Nizatidine, structure

Traditional or Hj antihistamine drugs block many effects caused by histamine however, it turns out that they are not able to withstand events mediated by H2 receptors, in particular excess gastric juice secretion. In 1977 an H2-receptor antagonist, cimetidine, was proposed, which revolutionized stomach ulcer treatment. Later on, ranitidine was proposed, followed by drugs with minor structural and pharmacological differences such as famotidine and nizatidine. 

Nizatidine Nizatidine is N-[2-[[[2-[(dimethylamino)methyl]-4-thiazolyl]methyl] thio] ethyl]-2-nitro-l,l-ethenediamine (16.2.15). According to its chemical structure, nizatidine is somewhat of a hybrid structure of ranitidine and famotidine, in which a side chain of ranitidine and carrying heterocycle, 2-aminothiazol, are used. Likewise, its synthesis also is a specific combination of pathways used for making both prototype drugs. 2-(Dimethyl-aminomethyl)-4-hydroxymethylthiazol serves as the initial compound, from which the desired nizatidine (16.2.15) is synthesized by subsequent reaction with 2-mercaptoethy-lamine hydrochloride and then with iV-methyl-l-methythio-2-nitroethenamine [71,72]. 

The discovery and development of cimetidine and ranitidine provided a revolution in the medical treatment and management of peptic ulcer disease. Subsequently, many pharmaceutical companies became involved in research programs to discover additional compounds as H2-receptor histamine antagonists. As a result, a very wide range of chemical structures now exists for this class of drug (for a review, see Cooper et al. [19]). Many of these compounds have been investigated in human studies, but only the above-mentioned five drugs - cimetidine, ranitidine, nizatidine, famotidine, and roxatidine - are marketed as medicines. 

A. Oassification and Prototypes Four H, blockers are available cimetidine is the prototype. Ranitidine, famotidine, and nizatidine differ only in being slightly less toxic than cimetidine. These drugs do not resemble H, blockers structurally. They are orally active, with half-lives of 1-3 hours. Because they are relatively nontoxic, they can be given in large doses, so that the duration of action of a single dose may be 12-24 hours. 

Interestingly, some histamine Hj-receptorantagonists, like ranitidine or nizatidine, in spite of their different pharmacological profile, showa certain structural relationship to nitenpyram (Fig. 8.48). Prior to the discovery of proton-pump inhibitors, these were the most important drugs for the treatment of stomach ulcers. 

---