SCH 206272: a potent, orally active tachykinin NK(1), NK(2), and NK(3) receptor antagonist.
Experiments were performed to characterize the pharmacology of SCH 206272 [(R,R)-1'[5-[(3,5-dichlorobenzoyl)methylamino]-3-(3,4-dichlorophenyl)-4(Z)-(methoxyimino)pentyl]-N-methyl-2-oxo-[1,4'bipiperidine]-3-acetamide] as a potent and selective antagonist of tachykinin (NK) NK(1), NK(2), and NK(3) receptors. SCH 206272 inhibited binding at human tachykinin NK(1), NK(2), and NK(3) receptors (K(i) = 1.3, 0.4, and 0.3 nM, respectively) and antagonized [Ca(2+)](i) mobilization in Chinese hamster ovary (CHO) cells expressing the cloned human tachykinin NK(1), NK(2), or NK(3) receptors. SCH 206272 inhibited relaxation of the human pulmonary artery (pK(b) = 7.7 +/- 0.3) induced by the tachykinin NK(1) receptor agonist, [Met-O-Me] substance P and contraction of the human bronchus (pK(b = 8.2 +/- 0.3) induced by the tachykinin NK(2) receptor agonist, neurokinin A. In isolated guinea pig tissues, SCH 206272 inhibited substance P-induced enhancement of electrical field stimulated contractions of the vas deferens, (pK(b = 7.6 +/- 0.2), NKA-induced contraction of the bronchus (pK(b) = 7.7 +/- 0.2), and senktide-induced contraction of the ileum. In vivo, oral SCH 206272 (0.1-10 mg/kg, p.o.) inhibited substance P-induced airway microvascular leakage and neurokinin A-induced bronchospasm in the guinea pig. In a canine in vivo model, SCH 206272 (0.1-3 mg/kg, p.o.) inhibited NK(1) and NK(2) activities induced by exogenous substance P and neurokinin A. Furthermore, in guinea pig models involving endogenously released tachykinins, SCH 206272 inhibited hyperventilation-induced bronchospasm, capsaicin-induced cough, and airway microvascular leakage induced by nebulized hypertonic saline. These data demonstrate that SCH 206272 is a potent, orally active tachykinin NK(1), NK(2), and NK(3) receptor antagonist. This compound may have beneficial effects in diseases thought to be mediated by tachykinins, such as cough, asthma, and chronic obstructive pulmonary disease.
Department of Allergy, Schering-Plough Research Institute, K15-1-1600, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA. john.anthes@spcorp.com
John C
JC
Anthes
Richard W
RW
Chapman
Christian
C
Richard
Stephen
S
Eckel
Michel
M
Corboz
John A
JA
Hey
Xiomara
X
Fernandez
Scott
S
Greenfeder
Robbie
R
McLeod
Susan
S
Sehring
Charles
C
Rizzo
Yvette
Y
Crawley
Neng-Yang
NY
Shih
John
J
Piwinski
Greg
G
Reichard
Pauline
P
Ting
Nick
N
Carruthers
Francis M
FM
Cuss
Motasim
M
Billah
William
W
Kreutner
Robert W
RW
Egan
D000081:Acetamides / Q000494:pharmacology*; D000284:Administration, Oral; D000818:Animals; D016084:Bronchoconstriction / Q000187:drug effects / Q000502:physiology; D016466:CHO Cells; D002199:Capillary Permeability; D002211:Capsaicin / Q000494:pharmacology; D003371:Cough / Q000139:chemically induced / Q000188:drug therapy; D006224:Cricetinae; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D006801:Humans; D007082:Ileum / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines / Q000494:pharmacology*; D011651:Pulmonary Artery / Q000187:drug effects / Q000502:physiology; D011869:Radioligand Assay; D018040:Receptors, Neurokinin-1 / Q000378:metabolism; D018041:Receptors, Neurokinin-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018042:Receptors, Neurokinin-3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014649:Vas Deferens / Q000187:drug effects / Q000502:physiology
D000081:Acetamides; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines; D018040:Receptors, Neurokinin-1; D018041:Receptors, Neurokinin-2; D018042:Receptors, Neurokinin-3; C472346:SCH 206272; D002211:Capsaicin