New substituted benzimidazole derivatives: a patent review (2013 – 2014)

The proton pump inhibitors rabeprazole, omeprazole, lansoprazole, and pantoprazole undergo an extensive hepatic biotransformation. In the liver, they are metabolized to varying degree by several cytochrome P450 (CYP) isoenzymes which are further categorized into subfamilies of related polymorphic gene products. The principal isoenzymes involved in the metabolism of proton pump inhibitors are CYP2C19 and CYP3A4. Of these two, minor mutations in CYP2C19 affect its activity in the liver and, in turn, the metabolic and pharmacokinetic profiles of the proton pump inhibitors. The metabolism of rabeprazole is less dependent on CYP2C19 and therefore is the least affected by this genetic polymorphism. Recent studies have brought to light the important role that this polymorphism plays in the therapeutic effectiveness of proton pump inhibitors during the treatment of acid-related diseases.

Ebola Zaire virus causes lethal hemorrhagic fever in humans, for which there is no effective treatment. A variety of adenosine analogues inhibit the replication of Ebola virus in vitro, probably by blocking the cellular enzyme, S-adenosyl-L-homocysteine hydrolase, thereby indirectly limiting methylation of the 5' cap of viral messenger RNA. We previously observed that adult, immunocompetent mice treated thrice daily for 9 days with 2.2-20 mg/kg of an adenosine analogue, carbocyclic 3-deazaadenosine, were protected against lethal Ebola virus challenge. We now report that a single inoculation of 80 mg/kg or less of the same substance, or of 1 mg/kg or less of another analogue, 3-deazaneplanocin A, provides equal or better protection, without causing acute toxicity. One dose of drug given on the first or second day after virus infection reduced peak viremia more than 1000-fold, compared with mock-treated controls, and resulted in survival of most or all animals. Therapy was less effective when administered on the day of challenge, or on the third day postinfection. Single or multiple doses of the same medications suppressed Ebola replication in severe combined immunodeficient mice, but even daily treatment for 15 consecutive days did not eliminate the infection.

The angiotensin II (AII) antagonistic action of azilsartan (AZL) [2-ethoxy-1-{[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylic acid] was investigated in radioligand binding and function studies. AZL inhibited the specific binding of ¹²⁵I-Sar¹-Ile⁸-AII to human angiotensin type 1 receptors with an IC₅₀ of 2.6 nM. The inhibitory effect of AZL persisted after washout of the free compound (IC(50) value of 7.4 nM). Olmesartan, telmisartan, valsartan, and irbesartan also inhibited the specific binding with IC₅₀ values of 6.7, 5.1, 44.9, and 15.8 nM, respectively. However, their inhibitory effects were markedly attenuated with washout (IC₅₀ values of 242.5, 191.6, >10,000, and >10,000 nM). AZL also inhibited the accumulation of AII-induced inositol 1-phosphate (IP1) in the cell-based assay with an IC₅₀ value of 9.2 nmol; this effect was resistant to washout (IC₅₀ value of 81.3 nM). Olmesartan and valsartan inhibited IP1 accumulation with IC₅₀ values of 12.2 and 59.8 nM, respectively. The activities of these compounds were markedly reduced after washout (IC₅₀ value of 908.5 and 22,664.4 nM). AZL was defined as an inverse agonist in an experiment by using a constitutively active mutant of human angiotensin type 1 receptors. In isolated rabbit aortic strips, AZL reduced the maximal contractile response to AII with a pD'₂ value of 9.9. The inhibitory effects of AZL on contractile responses induced by AII persisted after the strips were washed; these inhibitory effects were more potent than those of olmesartan. These results suggest that AZL is a highly potent and slowly dissociating AII receptor blocker. Its tight receptor binding might be expected to produce potent and long-lasting antihypertensive effects in preclinical and clinical settings.