypotensive effect;
hyperkalaemia with potassium-sparing diuretics.
ESAs: increased risk of hyperkalaemia; antagonism
of hypotensive effect.
Lithium: reduced excretion (possibility of enhanced
lithium toxicity).
Potassium salts: increased risk of hyperkalaemia.
Tacrolimus: increased risk of hyperkalaemia and
nephrotoxicity.
Metabolism
Telmisartan is metabolised by conjugation to the
glucuronide of the parent compound. No pharmacological
activity has been shown for the conjugate.
Telmisartan is excreted almost entirely in the faeces via
bile, mainly as unchanged drug.
Clinical claims and research
In several clinical studies, Telmisartan, at a once daily dosage, produced effective and sustained blood-pressure lowering effects with a low incidence of side effects (particularly treatment-related cough associated with ACE inhibitors in elderly patients).
