- Synthesis and pharmacological evaluation of glycine amide derivatives as novel vascular adhesion protein-1 inhibitors without CYP3A4 and CYP2C19 inhibition
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Vascular adhesion protein-1 (VAP-1) is a promising therapeutic target for the treatment of diabetic nephropathy. Here, we conducted optimization studies of our lead compound 1, which we previously reported as a novel VAP-1 inhibitor, to enhance the inhibition of human VAP-1 and to reduce CYP3A4 and CYP2C19 inhibition. As a result, we identified 3-chloro-4-{4-[5-(3-{[glycyl(methyl)amino]methyl}phenyl)pyrimidin-2-yl]piperazin-1-yl}benzoic acid (17h) as a novel orally active VAP-1 inhibitor, with 14-fold increased human VAP-1 inhibitory activity compared to 1, without CYP3A4 and CYP2C19 inhibition. Oral administration of 17h significantly inhibited the progression of proteinuria in streptozotocin (STZ) induced diabetic rats at 0.3 and 1?mg/kg, suggesting that this compound has potential to be a therapeutic agent for the treatment of diabetic nephropathy.
- Yamaki, Susumu,Koga, Yuji,Nagashima, Akira,Kondo, Mitsuhiro,Shimada, Yoshiaki,Kadono, Keitaro,Moritomo, Ayako,Yoshihara, Kosei
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p. 4110 - 4122
(2017/07/05)
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- GLYCINE COMPOUND
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[Problem] The present invention provides a compound which is useful as an active ingredient of a pharmaceutical composition, in particular, a pharmaceutical composition for preventing and/or treating VAP-1-related diseases. [Means for Solution] The present inventors have conducted intensive studies on a compound having a VAP-1 inhibitory activity, and as a result, they have found that a compound of the present invention or a salt thereof exhibits an excellent VAP-1 inhibitory activity and is useful for preventing and/or treating VAP-1-related diseases, in particular, diabetic nephropathy or diabetic macular edema, thereby completing the present invention. The present invention further relates to a pharmaceutical composition, in particular, a pharmaceutical composition for preventing and/or treating VAP-1-related diseases, which comprises the compound of the present invention or a salt thereof, and an excipient.
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Page/Page column 24; 26; 85
(2012/07/28)
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