NOVEL 4,5-DIHYDRO-4-OXO-3H-IMIDAZO[4,5-C]PYRIDINES - POTENT ANGIOTENSIN-II RECEPTOR ANTAGONISTS WITH HIGH-AFFINITY FOR BOTH THE AT(1) AND AT(2) SUBTYPES

The synthesis and pharmacological activity of balanced high affinity n on-peptide angiotensin II antagonists of the AT(1) and AT(2) subtype r eceptors have been presented. A series of previously prepared AT(1) se lective 4,5-dihydro-4-oxo-3H-imidazo[4,5-c]pyridines were modified at four different positions in order to increase the AT(2) binding affini ty by maintaining the nanomolar activity for the AT(1) receptor. The t argeted AT(2)/AT(1) IC50 binding ratio of similar to 1 was achieved wi th a number of compounds possessing a small alkyl chain at C-2, differ ent acetamide groups at N-5 and a 3-fluoro and 2'-carboxamidosulfonyl substituent at the biphenylmethyl moiety. These modifications led to a nalogue 12s, which exhibited an AT(2)/AT(1) ratio of 0.74, a subnanomo lar AT(1) antagonistic potency (0.18 nM) and a high metabolic stabilit y in rat and monkey liver microsomes in vitro. After oral administrati on of 3 mg/kg to cynomolgus monkeys, EMD 90423 (potassium salt of 12s) demonstrated good efficacy and a long duration of action as an antihy pertensive agent.