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

Takayuki Inoue; Masataka Morita; Takashi Tojo; Kousei Yoshihara; Akira Nagashima; Ayako Moritomo; Mitsuru Ohkubo; Hiroshi Miyake

doi:10.1016/j.bmc.2012.12.025

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. Epub 2012 Dec 29.

Authors

Takayuki Inoue¹, Masataka Morita, Takashi Tojo, Kousei Yoshihara, Akira Nagashima, Ayako Moritomo, Mitsuru Ohkubo, Hiroshi Miyake

Affiliation

¹ Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan. takayuki.inoue@astellas.com

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.

MeSH terms

Amine Oxidase (Copper-Containing) / antagonists & inhibitors*
Amine Oxidase (Copper-Containing) / metabolism
Animals
Binding Sites
Cell Adhesion Molecules / antagonists & inhibitors*
Cell Adhesion Molecules / metabolism
Diabetes Complications
Diabetes Mellitus, Experimental / metabolism
Diabetes Mellitus, Experimental / pathology
Enzyme Inhibitors / chemical synthesis*
Enzyme Inhibitors / pharmacokinetics
Enzyme Inhibitors / therapeutic use
Guanidines / chemical synthesis*
Guanidines / pharmacokinetics
Guanidines / therapeutic use
Half-Life
Humans
Macular Edema / drug therapy
Macular Edema / etiology
Male
Molecular Docking Simulation
Permeability / drug effects
Protein Structure, Tertiary
Rats
Rats, Sprague-Dawley
Structure-Activity Relationship
Thiazoles / chemical synthesis
Thiazoles / chemistry*
Thiazoles / pharmacokinetics
Thiazoles / therapeutic use

Substances

Cell Adhesion Molecules
Enzyme Inhibitors
Guanidines
N-(4-(2-(4-((amino(imino)methyl)amino)phenyl)ethyl)-1,3-thiazol-2-yl)acetamide
Thiazoles
AOC3 protein, human
Amine Oxidase (Copper-Containing)