Structure–Activity Relationships of 1,2‐Disubstituted Benzimidazoles: Selective Inhibition of Heme Oxygenase‐2 Activity

Devising ways to up‐ or down‐regulate heme oxygenase activity is attracting much interest as a strategy for the treatment of a variety of disorders. With a view of obtaining compounds that exhibit high potency and selectivity as inhibitors of the heme oxygenase‐2 (HO‐2) isozyme (constitutive) relative to the heme oxygenase‐1 (HO‐1) isozyme (inducible), several 1,2‐disubstituted 1H‐benzimidazoles were designed and synthesized. Specifically, analogues were synthesized in which the C2 substituent was the following: (1H‐imidazol‐1‐yl)methyl, (N‐morpholinyl)methyl, cyclopentylmethyl, cyclohexylmethyl, or (norborn‐2‐yl)methyl. Compounds with the cyclic system in the C2 substituent being a carbocyclic ring, especially cyclohexyl or norborn‐2‐yl, and the N1 substituent being a ring‐substituted benzyl group, especially 4‐chlorobenzyl or 4‐bromobenzyl, best exhibited the target criteria of high potency and selectivity toward inhibition of HO‐2. The new candidates should be useful pharmacological tools and may have therapeutic applications.