Losartan. Losartan, 2-butyl-4-chloro-1-[^-(tf-1H-tetra-zol-5-yl-phenyl)benzyl]imidazole-5-methanol monopotassium salt (Cozarr), was the first nonpeptide imidazole to be introduced as an orally active angiotensin II antagonist with high specificity for AT1. When administered to patients, it undergoes extensive first-pass metabolism, with the 5-methanol being oxidized to a carboxylic acid. This metabolism is mediated by CYP 2C9 and 3A4 isozymes. The 5-methanol metabolite is approximately 15 times more potent than the parent hydroxyl compound. Because the parent hy-droxyl compound has affinity for the AT1 receptor, strictly speaking, it is not a prodrug.13

Candesartan. Candesartan, (+)-1-[[(cyclohexyloxy)car-bonyl]-oxy]ethyl 2- ethoxy-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-benzimidazole-7-carboxylate (Atacand), like losartan, possesses the acidic tetrazole system, which most likely plays a role in binding to the angiotensin II receptor similarly to the acidic groups of angiotensin II. Also, the imidazole system has been replaced with a benzimidazole possessing an ester at position 7. This ester must be hy-drolyzed to the free acid. Fortunately, this conversion takes place fairly easily because of the carbonate in the ester side chain. This facilitates hydrolysis of the ester so much that conversion to the free acid takes place during absorption from the gastrointestinal tract.

Irbesartan. Irbesartan, 2-butyl-3-[[29-(1H-tetrazol-5-yl)[1,19-biphenyl]-4-yl]methyl]1,3-diazaspiro[4,4]non-1en-4-one (Avapro), like losartan, possesses the acidic tetrazole system, which most likely plays a role, similar to the acidic groups of angiotensin II, in binding to the angiotensin II receptor. In addition, the biphenyl system that serves to separate the tetrazole from the aliphatic nitrogen is still present. A major difference in this agent is that it does not possess the acidic side chain. Even so, irbesartan has good affinity for the angiotensin II receptor because of hydrogen bonding with the carbonyl moiety of the amide system. Also, this particular agent does not require metabolic activation as candesartan does.

Telmisartan. Telmisartan, 4' -[(1,4' -dimethyl-2' -propyl [2,6' -bi-1H-benzimidazol]-1' - yl)methyl]-[1,1' -biphenyl]-2-carboxylic acid (Micardis), does not appear to bear any structural relationship to this class, but there is actually a great deal of overlap in the chemical architecture with other agents. The first, and most significant, difference is the replacement of the acidic tetrazole system with a simple carboxylic acid. This acid, like the tetrazole, plays a role in receptor binding. The second difference is the lack of a carboxylic acid near the im-idazole nitrogen that also contributes to receptor binding.14 As with irbesartan, however, there is not a need for this group to be acidic but, rather, to be one that participates in receptor binding. The second imidazole ring, much like a purine base in deoxyribonucleic acid (DNA), can hydrogen bond with the angiotensin II receptor.

Olmesartan. Olmesartan medoxomil, (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl-5-(2-hydroxypropan-2-yl)-2-

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