1. Synthesis and structure activity relationships of glycine amide derivatives as novel Vascular Adhesion Protein-1 inhibitors
- Author
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Takafumi Akabane, Akira Nagashima, Ayako Moritomo, Jiro Fujiyasu, Susumu Yamaki, Kosei Yoshihara, Keitaro Kadono, Masahiro Neya, Suzuki Daisuke, and Mitsuhiro Kondo
- Subjects
0301 basic medicine ,Stereochemistry ,Clinical Biochemistry ,Glycine ,Pharmaceutical Science ,CHO Cells ,Inhibitory postsynaptic potential ,01 natural sciences ,Biochemistry ,03 medical and health sciences ,Glycine amide ,chemistry.chemical_compound ,Structure-Activity Relationship ,Cricetulus ,Drug Stability ,Oral administration ,Amide ,Drug Discovery ,Acetamides ,Moiety ,Animals ,Humans ,Molecular Biology ,Enzyme Assays ,Chemistry ,Organic Chemistry ,Adhesion ,bacterial infections and mycoses ,respiratory tract diseases ,0104 chemical sciences ,Rats ,Molecular Docking Simulation ,010404 medicinal & biomolecular chemistry ,030104 developmental biology ,Molecular Medicine ,Amine Oxidase (Copper-Containing) ,Cell Adhesion Molecules ,Ex vivo ,VASCULAR ADHESION PROTEIN 1 - Abstract
Vascular Adhesion Protein-1 (VAP-1) is a promising therapeutic target for the treatment of several inflammatory-related diseases including diabetic microvascular complication. We identified glycine amide derivative 3 as a novel structure with moderate VAP-1 inhibitory activity. Structure-activity relationship studies of glycine amide derivatives revealed that the tertiary amide moiety is important for stability in rat blood and that the position of substituents on the left phenyl ring plays an important role in VAP-1 inhibitory activity. We also found that low TPSA values and weak basicity are both important for high PAMPA values for glycine amide derivatives. These findings led to the identification of a series of orally active compounds with enhanced VAP-1 inhibitory activity. Of these compounds, 4g exhibited the most potent ex vivo efficacy, with plasma VAP-1 inhibitory activity of 60% after oral administration at 1mg/kg.
- Published
- 2016