Discovery of novel, orally active dual NK1/NK2 antagonists.
Exploration of the SAR around selective NK2 antagonists, SR48968 and ZD7944, led to the discovery that naphth-1-amide analogues provide potent dual NK1 and NK2 antagonists. ZD6021 inhibited binding of [3H]-NKA or [3H]-SP to human NK1 and NK2 receptors, with high-affinity (K(i)=0.12 and 0.62nM, respectively). In functional assays ZD6021 had, at 10(-7)M, in human pulmonary artery pK(B)=8.9 and in human bronchus pK(B)=7.3, for NK1 and NK2, respectively. Oral administration of ZD6021 to guinea pigs dose-dependently attenuated ASMSP induced extravasation of plasma proteins, ED(50)=0.5mg/kg, and NK2 mediated bronchoconstriction, ED(50)=13mg/kg.
Bernstein
P R
PR
CNS Discovery Research, AstraZeneca Pharmaceuticals LP, 1800 Concord Pike, PO Box 15437, Wilmington, DE 19850-5437, USA. peter.bernstein@astrazeneca.com
Aharony
D
D
Albert
J S
JS
Andisik
D
D
Barthlow
H G
HG
Bialecki
R
R
Davenport
T
T
Dedinas
R F
RF
Dembofsky
B T
BT
Koether
G
G
Kosmider
B J
BJ
Kirkland
K
K
Ohnmacht
C J
CJ
Potts
W
W
Rumsey
W L
WL
Shen
L
L
Shenvi
A
A
Sherwood
S
S
Stollman
D
D
Russell
K
K
D000284:Administration, Oral; D000818:Animals; D001549:Benzamides / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D023421:Models, Animal; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D018041:Receptors, Neurokinin-2 / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013454:Sulfoxides / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*
D001549:Benzamides; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines; D018041:Receptors, Neurokinin-2; D013454:Sulfoxides; C430919:ZD 6021; C440390:ZD 7944; C073839:SR 48968