ABSTRACT
A series of structurally novel aryl ureas was derived from optimization of the HTS lead as selective histamine H3 receptor (H3R) antagonists. The SAR was explored and the data obtained set up the starting point and foundation for further optimization. The most potent tool compounds, as exemplified by compounds 2l, 5b, 5d, and 5e, displayed antagonism potencies in the subnanomolar range in in vitro human-H3R FLIPR assays and rhesus monkey H3R binding assays.
Subject(s)
Amides/chemistry , Histamine H3 Antagonists/chemistry , Receptors, Histamine H3/chemistry , Urea/chemistry , Amides/metabolism , Amides/therapeutic use , Animals , Drug Evaluation, Preclinical , HEK293 Cells , Histamine H3 Antagonists/metabolism , Histamine H3 Antagonists/therapeutic use , Humans , Macaca mulatta , Obesity/drug therapy , Protein Binding , Rats , Receptors, Histamine H3/genetics , Receptors, Histamine H3/metabolism , Structure-Activity Relationship , Urea/metabolism , Urea/therapeutic useABSTRACT
A novel series of histamine H3 receptor (H3R) 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 H3R 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 H3R antagonist template with improved in vitro potency and oral efficacy and has its merits as a new lead for further optimization.
Subject(s)
Amides/chemistry , Benzamides/chemistry , Histamine H3 Antagonists/chemistry , Pyrrolidines/chemistry , Receptors, Histamine H3/chemistry , Urea/chemistry , Administration, Oral , Amides/metabolism , Amides/therapeutic use , Animals , Benzamides/metabolism , Benzamides/therapeutic use , Caco-2 Cells , Drug Evaluation, Preclinical , Drug Inverse Agonism , Histamine H3 Antagonists/metabolism , Histamine H3 Antagonists/therapeutic use , Humans , Mice , Microsomes/metabolism , Obesity/drug therapy , Protein Binding , Pyrrolidines/metabolism , Pyrrolidines/therapeutic use , Rats , Receptors, Histamine H3/genetics , Receptors, Histamine H3/metabolism , Structure-Activity Relationship , Urea/metabolism , Urea/therapeutic useABSTRACT
We exploit the concept of using hydrogen bonds to link multiple ligands for maintaining simultaneous interactions with polyvalent binding sites. This approach is demonstrated by the syntheses and evaluation of pseudo-bivalent ligands as potent inhibitors of human beta-tryptase.