Design and synthesis of a novel, achiral class of highly potent and selective, orally active neurokinin-1 receptor antagonists.
The discovery of a novel, achiral pyridine class of potent and orally active neurokinin-1 (NK(1)) receptor antagonists is described. The evaluation of this class is briefly outlined, leading to the identification of netupitant 21 and befetupitant 29, two new proprietary chemical entities with high affinity and excellent CNS penetration.
Hoffmann
Torsten
T
F. Hoffmann-La Roche Ltd, Pharma Research, CH-4070 Basel, Switzerland. torsten.hoffmann@roche.com
Bös
Michael
M
Stadler
Heinz
H
Schnider
Patrick
P
Hunkeler
Walter
W
Godel
Thierry
T
Galley
Guido
G
Ballard
Theresa M
TM
Higgins
Guy A
GA
Poli
Sonia M
SM
Sleight
Andrew J
AJ
D000284:Administration, Oral; D000588:Amines / Q000737:chemistry; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003432:Cross-Linking Reagents / Q000737:chemistry; D015195:Drug Design; D006801:Humans; D015394:Molecular Structure; D064729:Neurokinin-1 Receptor Antagonists; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011743:Pyrimidines / Q000737:chemistry; D018040:Receptors, Neurokinin-1 / Q000378:metabolism; D012680:Sensitivity and Specificity; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D010879:Piperazines; D044482:Benzeneacetamides
D000588:Amines; D003432:Cross-Linking Reagents; D064729:Neurokinin-1 Receptor Antagonists; D011725:Pyridines; D011743:Pyrimidines; D018040:Receptors, Neurokinin-1; C508854:netupitant; D010879:Piperazines; D044482:Benzeneacetamides; C508855:befetupitant