Cinnamic acids and mono-substituted benzoic acids as useful capping groups for the preparation of hNK2 receptor antagonists.
NK(2) antagonists have been reported to be potentially useful for the treatment of a number of chronic diseases, such as asthma, irritable bowel syndrome, cystitis, and depression. Starting from an in-house prepared library of capped dipeptides, we have identified a series of molecules with subnanomolar binding affinity for the hNK(2) receptor. These molecules are composed by three well-defined regions: a planar aromatic acyl system as N-terminal capping group, a rigid and quite lipophilic core, and a flexible and relatively hydrophilic C-terminal capping group. Here we report how we were able to manipulate the N-terminal capping group to obtain significant in vivo activity after i.v. and i.d. administration.
Porcelloni
Marina
M
Menarini Ricerche S.p.A., via Tito Speri 10, 00040 Pomezia, Rome, Italy.
D'Andrea
Piero
P
Altamura
Maria
M
Catalioto
Rose-Marie
RM
Giuliani
Sandro
S
Meini
Stefania
S
Fattori
Daniela
D
D000818:Animals; D001565:Benzoates / Q000737:chemistry*; D018938:Caco-2 Cells; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D002934:Cinnamates / Q000737:chemistry*; D003106:Colon / Q000187:drug effects; D015195:Drug Design; D006168:Guinea Pigs; D006801:Humans; D008956:Models, Chemical; D015233:Models, Statistical; D010455:Peptides / Q000737:chemistry; D017434:Protein Structure, Tertiary; D018041:Receptors, Neurokinin-2 / Q000037:antagonists & inhibitors*
D001565:Benzoates; D002934:Cinnamates; D010455:Peptides; D018041:Receptors, Neurokinin-2; C029010:cinnamic acid