Novel 4,5-dihydro-4-oxo-3H-imidazo[4,5-c]pyridines. Potent angiotensin II receptor antagonists with high affinity for both the AT1 and AT2 subtypes

Article abstract of DOI:10.1016/S0223-5234(97)84011-1

The synthesis and pharmacological activity of balanced high affinity non-peptide angiotensin II antagonists of the AT₁ and AT₂ subtype receptors have been presented. A series of previously prepared AT₁ selective 4,5-dihydro-4-oxo-3H-imidazo[4,5-c]pyridines were modified at four different positions in order to increase the AT₂ binding affinity by maintaining the nanomolar activity for the AT₁ receptor. The targeted AT₂/AT₁ IC₅₀ binding ratio of ~ 1 was achieved with a number of compounds possessing a small alkyl chain at C-2, different acetamide groups at N-5 and a 3-fluoro and 2'-carboxamidosulfonyl substituent at the biphenylmethyl moiety. These modifications led to analogue 12s, which exhibited an AT₂/AT₁ ratio of 0.74, a subnanomolar AT₁ antagonistic potency (0.18 nM) and a high metabolic stability in rat and monkey liver microsomes in vitro. After oral administration of 3 mg/kg to cynomolgus monkeys, EMD 90423 (potassium salt of 12s) demonstrated good efficacy and a long duration of action as an antihypertensive agent.