Antiulcer agents. 4. Conformational considerations and the antiulcer activity of substituted imidazo[1,2-a]pyridines and related analogs

• Published in: Journal of medicinal chemistry Vol. 32; no. 8; pp. 1686 - 1700
• Main Authors: Kaminski, James J, Puchalski, Chester, Solomon, Daniel M, Rizvi, Razia K, Conn, David J, Elliott, Arthur J, Lovey, Raymond G, Guzik, Henry, Chiu, P. J. S
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 01-08-1989
• Subjects: Animals; Anti-Ulcer Agents - chemical synthesis; Chemical Phenomena; Chemistry; Dogs; gastric acid; Gastric Acid - metabolism; Gastric Mucosa - drug effects; H super(+)/K super(+)-transporting ATPase; Imidazoles - chemical synthesis; Imidazoles - pharmacology; Models, Molecular; Molecular Conformation; Pyridines - chemical synthesis; Pyridines - pharmacology; Rats; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00128a005

Definition of the interrelationship between the conformational characteristics of a series of substituted imidazo[1,2-a]pyridines and their antiulcer activity was investigated by examining the conformational properties of 3-cyano-2-methyl-8-(phenylmethoxy)imidazo[1,2-a]pyridine (1), using a variety of experimental and theoretical methods. The results of these studies was the identification of two distinctly different candidates, designated the "folded" and the "extended" conformation, respectively, to represent the two possible minimum-energy conformations of 1. In order to select the biologically relevant conformer, a group of 3-substituted 2-methylimidazo[1,2-a]pyridines, having either a cis or a trans 2-phenylethenyl substituent at the 8-position were designed as conceptually simple and synthetically accessible semirigid analogues of the respective candidate conformers. Gastric antisecretory activity was found to reside only in the trans isomers (compounds 11, 15, and 17), which mimic the "extended" conformation. This observation led to the construction of 8,9-dihydro-2-methyl-9-phenyl-7H-imidazo[1,2-a]pyrano[2,3-c]pyridi ne-3- acetonitrile (40), a rigid tricyclic analogue that is effectively locked in the "extended" conformation and that exhibited an antiulcer profile comparable to that of prototype 1. These results unequivocally demonstrate that, in accord with expectation for a drug operating at a specific receptor, the conformational characteristics of the molecule have a substantial effect in determining its antiulcer activity. More precisely, it has been demonstrated that it is the "extended" conformation of 1 that represents the "bioactive" form of the drug. These results constitute the basis for a molecular probe that should aid in the investigation of the as yet uncharacterized gastric proton pump enzyme (H+/K+-ATPase), by means of which 1 and its analogues presumably exert their pharmacologic actions.