Synthesis and structure activity relationships of glycine amide derivatives as novel Vascular Adhesion Protein-1 inhibitors.
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.
Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan. Electronic address: susumu.yamaki@astellas.com.
Susumu
S
Yamaki
Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
Daisuke
D
Suzuki
Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
Jiro
J
Fujiyasu
Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
Masahiro
M
Neya
Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
Akira
A
Nagashima
Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
Mitsuhiro
M
Kondo
Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
Takafumi
T
Akabane
Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
Keitaro
K
Kadono
Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
Ayako
A
Moritomo
Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
Kosei
K
Yoshihara
D000081:Acetamides / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D006631:Amine Oxidase (Copper-Containing) / Q000037:antagonists & inhibitors*; D000818:Animals; D016466:CHO Cells; D015815:Cell Adhesion Molecules / Q000037:antagonists & inhibitors*; D003412:Cricetulus; D004355:Drug Stability; D057075:Enzyme Assays; D005998:Glycine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D062105:Molecular Docking Simulation; D051381:Rats; D013329:Structure-Activity Relationship
D000081:Acetamides; D015815:Cell Adhesion Molecules; C076668:AOC3 protein, human; D006631:Amine Oxidase (Copper-Containing); C510433:vascular adhesion protein-1, rat; D005998:Glycine
Diabetic microvascular complication; Glycine amide; PAMPA; Vascular Adhesion Protein-1