Study On The Quantitative Structure-activity & Pharmacokinetics Relationship And Molecule Design Of Sulfonylamido Pyrimidines As Endothelin Receptor Antagonists

In 1988, endothelin(ET) was isolated from the supernatant of cultured porcine endothelium cell monolayer. The 21 amino acid peptide was characterized as the most potent vasoconstrictors ever reported. As it turned out, there are three different endothelins(ET-1,ET-2,ET-3) in man that act their biological effects through specific binding to two closely related G-protein coupled receptor, the endothelin receptor ET_A and ET_B. Studies have shown, ET is closely related with the pathology of a lot of clinical diseases and physiological change, such as the hypertension, renal failure, congestive heart failure(CHF),Brain apoplexy, cerebral vasospasm, acute myocardial infarction, atherosclerosis, pulmonary arterial hypertension(PAH),artery sclerosis, angina, asthma, etc. Because peptide endothelin receptor antagonists have some shortcoming, such as short half-life ,low bioavailability and bad orally activity, etc. The research of the non-peptide endothelin receptor antagonists has become the hotspot problem in the field of drug. By means of widely drug delivery and design, we have obtained many non-peptide compounds that show high affinity towards the endothelin receptor, and improving the biology activity by further modifies structure. In the paper, study on the quantitative structure-activity& pharmacokinetics relationship and molecule design of sulfonylamido pyrimidines as endothelin receptor antagonist, To provide reference for developing high efficiency and specially good effect drug. Select 107 sulfonylamido pyrimidine compounds which have the drug efficacy foundation of Bosentan. The 13 molecule structure parameters have been calculated by quantum chemistry. And analyzed the correlation between the 13 structure parameters of sulfonylamido pyrimidines and their activities, then analyzed the autocorrelation of the structure parameters, finally, select 5 structure parameters as the neural network import parameters, And analyze the QSAR model between the structure of sulfonylamido pyrimidines and their activitives by means of neural network. The result showed that 5 structure parameters was relatively reasonable, on certain level, could embody biology activity changed regular of these compounds. A QSAR model which has splendid predict capability by BP neural network. The paper took Bosentan as the formwork, designed 59 new sulfonylamido pyrimidine compounds through modifying and optimizing their formwork. Utilizing the above-mentioned QSAR model, initially 6 non-peptide endothlin receptor antagonists advance compounds were filtrated, then the QSPR model between the structure parameters of 48 sulfanilamide drugs and their bioavailability was established to predict the bioavailability of above-mentioned sulfonylamido pyrimidines which had high biology activity. And 6 structure parameters were selected as the neural net import value, Combine with the QSPR model, 4 advance compounds were filtrated ultimately.