title: Novel azo derivatives as prodrugs of 5-aminosalicylic acid and amino derivatives with potent platelet activating factor antagonist activity.
abstract: This paper describes the synthesis of a series of azo compounds able to deliver 5-aminosalicylic acid (5-ASA) and a potent platelet activating factor (PAF) antagonist in a colon-specific manner for the purpose of treating ulcerative colitis. We found it possible to add an amino group on the aromatic moiety of our reported 1-[(1-acyl-4-piperidyl)methyl]-1H-2-methylimidazo[4,5-c]pyridine derivatives or on British Biotech compounds BB-882 and BB-823 maintaining a high level of activity as PAF antagonist. A selected compound UR-12715 (49c) showed an IC(50) of 8 nM in the in vitro PAF-induced aggregation assay, and an ID(50) of 29 microg/kg in the in vivo PAF-induced hypotension test in normotensive rats. Through attachment of 49c to the 5-ASA via azo functionality we obtained UR-12746 (70). Pharmacokinetics experiments with [14C]-70 allow us to reach the following conclusions, critical in the design of these new prodrugs of 5-ASA. Neither the whole molecule 70 nor the carrier 49c were absorbed after oral administration of [14C]-70 in rat as was demonstrated by the absence of plasma levels of radioactivity and the high recovery of it in feces. Effective cleavage of azo bond (84%) by microflora in the colon is achieved. These facts ensure high topical concentrations of 5-ASA and 49c in the colon. Additionally, 70 exhibited a potent anticolitic effect in the trinitrobenzenesulfonic acid-induced colitis model in the rat. This profile suggests that UR-12746 (70) provides an attractive new approach to the treatment of ulcerative colitis.
authors.affiliation: Research Center, J. Uriach & Cía.S.A., Degà Bahí 59-67, 08026 Barcelona, Spain. chem-carceller@uriach.com
authors.forename: E
authors.initials: E
authors.lastname: Carceller
authors.forename: J
authors.initials: J
authors.lastname: Salas
authors.forename: M
authors.initials: M
authors.lastname: Merlos
authors.forename: M
authors.initials: M
authors.lastname: Giral
authors.forename: R
authors.initials: R
authors.lastname: Ferrando
authors.forename: I
authors.initials: I
authors.lastname: Escamilla
authors.forename: J
authors.initials: J
authors.lastname: Ramis
authors.forename: J
authors.initials: J
authors.lastname: García-Rafanell
authors.forename: J
authors.initials: J
authors.lastname: Forn
mesh_terms: D000588:Amines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000636:Aminosalicylic Acids; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D001372:Aza Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001391:Azo Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D003093:Colitis, Ulcerative / Q000139:chemically induced / Q000188:drug therapy; D004353:Drug Evaluation, Preclinical; D005260:Female; D007022:Hypotension / Q000188:drug therapy; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D019804:Mesalamine / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors*; D010974:Platelet Aggregation / Q000187:drug effects; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014302:Trinitrobenzenesulfonic Acid
chemical_list: C435198:1-((1-(3-(4-aminophenyl)-3-phenylpropenoyl)-4-piperidyl)methyl)-1H-2-methylimidazo(4,5-c)pyridine; D000588:Amines; D000636:Aminosalicylic Acids; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001372:Aza Compounds; D001391:Azo Compounds; D007093:Imidazoles; D010972:Platelet Activating Factor; D011355:Prodrugs; D011725:Pyridines; D019804:Mesalamine; D014302:Trinitrobenzenesulfonic Acid; C419382:UR 12746