Identified a morpholinyl-4-piperidinylacetic acid derivative as a potent oral active VLA-4 antagonist.
An investigation into the structure-activity relationship of a lead compound, prolyl-5-aminopentanoic acid 4, led to the identification of a novel series of 4-piperidinylacetic acid, 1-piperazinylacetic acid, and 4-aminobenzoic acid derivatives as potent VLA-4 antagonists with low nanomolar IC(50) values. A representative compound morpholinyl-4-piperidinylacetic acid derivative (13d: IC(50)=4.4 nM) showed efficacy in the Ascaris-antigen sensitized murine airway inflammation model by oral administration.
Chiba
Jun
J
Medicinal Chemistry Research Laboratory, Daiichi Pharmaceutical Co. Ltd, 16-13 Kitakasai 1-chome, Edogawa-ku, Tokyo 134-8630, Japan. chiba2mk@daiichipharm.co.jp
Machinaga
Nobuo
N
Takashi
Tohru
T
Ejima
Akio
A
Takayama
Gensuke
G
Yokoyama
Mika
M
Nakayama
Atsushi
A
Baldwin
John J
JJ
McDonald
Edward
E
Moriarty
Kevin J
KJ
Sarko
Christopher R
CR
Saionz
Kurt W
KW
Swanson
Robert
R
Hussain
Zahid
Z
Wong
Angela
A
D000284:Administration, Oral; D000818:Animals; D001249:Asthma / Q000209:etiology / Q000378:metabolism; D039041:Integrin alpha4beta1 / Q000037:antagonists & inhibitors*; D051379:Mice; D009025:Morpholines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D010880:Piperidines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*
D039041:Integrin alpha4beta1; D009025:Morpholines; D010880:Piperidines; C500014:morpholinyl-4-piperidinylacetic acid