1. Synthesis, biological evaluation, and pharmacokinetic study of prolyl-1-piperazinylacetic acid and prolyl-4-piperidinylacetic acid derivatives as VLA-4 antagonists
- Author
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Zahid Hussain, Baldwin John J, Tohru Takashi, Kurt W. Saionz, K.J.M. Moriarty, Mika Yokoyama, Edward Mcdonald, Sarko Christopher Ronald, Nobuo Machinaga, Angela Wong, Atsushi Nakayama, Jun Chiba, Gensuke Takayama, and Robert Swanson
- Subjects
Male ,Magnetic Resonance Spectroscopy ,Proline ,Stereochemistry ,Clinical Biochemistry ,Pharmaceutical Science ,Acetates ,Integrin alpha4beta1 ,Spectrometry, Mass, Fast Atom Bombardment ,Biochemistry ,Piperazines ,Pyrrolidine ,Rats, Sprague-Dawley ,chemistry.chemical_compound ,Dogs ,Piperidines ,Pharmacokinetics ,Drug Discovery ,Ic50 values ,Animals ,Molecular Biology ,Biological evaluation ,Plasma clearance ,Chromatography ,Chemistry ,Organic Chemistry ,VLA-4 ,Rats ,Molecular Medicine ,Prolyl-4-piperidinylacetic acid ,Prolyl-1-piperazinylacetic acid - Abstract
A series of prolyl-1-piperazinylacetic acid and prolyl-4-piperidinylacetic acid derivatives were synthesized and evaluated for their activity as VLA-4 antagonists. Of 22 compounds synthesized, 19 compounds showed potent activity with low nanomolar IC50 values. In addition, the representative compounds 11o and 11p with a hydroxy group in the pyrrolidine ring showed moderate plasma clearance in rats (11o, 30 ml/min/kg and 11p, 21 ml/min/kg) and in dogs (11o, 12 ml/min/kg and 11p, 9 ml/min/kg).
- Published
- 2006
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