Identified a morpholinyl-4-piperidinylacetic acid derivative as a potent oral active VLA-4 antagonist

  • Bioorg Med Chem Lett. 2005 Jan 3;15(1):41-5. doi: 10.1016/j.bmcl.2004.10.041.
Jun Chiba  1 ,  Nobuo Machinaga ,  Tohru Takashi ,  Akio Ejima ,  Gensuke Takayama ,  Mika Yokoyama ,  Atsushi Nakayama ,  John J Baldwin ,  Edward McDonald ,  Kevin J Moriarty ,  Christopher R Sarko ,  Kurt W Saionz ,  Robert Swanson ,  Zahid Hussain ,  Angela Wong
Affiliations
  • 1. Medicinal Chemistry Research Laboratory, Daiichi Pharmaceutical Co. Ltd, 16-13 Kitakasai 1-chome, Edogawa-ku, Tokyo 134-8630, Japan. [email protected]
PMID: 15582407 DOI: 10.1016/j.bmcl.2004.10.041
Abstract

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.