Insertion of an aspartic acid moiety into cyclic pseudopeptides: synthesis and biological characterization of potent antagonists for the human Tachykinin NK-2 receptor.
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).
Fedi
Valentina
V
Menarini Ricerche S.p.A., Via dei Sette Santi 3, I-50131 Florence, Italy. vfedi@menarini-ricerche.it
Altamura
Maria
M
Balacco
Giuseppe
G
Canfarini
Franca
F
Criscuoli
Marco
M
Giannotti
Danilo
D
Giolitti
Alessandro
A
Giuliani
Sandro
S
Guidi
Antonio
A
Harmat
Nicholas J S
NJ
Nannicini
Rossano
R
Pasqui
Franco
F
Patacchini
Riccardo
R
Perrotta
Enzo
E
Tramontana
Manuela
M
Triolo
Antonio
A
Maggi
Carlo Alberto
CA
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
D001993:Bronchodilator Agents; C107754:MEN 11420; D010456:Peptides, Cyclic; D018041:Receptors, Neurokinin-2; D001224:Aspartic Acid