Subject(s)
Estradiol Congeners/chemical synthesis , Indoles/chemical synthesis , Animals , Bone Density/drug effects , Cell Line , Estradiol Congeners/chemistry , Estradiol Congeners/metabolism , Estradiol Congeners/pharmacology , Female , Indoles/chemistry , Indoles/metabolism , Indoles/pharmacology , Models, Molecular , Organ Size , Ovariectomy , Radioligand Assay , Rats , Structure-Activity Relationship , Transfection , Uterus/drug effectsABSTRACT
We previously described a series of 3-(1H-indazol-3-ylmethyl)-1,5-benzodiazepine CCK-A agonists exemplified by compound 1 (GW 5823), which is the first reported binding selective CCK-A full agonist demonstrating oral efficacy in a rat feeding model. In this report we describe analogs of compound 1 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 vivo mouse gallbladder emptying assay revealed compound 1 to be the most potent and efficacious of all the analogs tested. The pharmacokinetic and pharmacodynamic profile of 1 in rats is also discussed.
Subject(s)
Benzodiazepines/chemistry , Indazoles/chemistry , Receptors, Cholecystokinin/agonists , Administration, Oral , Alkylation , Animals , Benzodiazepines/administration & dosage , Benzodiazepines/pharmacology , Benzodiazepinones/pharmacology , CHO Cells , Cricetinae , Devazepide , Gallbladder/drug effects , Gallbladder/metabolism , Guinea Pigs , Hormone Antagonists/pharmacology , Indazoles/administration & dosage , Indazoles/pharmacology , Mice , Models, Chemical , Rats , Receptor, Cholecystokinin A , Receptor, Cholecystokinin B , Receptors, Cholecystokinin/metabolismABSTRACT
A series of modifications were made to the C-3 substituent of the 1,5-benzodiazepine CCK-A agonist 1. Replacement of the inner urea NH and addition of a methyl group to generate a C-3 quaternary carbon resulted in acetamide 6, which showed CCK-A receptor binding selectivity and sub-micromolar agonist activity in vitro. Benzodiazepine 6 was active in an in vivo mouse gallbladder emptying assay and represents a novel orally active, binding selective CCK-A agonist.
Subject(s)
Acetanilides , Azepines/chemical synthesis , Cholecystokinin/agonists , Animals , Azepines/metabolism , Azepines/pharmacology , Gallbladder/drug effects , Gallbladder/physiology , Guinea Pigs , Mice , Molecular Structure , Muscle Contraction/drug effects , Receptors, Cholecystokinin/metabolismABSTRACT
A variety of C17 amide-substituted 6-azaandrost-4-en-3-ones were prepared and tested versus human type 1 and 2 steroid 5 alpha-reductase (5AR) and human adrenal 3 beta-hydroxy-delta 5-steroid dehydrogenase/3-keto-delta 5-steroid isomerase (3BHSD) in order to optimize potency versus both isozymes of 5AR and selectivity versus 3BHSD. Two series of potent and selective C17 amides were discovered, 2,5-disubstituted anilides and (arylcycloalkyl)amides. Compounds from each series with picomolar IC50's versus human type 2 5AR and low nanomolar to picomolar IC50's versus human type 1 5AR possessing 100-500-fold selectivity versus 3BHSD were identified. A conformational model to predict 3BHSD potency was developed which could rationalize 3BHSD potency within three different series of compounds. Evaluation of some optimal compounds from this series in a chronic castrated rat model of 5AR inhibitor induced prostate involution, and pharmacokinetic measurements identified compounds (9, 12, 16, and 29) with good in vivo efficacy and half-life in the dog. An intact rat model of in vivo selectivity for 5AR versus 3BHSD inhibition was also developed. Dual inhibitors of both human 5AR's may show advantages over type 2 selective 5AR inhibitors, such as finasteride (1), in the treatment of disease states which depend upon dihydrotestosterone.
