Optimization Of 3-(1h-Indazol-3-Ylmethyl)-1,5-Benzodiazepines As Potent, Orally Active Cck-A Agonists

We previously described a series of 3-(1H-indazol-3-ylmethyl)-1,5-benzodiazepine CCK-A agonists exemplified by compound I (GW 5823), which is the first reported binding selective CCK-A frail agonist demonstrating oral efficacy in a rat feeding model. In this report we describe analogs of compound I designed to explore changes to the C3 and N1, pharmacophores and their effect on agonist; activity and receptor selectivity. Agonist efficacy in this series was affected by stereoelectronic factors within the C3 moiety. Binding affinity for the CCK-A vs CCK-B receptor showed little dependence on the structure of the C3 moiety but was affected by the nature of the second substituent at C3. Structure-activity relationships at the N1-anilidoacetamide ''trigger'' moiety within the C3 indazole series were also investigated. Both agonist efficacy and binding affinity within this series were modulated by variation of substituents on the N1-anilidoacetamide moiety. Evaluation of several analogs in an irt vivo mouse gallbladder emptying assay revealed compound 1 to be the mast potent and efficacious of all the analogs tested. The pharmacokinetic and pharmacodynamic profile of 1 in rats is also discussed.