Add time:08/01/2019         Source:sciencedirect.com

SummaryThe 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.

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