Dissertation > Excellent graduate degree dissertation topics show

Design, Synthesis and Evaluation of Phospholipid Transfer Protein Inhibitors

Author: LiuChengChun
Tutor: MaoJunWen
School: PLA Military Academy of Medical Sciences
Course: Preventive Medicine in Military
Keywords: Phospholipid transfer protein (PLTP) Cholesteryl ester transfer protein (CETP) Inhibitors Atherosclerosis Organic Synthesis
CLC: R543.5
Type: Master's thesis
Year: 2007
Downloads: 83
Quote: 0
Read: Download Dissertation

Abstract


Atherosclerosis is the most frequent underlying cause of cardiovascular disease and cerebrovascular disease and is the leading cause of death in industrialized nations. With developing of economy and society in China, the incidence of atherosclerosis is increasing remarkably. The pathogenesis of atherosclerosis is very complicated. Among many risk factors, lipid abnormality is the most important effect factor. The clinical manifests of dyslipidemia are high levels of low density lipoprotein cholesterol （LDLc） and / or low levels of high density lipoprotein cholesterol （HDLc）.Phospholipid transfer protein （PLTP） and Cholesteryl ester transfer protein （CETP）, both belonging to the same protein family, are both important modulators of HDL. Torcetrapib （Pfizer）, a CETP inhibitor, can raise levels of HDL cholesterol and now is developing actively in phase III clinical trial for atherosclerosis prevention and treatment by combined with Atorvastatin.The results of the study on mice with stable over-expression of human PLTP and mice with PLTP gene knock-out and the study of epidemiology had shown that PLTP inhibitors have the potentiality as a new drug target to prevent and treat atherosclerosis. Until now, there is no PLTP inhibitor being published as a lead for drug design, this project takes the hint compound found by our project group as a lead and designes some novel target compounds with combination of traditional drug design and structure-based drug design.By now, twenty-four target compounds were synthesized and structurally confirmed by 1H-NMR MS. The target compounds were evaluated in vitro for inhibition against PLTP and CETP. Radiolabeled method were used to measure PLTP inhibition . It has been shown that six compounds have remarkable PLTP inhibitory effects with IC50 ranging from 20 to 90μM. It is found that compound #16 #17 #18 have the best activities against PLTP with IC50 20μM ,which are essentially the same as the most potent PLTP selective inhibitor with IC50 15μM found by Dr.GUO in the world, and they have remarkable PLTP selective inhibitory effect and IC50 ranging from 25 to 90μM; #22 have the best activities against CETP with IC50 25μM, particularly ,CETP selective inhibitors are first found in this project.The structure-activity relationships（SAR） of the PLTP inhibitory activity of the target compounds were investigated. The SAR could guide molecular design of PLTP and CETP inhibitor in the next step.

Related Dissertations

  1. Study of Inhibitors of Aluminum Anode in NaCl Solution,TG174.42
  2. Serum A-FABP Levels and Its Expression in Atherosclerotic Plaques of Diabetes Mellitus,R587.1
  3. Study on the Synthetic Process of Vat Pink R,TQ616.2
  4. Characterization of Two Trehalases in Nilaparvata Lugens (St(?)l) and the Inhibitory Effect of Xenobiotics Against Trehalase,S433.3
  5. The Changes of Intimal Macrophages, Smooth Muscle Cells, Collagen, and Cpt-Ⅰ, GLUT-4 of Vascular Media in Human Lower Limb Artery with Atherosclerotic Stenosis,R543.5
  6. Effect of High Glucose on Chemokine Ligand 16 (CXCL16) Expression and Secretion in THP-1 Macrophages and Intervention of Aspirin in the Activity,R587.2
  7. Correlation Research of Plasma Apolipoprotein CⅢ and High Sensitive C-reactive Protein with Atherothrombotic Cerebral Infarction,R743.33
  8. Studies on the Preparation and Nutrient Release Characteristics of Low Molecular Weight Polylactic Acid Coated Urea,S145.6
  9. Comparison of Urease/Nitrification Inhititors and Influence of 3,4-Dimethylpyrazole Phosphate (DMPP) on Nitrogen Patch and Wheat Root Micro-Distribution,S512.1
  10. Role of G31P in Smooth Muscle Migration of A7r5 Cells Induced by Interleukin-8,R363
  11. Study on Screening of Bacterial Quorum Sensing from Plant Extraction and Their Inhibitions on Biofilm Formation,Q93
  12. The Impact of Histone Deacetylase Inhibitor Trichostatin a on Proliferation and Apoptosis of Porcine Granulosa Cells,S828
  13. The Effect of P-selectin on the Maturation of Dendritic Cells from Human Peripheral Blood,R543.5
  14. The Study of Protection of Amino Acid and Peptide Bond Synthesis,O629.71
  15. The Small Organic Molecules Targeted Human Telomeric G-quadruplex DNA: Design, Synthesis and Binding Properties,TQ460.1
  16. The Effects and Mechanism of Cellular Repressor of ELA-stimulated Genes on Pathological Vascular Endothelium Apoptosis,R363
  17. Carotid Artery Wall Elasticity and Carotid Atherosclerosis in Diabetes Mellitus Patients with Microalbuminuria Using Ultrasonographic Elastography and High-freguency Ultrasound,R445.1
  18. Correlative Study on Plasma Level of Resistin in Patients with Coronary Atherosclerosis Disease,R541.4
  19. Experimental Study on Antiatherosclerosis with EL Antisense,R543.5
  20. Relationship between Carotid Artery Atherosclerosis and Coronary Artery Lesion in Patients with Coronary Heart Disease,R541.4
  21. Relationship Between Chronic Obstructive Pulmonary Disease and Coronary Atherosclerotic,R563.9

CLC: > Medicine, health > Internal Medicine > Heart, blood vessels ( circulatory ) disease > Vascular disease > Artery disease
© 2012 www.DissertationTopic.Net  Mobile