Discovery of aryl ureas and aryl amides as potent and selective histamine H3 receptor antagonists for the treatment of obesity (part II).

Abstract A novel series of histamine H 3 receptor (H 3 R) antagonists was derived from an arylurea lead series ( 1 ) via bioisosteric replacement of the urea functionality by an amide linkage. The arylamide series was optimized through SAR studies by a broad variation of substituents in the left-hand side benzoyl residue (analogs 2a – 2ag ) or replacement of the benzoyl moiety by heteroarylcarbonyl residues (analogs 5a – 5n ). Compounds 2p and 2q were identified within the series as potent and selective H 3 R antagonists/inverse agonists with acceptable overall profile. Compound 2q was orally active in food intake inhibition in diet-induced obese (DIO) mice. Compound 2q represents a novel H 3 R antagonist template with improved in vitro potency and oral efficacy and has its merits as a new lead for further optimization.