A novel histamine 2(H2) receptor antagonist with gastroprotective activity. I. Synthesis and pharmacological...

In an attempt to develop new types of anti-ulcer agents, a series of N-(phenoxypropyl)acetamide derivatives with a thioether moiety and their sulfur-oxidized analogues were synthesized and evaluated for histamine H2-receptor antagonistic activity, Ca antagonistic activity and gastric anti-secretory activity in the lumen-perfuseed rat. Selected compounds were also tested for gastroprotective activity, which was expected to be based on Ca antagonistic activity. Structure-activity relationships are discussed. As a thioether moiety, -CH2-S(O)p-CH2-Ar (Ar; phenyl or furyl) was found to be optimal for the above activities. Especially, N-[3-[(3-(piperidinomethyl) phenoxy]propyl]acetamide with a benzyl sulfinyl, benzylsulfonyl, furfurylsulfinyl or furfurylsulfonyl group showed potent gastroprotective activity upon oral administration in a rat model. These compounds are candidates for novel anti-ulcer drugs with gastric anti-secretory and gastroprotective activities. 2-Furfurylsulfinyl-N-[3-[(piperidinomethyl)phenoxy]propyl]ac etamide was the most potent among the compounds tested and was given the code designation FRG-8701.