Synthesis and biological evaluation of benzoic acid derivatives as potent, orally active VLA-4 antagonists
| Autor: | Atsushi Satoh, Masao Tsubokawa, Jun Chiba, Fumito Muro, Nobuo Machinaga, Atsushi Nakayama, Yutaka Iigou, Shin Iimura, Yoshiyuki Yoneda, Gensuke Takayama, Tohru Takashi, Mika Yokoyama, Toshiyuki Watanabe |
|---|---|
| Rok vydání: | 2007 |
| Předmět: |
Stereochemistry
Clinical Biochemistry Administration Oral Pharmaceutical Science Integrin alpha4beta1 Pharmacology Benzoates Biochemistry Chemical synthesis Inhibitory Concentration 50 Mice Structure-Activity Relationship chemistry.chemical_compound Dogs Pharmacokinetics Oral administration Drug Discovery Animals Pleurisy Molecular Biology IC50 Benzoic acid Inflammation Organic Chemistry Antagonist Biological activity Rats Bioavailability Disease Models Animal chemistry Molecular Medicine |
| Zdroj: | Bioorganic & Medicinal Chemistry. 15:1679-1693 |
| ISSN: | 0968-0896 |
| DOI: | 10.1016/j.bmc.2006.12.006 |
| Popis: | A series of benzoic acid derivatives was synthesized as VLA-4 antagonists. Introduction of chlorine or bromine into the 3-position on the central benzene of the diphenylurea portion as in lead compound 2 led to improvement in the pharmacokinetic properties. In particular, 12l demonstrated an acceptable plasma clearance and bioavailability in mice and rats as well as dogs (mice, CL = 18.5 ml/min/kg, F = 28 % ; rats, CL = 5.2 ml/min/kg, F = 36 % ; dogs, CL = 3.6 ml/min/kg, F = 55 % ). Additionally, 12l exhibited potent activity with an IC50 value of 0.51 nM and efficacy by oral administration at a dosage of 10 mg/kg in a rat pleurisy model. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect