title: A new class of anti-thrombosis hexahydropyrazino-[1',2':1,6]pyrido-[3,4-b]-indole-1,4-dions: design, synthesis, logK determination, and QSAR analysis.
abstract: Based on the fact that the cyclization of N-[(3S)]-1,2,3,4-tetrahydro-beta-carboline-3-carboxyl]-l-lysine in both of acetic acid aqueous (5%) and rat plasma gave the same product and the hypothesis that the cyclization product is antithrombotic active, we report the synthesis, in vitro anti-aggregation, and in vivo anti-thrombosis activity of 20 hexahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dions (5a-t) as potential anti-thrombosis agents in this study. Two intermediates (tetrahydro-beta-carboline-3-carboxy-l-amino acid benzylesters, 2-aminoacyltetrahydro-beta-carboline-3-carboxylic acid benzylesters) were prepared and used for the cyclization to form 5a-t. Coupling hydrochloric acid salt of tetrahydro-beta-carboline-3-carboxylic acid esters and Boc-amino acids in the reported literature usually generates very low yield products accompanied by racemization. However, in our case, the free base of tetrahydro-beta-carboline-3-carboxylic acid benzylester produced the desired products in high yields and without racemization. The anti-thrombosis results from both in vitro and in vivo studies revealed that 5a-t may be a new class of anti-thrombosis agents with potent effective concentration at 0.5mumol/kg with oral administration. Moreover, a QSAR analysis was performed on these 20 compounds by using molecular descriptors generated by e-dragon server. Although the activities of these compounds are weakly correlated with the logP values, the current QSAR analysis revealed that the anti-thrombotic activity of these compounds can be explained by their steric and electrostatic effects.
authors.affiliation: College of Pharmaceutical Sciences, Peking University, Beijing, PR China.
authors.forename: Jiawang
authors.initials: J
authors.lastname: Liu
authors.forename: Guofeng
authors.initials: G
authors.lastname: Wu
authors.forename: Guohui
authors.initials: G
authors.lastname: Cui
authors.forename: Wei-Xuan
authors.initials: WX
authors.lastname: Wang
authors.forename: Ming
authors.initials: M
authors.lastname: Zhao
authors.forename: Chao
authors.initials: C
authors.lastname: Wang
authors.forename: Ziding
authors.initials: Z
authors.lastname: Zhang
authors.forename: Shiqi
authors.initials: S
authors.lastname: Peng
mesh_terms: D000284:Administration, Oral; D000818:Animals; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology*; D007211:Indoles / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology*; D007275:Injections, Intravenous; D015394:Molecular Structure; D010974:Platelet Aggregation / Q000187:drug effects; D011728:Pyridones / Q000737:chemistry*; D021281:Quantitative Structure-Activity Relationship; D051381:Rats; D013552:Swine; D013997:Time Factors
chemical_list: D005343:Fibrinolytic Agents; D007211:Indoles; D011728:Pyridones