Discovery of 3-Aryl-4-isoxazolecarboxamides as TGR5 Receptor Agonists

• Published in: Journal of medicinal chemistry Vol. 52; no. 24; pp. 7962 - 7965
• Main Authors: Evans, Karen A, Budzik, Brian W, Ross, Sean A, Wisnoski, David D, Jin, Jian, Rivero, Ralph A, Vimal, Mythily, Szewczyk, George R, Jayawickreme, Channa, Moncol, David L, Rimele, Thomas J, Armour, Susan L, Weaver, Susan P, Griffin, Robert J, Tadepalli, Sarva M, Jeune, Michael R, Shearer, Todd W, Chen, Zibin B, Chen, Lihong, Anderson, Donald L, Becherer, J. David, De Los Frailes, Maite, Colilla, Francisco Javier
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 24.12.2009; Amer Chemical Soc
• Subjects: Amides - chemistry; Amides - pharmacokinetics; Amides - pharmacology; Animals; Biological and medical sciences; Chemistry, Medicinal; Diabetes Mellitus, Type 2 - drug therapy; Diabetes Mellitus, Type 2 - metabolism; Disease Models, Animal; Dogs; General and cellular metabolism. Vitamins; Glucagon-Like Peptide 1 - secretion; Glucose - administration & dosage; Humans; Isoxazoles - chemistry; Isoxazoles - pharmacokinetics; Isoxazoles - pharmacology; Life Sciences & Biomedicine; Medical sciences; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Rats; Receptors, G-Protein-Coupled - agonists; Science & Technology; ACID-DERIVATIVES; GLP-1; Steroid; Agonist; Five membered ring; Intravenous administration; Rat; Gastrointestinal hormone; TGR5 receptor; Structure activity relation; G protein coupled receptor; Chlorine Organic compounds; Bile acid; Chemical synthesis; Dog; Non steroid compound; Intrajejunal administration; Oxygen nitrogen heterocycle; Human; Fissipedia; Carnivora; Rodentia; Benzene derivatives; Oral administration; In vitro; Glucagon like peptide 1; In vivo; Vertebrata; Mammalia; Animal; Affinity; Carboxamide; Pharmacokinetics
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm901434t

A series of 3-aryl-4-isoxazolecarboxamides identified from a high-throughput screening campaign as novel, potent small molecule agonists of the human TGR5 G-protein coupled receptor is described. Subsequent optimization resulted in the rapid identification of potent exemplars 6 and 7 which demonstrated improved GLP-1 secretion in vivo via an intracolonic dose coadministered with glucose challenge in a canine model. These novel TGR5 receptor agonists are potentially useful therapeutics for metabolic disorders such as type II diabetes and its associated complications.