title: Insertion of an aspartic acid moiety into cyclic pseudopeptides: synthesis and biological characterization of potent antagonists for the human Tachykinin NK-2 receptor.
abstract: A new series of monocyclic pseudopeptide tachykinin NK-2 receptor antagonists has been derived from the lead compound MEN11558. A synthesis for these molecules sharing the same intermediate was designed and performed. The replacement of the succinic moiety with an aspartic acid and the functionalization of its amino group with a wide variety of substituents led to very potent and selective NK-2 antagonists. Best results were obtained through the insertion in position 12 of an amino group with R configuration, linked by a short spacer to a saturated nitrogen heterocycle (morpholine, piperidine, or piperazine). The study led to compounds 54 and 57, endowed with high in vivo potency at very low doses and long duration of action in animal models of bronchoconstriction. In particular 54 and 57 completely inhibited NK-2 agonist induced bronchoconstriction in guinea pig after intratracheal administration at subnanomolar doses (ED(50) = 0.27 nmol/kg and 0.15 nmol/kg, respectively).
authors.affiliation: Menarini Ricerche S.p.A., Via dei Sette Santi 3, I-50131 Florence, Italy. vfedi@menarini-ricerche.it
authors.forename: Valentina
authors.initials: V
authors.lastname: Fedi
authors.forename: Maria
authors.initials: M
authors.lastname: Altamura
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Balacco
authors.forename: Franca
authors.initials: F
authors.lastname: Canfarini
authors.forename: Marco
authors.initials: M
authors.lastname: Criscuoli
authors.forename: Danilo
authors.initials: D
authors.lastname: Giannotti
authors.forename: Alessandro
authors.initials: A
authors.lastname: Giolitti
authors.forename: Sandro
authors.initials: S
authors.lastname: Giuliani
authors.forename: Antonio
authors.initials: A
authors.lastname: Guidi
authors.forename: Nicholas J S
authors.initials: NJ
authors.lastname: Harmat
authors.forename: Rossano
authors.initials: R
authors.lastname: Nannicini
authors.forename: Franco
authors.initials: F
authors.lastname: Pasqui
authors.forename: Riccardo
authors.initials: R
authors.lastname: Patacchini
authors.forename: Enzo
authors.initials: E
authors.lastname: Perrotta
authors.forename: Manuela
authors.initials: M
authors.lastname: Tramontana
authors.forename: Antonio
authors.initials: A
authors.lastname: Triolo
authors.forename: Carlo Alberto
authors.initials: CA
authors.lastname: Maggi
mesh_terms: D000818:Animals; D001224:Aspartic Acid; D016084:Bronchoconstriction / Q000187:drug effects; D001993:Bronchodilator Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D006168:Guinea Pigs; D006801:Humans; D008297:Male; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000494:pharmacology; D018041:Receptors, Neurokinin-2 / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D001993:Bronchodilator Agents; C107754:MEN 11420; D010456:Peptides, Cyclic; D018041:Receptors, Neurokinin-2; D001224:Aspartic Acid