title: A novel histamine 2(H2) receptor antagonist with gastroprotective activity. I. Synthesis and pharmacological evaluation of N-phenoxypropylacetamide derivatives with thioether function.
abstract: 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.
authors.affiliation: Pharmaceuticals Research Laboratories, Fujirebio Inc., Tokyo, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Sekine
authors.forename: N
authors.initials: N
authors.lastname: Hirakawa
authors.forename: N
authors.initials: N
authors.lastname: Kashiwaba
authors.forename: H
authors.initials: H
authors.lastname: Matsumoto
authors.forename: T
authors.initials: T
authors.lastname: Kutsuma
authors.forename: T
authors.initials: T
authors.lastname: Yamaura
authors.forename: A
authors.initials: A
authors.lastname: Sekine
mesh_terms: D000081:Acetamides / Q000138:chemical synthesis* / Q000494:pharmacology; D000284:Administration, Oral; D000818:Animals; D000897:Anti-Ulcer Agents / Q000138:chemical synthesis*; D052160:Benzothiazoles; D002121:Calcium Channel Blockers / Q000737:chemistry; D005744:Gastric Acid / Q000378:metabolism; D006635:Histamine H2 Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology; D008297:Male; D010477:Perfusion; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013270:Stomach / Q000187:drug effects; D013329:Structure-Activity Relationship; D013440:Sulfides / Q000737:chemistry; D013844:Thiazoles / Q000737:chemistry
chemical_list: D000081:Acetamides; D000897:Anti-Ulcer Agents; D052160:Benzothiazoles; D002121:Calcium Channel Blockers; D006635:Histamine H2 Antagonists; D010880:Piperidines; D013440:Sulfides; D013844:Thiazoles; C068077:FRG 8701; C035950:fosfedil; C053742:roxatidine acetate