title: Design and synthesis of a novel, achiral class of highly potent and selective, orally active neurokinin-1 receptor antagonists.
abstract: 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.
authors.affiliation: F. Hoffmann-La Roche Ltd, Pharma Research, CH-4070 Basel, Switzerland. torsten.hoffmann@roche.com
authors.forename: Torsten
authors.initials: T
authors.lastname: Hoffmann
authors.forename: Michael
authors.initials: M
authors.lastname: Bös
authors.forename: Heinz
authors.initials: H
authors.lastname: Stadler
authors.forename: Patrick
authors.initials: P
authors.lastname: Schnider
authors.forename: Walter
authors.initials: W
authors.lastname: Hunkeler
authors.forename: Thierry
authors.initials: T
authors.lastname: Godel
authors.forename: Guido
authors.initials: G
authors.lastname: Galley
authors.forename: Theresa M
authors.initials: TM
authors.lastname: Ballard
authors.forename: Guy A
authors.initials: GA
authors.lastname: Higgins
authors.forename: Sonia M
authors.initials: SM
authors.lastname: Poli
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Sleight
mesh_terms: 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
chemical_list: 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