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Manufacture Business Practice, Clinical Trials, Drug Delivery, Small Molecules, Trends & Forecasts

Binding thermodynamics of substituted diaminopyrimidine renin inhibitors

sponsored by Malvern Panalytical

The current work has shown that a combination of library screening, molecular modeling, analysis of structural, thermodynamic, and inhibition data provided a valuable tool for structure based drug design. Even when structural data are not available, thermodynamic data can provide insight into drug design but interpretation of thermodynamic data is more insightful when structural data are available. Some insight into drug design that thermodynamic data provide is intuitive to skilled medicinal chemists, but there are situations that are not apparent without thermodynamic measurements. This work used a combination of structural, thermodynamic, and inhibition data to design unique potent small molecule inhibitors of renin.

Introduction

*Abbreviations used: NHANES, National Health and Nutrition Examination Survey; ACE, angiotensin-converting enzyme; ARB, angiotensin II receptor blocker; CHO, Chinese hamster ovary; DMEM, Dulbecco’s modified Eagle’s medium; FBS, fetal bovine serum; DMSO, dimethyl sulfoxide; MWCO, molecular weight cutoff; TPCK trypsin, N-tosyl-Lphenylalanine chloro-methyl ketone-trypsin; PEG, polyethylene glycol; ITC, isothermal titration calorimetry; S3sp, S3 subpocket; VDW, van der Waals.

Analysis of data from the 1999-2002 National Health and Nutrition Examination Survey (NHANES)* indicated that an estimated 65 million individuals in the United States have hypertension.1 This analysis also determined that only 63.4% of the individuals sampled knew they were hypertensive, 45.3% were being treated, 29.3% had their blood pressure under control, but 70.7% of the total hypertensive population (~46 million people) did not1. Comparison of this data to earlier data indicated that since 1960 there have been improvements in awareness, treatment, and control of hypertension,2 but there is substantial room to improve both the identification of individuals at risk for hypertension and the treatment options. Current treatment options for hypertension range from lifestyle modifications, including lowering salt intake and reducing weight, to pharmaceutical intervention. Pharmaceutical therapies currently available include diuretics, alpha-blockers, alpha-beta-blockers, beta-blockers, calcium channel blockers, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin II receptor blockers (ARB).3

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