title: hNK2 receptor antagonists. The use of intramolecular hydrogen bonding to increase solubility and membrane permeability.
abstract: Starting from in-house capped tripeptide libraries, we have developed two series of compounds as potent antagonists of the hNK(2) receptor with a reduced peptide character. These two series maintained a crucial amide bond, which could not be methylated or substituted with classical isostere without a dramatic loss in binding affinity, very likely due conformational changes. We report here the planning, synthesis and evaluation of molecules belonging to the selected chemical series, which contain a strategically placed hydrogen bond acceptor. The aim of the work was to improve membrane permeability via the formation of an intramolecular hydrogen bonding, and at the same time to maintain the structural characteristics geometry and polarity of the amide linkage so as to retain a relevant binding affinity for the biological target.
authors.affiliation: Menarini Ricerche, Pomezia, Rome, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Ettorre
authors.forename: Piero
authors.initials: P
authors.lastname: D'Andrea
authors.forename: Sandro
authors.initials: S
authors.lastname: Mauro
authors.forename: Marina
authors.initials: M
authors.lastname: Porcelloni
authors.forename: Cristina
authors.initials: C
authors.lastname: Rossi
authors.forename: Maria
authors.initials: M
authors.lastname: Altamura
authors.forename: Rose M
authors.initials: RM
authors.lastname: Catalioto
authors.forename: Sandro
authors.initials: S
authors.lastname: Giuliani
authors.forename: Carlo Alberto
authors.initials: CA
authors.lastname: Maggi
authors.forename: Daniela
authors.initials: D
authors.lastname: Fattori
mesh_terms: D002463:Cell Membrane Permeability; D006860:Hydrogen Bonding; D009682:Magnetic Resonance Spectroscopy; D009842:Oligopeptides / Q000494:pharmacology; D018041:Receptors, Neurokinin-2 / Q000037:antagonists & inhibitors*; D012995:Solubility
chemical_list: D009842:Oligopeptides; D018041:Receptors, Neurokinin-2