Synthetic study of VLA-4/VCAM-1 inhibitors: synthesis and structure-activity relationship of piperazinylphenylalanine derivatives.
To improve the poor pharmacokinetic characteristics of VLA-4 inhibitors, novel piperazinylphenylalanine derivatives were designed. This structure is expected to improve physicochemical properties by increasing overall basicity. By changing components at the 4-position of piperazine and the terminal group of the amido bond, 12t was found to be the most potent of this series of compounds. In addition, dichlorobenzoyl derivative 12aa exhibited better oral availability and showed efficacy in an in vivo model after oral administration.
Saku
Osamu
O
Pharmaceutical Research Center, Kyowa Hakko Kogyo Co., Ltd, 1188 Shimotogari, Nagaizumi-cho, Suntou-gun, Shizuoka 411-8731, Japan.
Ohta
Kiminori
K
Arai
Eri
E
Nomoto
Yuji
Y
Miura
Hiroko
H
Nakamura
Hiroaki
H
Fuse
Eiichi
E
Nakasato
Yoshisuke
Y
D000284:Administration, Oral; D000818:Animals; D020650:Combinatorial Chemistry Techniques; D015195:Drug Design; D039041:Integrin alpha4beta1 / Q000037:antagonists & inhibitors*; D051379:Mice; D015394:Molecular Structure; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010879:Piperazines / Q000008:administration & dosage / Q000097:blood / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D019010:Vascular Cell Adhesion Molecule-1 / Q000187:drug effects*
D039041:Integrin alpha4beta1; D010879:Piperazines; D019010:Vascular Cell Adhesion Molecule-1; D010649:Phenylalanine