- Novel 1H-imidazol-2-amine derivatives as potent and orally active vascular adhesion protein-1 (VAP-1) inhibitors for diabetic macular edema treatment
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Novel thiazole derivatives were synthesized and evaluated as vascular adhesion protein-1 (VAP-1) inhibitors. Although we previously identified a compound (2) with potent VAP-1 inhibitory activity in rats, the human activity was relatively weak. Here, to improve the human VAP-1 inhibitory activity of compound 2, we first evaluated the structure-activity relationships of guanidine bioisosteres as simple small molecules and identified a 1H-benzimidazol-2-amine (5) with potent activity compared to phenylguanidine (1). Based on the structure of compound 5, we synthesized a highly potent VAP-1 inhibitor (37b; human IC50 = 0.019 μM, rat IC50 = 0.0051 μM). Orally administered compound 37b also markedly inhibited ocular permeability in streptozotocin-induced diabetic rats after oral administration, suggesting it is a promising compound for the treatment of diabetic macular edema.
- Inoue, Takayuki,Morita, Masataka,Tojo, Takashi,Nagashima, Akira,Moritomo, Ayako,Miyake, Hiroshi
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p. 3873 - 3881
(2013/07/19)
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- IMIDAZOLE DERIVATIVES
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The invention relates to imidazole derivatives which have a good affinity to the trace amine associated receptors (TAARs), especially for TAAR1. The invention also relates to a pharmaceutically-suitable acid-addition salt of the above compound. The invention further relates to a composition comprising an imidazole derivative as described above, or a pharmaceutically-suitable acid-addition salt thereof, and to processes for preparing such compounds.
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Page/Page column 19
(2008/12/06)
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