Optimization of 3-(1H-Indazol-3-ylmethyl)-1,5-benzodiazepines as Potent, Orally Active CCK-A Agonists

• Published in: Journal of medicinal chemistry Vol. 40; no. 17; pp. 2706 - 2725
• Main Authors: Henke, Brad R, Aquino, Christopher J, Birkemo, Larry S, Croom, Dallas K, Dougherty, Robert W, Ervin, Gregory N, Grizzle, Mary K, Hirst, Gavin C, James, Michael K, Johnson, Michael F, Queen, Kennedy L, Sherrill, Ronald G, Sugg, Elizabeth E, Suh, Edward M, Szewczyk, Jerzy W, Unwalla, Rayomand J, Yingling, Jeff, Willson, Timothy M
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 15.08.1997; Amer Chemical Soc
• Subjects: Administration, Oral; Alkylation; Animals; Benzodiazepines - administration & dosage; Benzodiazepines - chemistry; Benzodiazepines - pharmacology; Benzodiazepinones - pharmacology; Biological and medical sciences; Chemistry, Medicinal; CHO Cells; Cricetinae; Devazepide; Digestive system; Gallbladder - drug effects; Gallbladder - metabolism; Guinea Pigs; Hormone Antagonists - pharmacology; Indazoles - administration & dosage; Indazoles - chemistry; Indazoles - pharmacology; Life Sciences & Biomedicine; Medical sciences; Mice; Models, Chemical; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Rats; Receptor, Cholecystokinin A; Receptor, Cholecystokinin B; Receptors, Cholecystokinin - agonists; Receptors, Cholecystokinin - metabolism; Science & Technology; CHOLECYSTOKININ ANTAGONISTS; GASTRIN RECEPTOR; C-TERMINAL OCTAPEPTIDE; HUMAN BRAIN; CHROMOSOMAL LOCALIZATION; FUNCTIONAL EXPRESSION; RECEPTOR LIGANDS; GALLBLADDER; MOLECULAR-CLONING; DECREASES FOOD-INTAKE; Agonist; Nitrogen heterocycle; Rodentia; Lactam; Oral administration; Bioavailability; In vitro; Indazole derivatives; In vivo; Vertebrata; Mammalia; Structure activity relation; Mouse; Animal; Bicyclic compound; Peptidergic receptor; Benzodiazepine derivatives; Carboxamide; Intraduodenal administration; Aromatic compound; Anorectic; Cholecystokinin; Pharmacokinetics; Chemical synthesis

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 d...