Novel type of plasmin inhibitors: providing insight into P4 moiety and alternative scaffold to pyrrolopyrimidine.
Here we report a series of plasmin inhibitors which were originally derived from the parent structure of 1 and 2. Our efforts focused on the optimization of the P4 moiety of 2 and on the quest of alternative scaffold to pyrrolopyrimidine in the parent compounds. The results of the former gave us pivotal information on the further optimization of the P4 moiety in plasmin inhibitors and those of the latter revealed that appropriate moieties extending from the benzimidazole scaffold engaged with S4 pocket in the active site of plasmin.
Hiroshima International University, Faculty of Clinical Nutrition, 5-1-1, Hirokoshingai, Kure, Hiroshima 737-0112, Japan. Electronic address: n-teno@ps.hirokoku-u.ac.jp.
Naoki
N
Teno
Computer-Aided Molecular Modeling Research Center, Kansai (CAMM-Kansai), 3-32-302, Tsuto-Otsuka, Nishinomiya 663-8241, Japan.
Keigo
K
Gohda
Kobe Research Projects on Thrombosis and Haemostasis, 3-15-18, Asahigaoka, Tarumi-ku, Kobe 655-0033, Japan.
Keiko
K
Wanaka
Kobe Gakuin University, Faculty of Pharmaceutical Sciences, 1-1-3, Minatojima, Chuo-ku, Kobe 650-8586, Japan.
Yuko
Y
Tsuda
Hiroshima International University, Faculty of Pharmaceutical Sciences, 5-1-1, Hirokoshingai, Kure, Hiroshima 737-0112, Japan.
Maiko
M
Akagawa
Hiroshima International University, Faculty of Pharmaceutical Sciences, 5-1-1, Hirokoshingai, Kure, Hiroshima 737-0112, Japan.
Eriko
E
Akiduki
Hiroshima International University, Faculty of Pharmaceutical Sciences, 5-1-1, Hirokoshingai, Kure, Hiroshima 737-0112, Japan.
Mitsuhito
M
Araki
Hiroshima International University, Faculty of Pharmaceutical Sciences, 5-1-1, Hirokoshingai, Kure, Hiroshima 737-0112, Japan.
Arisa
A
Masuda
Hiroshima International University, Faculty of Pharmaceutical Sciences, 5-1-1, Hirokoshingai, Kure, Hiroshima 737-0112, Japan.
Tadamune
T
Otsubo
Hiroshima International University, Faculty of Clinical Nutrition, 5-1-1, Hirokoshingai, Kure, Hiroshima 737-0112, Japan.
Yukiko
Y
Yamashita
D000933:Antifibrinolytic Agents / Q000138:chemical synthesis / Q000737:chemistry*; D001562:Benzimidazoles / Q000737:chemistry; D020134:Catalytic Domain; D005341:Fibrinolysin / Q000037:antagonists & inhibitors* / Q000737:chemistry; D005343:Fibrinolytic Agents / Q000737:chemistry*; D006801:Humans; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry*; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry*; D013329:Structure-Activity Relationship
D000933:Antifibrinolytic Agents; D001562:Benzimidazoles; D005343:Fibrinolytic Agents; D011743:Pyrimidines; D011758:Pyrroles; C527741:pyrrolopyrimidine; D005341:Fibrinolysin
Benzimidazole; P4 moiety; Plasmin inhibitors; Pyrrolopyrimidine; Scaffold; Structure–activity relationship