Synthesis and SAR study of new thiazole derivatives as vascular adhesion protein-1 (VAP-1) inhibitors for the treatment of diabetic macular edema

  • Bioorg Med Chem. 2013 Mar 1;21(5):1219-33. doi: 10.1016/j.bmc.2012.12.025.
Takayuki Inoue  1 ,  Masataka Morita ,  Takashi Tojo ,  Kousei Yoshihara ,  Akira Nagashima ,  Ayako Moritomo ,  Mitsuru Ohkubo ,  Hiroshi Miyake
Affiliations
  • 1. Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan. [email protected]
PMID: 23337801 DOI: 10.1016/j.bmc.2012.12.025
Abstract

Vascular adhesion protein-1 (VAP-1), an amine oxidase that is also known as a semicarbazide-sensitive amine oxidase (SSAO), is present in particularly high levels in human plasma, and is considered a potential therapeutic target for various inflammatory diseases, including diabetes complications such as macular edema. In our VAP-1 Inhibitor program, structural modifications following high-throughput screening (HTS) of our compound library resulted in the discovery that thiazole derivative 10, which includes a guanidine group, shows potent human VAP-1 inhibitory activity (IC(50) of 230 nM; rat IC(50) of 14 nM). Moreover, compound 10 exhibited significant inhibitory effects on ocular permeability in STZ-induced diabetic rats.

Products