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

Abstract

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.

New pharmacological agents for the treatment of gastro‐oesophageal reflux disease

“…The interaction of SCH28080 with H + , K + ‐ATPase has been studied extensively, 52–55 although hepatotoxicity precluded its clinical use 56 . Several other compounds based on the SCH28080 structure, but exhibiting improved bioavailability and better toxicological profiles, have also been studied 57 . However, it was recognized that these agents could be further developed by improving their ability to control intragastric acidity throughout both day and night 58 …”

Insights on the Chemical Behavior of Ethyl Cyanoformate: Dipolarophile, Cyano or Ethoxycarbonyl Source

“…Imidazo[1,2‐ a ]pyridine (azaindolizine) ring proved to be an attractive scaffold found in the structure of molecules displaying a wide range of applications in medicinal chemistry including antiviral, anticancer, antifungal, anti‐inflammatory and antiulcer activities with several candidates attending clinical trials . For example, “azaindolizines” are known as retinoic acid receptor‐related orphan receptor gamma (RORγ or RORc) inverse agonists ( e. g .…”

Synthesis of 5-amino-N′-(9H-fluoren-9-ylidene)-8-nitro-7-aryl-1,2,3,7-tetrahydroimidazo[1,2-a]pyridine-6-carbohydrazide derivatives based on heterocyclic ketene aminals

“…Imidazopyridines have shown a broad spectrum of pharmacological and biological activities. 1 Among the various derivatives, the imidazo [1,2-a]pyridine framework is likely the most important construction due to its vital role as a key structure in drugs and biologically active compounds with properties such as anti-inammatory, 2,3 antiviral, [4][5][6] antiulcer agents, 7,8 antifungal, 9 anticancer, 10 anxiolytic, 11 anti-ulcer, 12 and antiprotozoal. 13 They are included in marketed drugs such as the clinical anti-ulcer compound zolpidem and alpidem, 14 olprinone, 15 zolimidine, 16 necopidem and saripidem, 17 soraprazan and minodronic acid 18 (Fig.…”