Discovery of orally bioavailable NK1 receptor antagonists.
Benzyloxyphenethylpiperazines are a new class of high affinity NK1 receptor antagonists. Oral bioavailability and selectivity can be fine tuned by the nature of the substituents on the basic nitrogen atom. Addition of substituents with a carboxylic acid group led to very selective and orally active NK1 antagonists free of interaction with L-type calcium channels.
Genicot
C
C
Chemistry Department, UCB Pharma, Chemin du Foriest, B-1420, Braine-l'Alleud, Belgium. christophe.genicot@ucb-group.com
Christophe
B
B
Collart
P
P
Gillard
M
M
Goossens
L
L
Hénichart
J-P
JP
Lassoie
M-A
MA
Moureau
F
F
Neuwels
M
M
Nicolas
J-M
JM
Pasau
P
P
Quéré
L
L
Ryckmans
T
T
Stiernet
F
F
Taverne
T
T
Van Keulen
B J
BJ
D000215:Acylation; D000478:Alkylation; D000818:Animals; D001682:Biological Availability; D016466:CHO Cells; D002264:Carboxylic Acids / Q000737:chemistry / Q000494:pharmacology; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D006224:Cricetinae; D018360:Crystallography, X-Ray; D006168:Guinea Pigs; D006801:Humans; D007202:Indicators and Reagents; D008958:Models, Molecular; D008968:Molecular Conformation; D064729:Neurokinin-1 Receptor Antagonists; D009584:Nitrogen; D010879:Piperazines / Q000138:chemical synthesis* / Q000494:pharmacology*; D011654:Pulmonary Edema / Q000139:chemically induced / Q000517:prevention & control; D013329:Structure-Activity Relationship
D002264:Carboxylic Acids; D007202:Indicators and Reagents; D064729:Neurokinin-1 Receptor Antagonists; D010879:Piperazines; D009584:Nitrogen