Lipophilicity as key factor for oral bioavailability of 1-aryl-3-methyl succinimide derivates

INTRODUCTION: Prediction of bioavailability of a drug candidate in the early stage of drug design and development followed by the selection of compounds with favorable structural properties are the key for later clinical efficiency of the potential therapeutic molecule. Lipophilicity is the pivotal physico-chemical property affecting permeability through biological barriers, potency, distribution, and elimination of a drug in the body. Since lipophilicity influence many biological properties, it is the most frequently applied parameter in drug discovery SAR studies. OBJECTIVES: To assess the influence of lipophilicity on the oral absorption of newly synthesized 1-aryl-3-methyl succinimide derivates which is determined in silico as Caco-2 permeability, absorption constant and percent of absorbed molecules. METHOD / DESIGN: Reversed chromatography was applied to determine experimentally the anisotropic lipophilicity of thirteen newly synthesized 1-aryl-3-methyl succinimide derivates. The mobile phase was mixture of water and methanol with a varying fraction of the organic solvent while as the stationary phase precoated RP-18W/UV 254 plates (Macherey-Nagel GMBH and Co., Düren, Germany) were applied. After development, the spots were detected at 254 nm with UV lamp. Software package i-lab 2.0 (https://ilab.acdlabs.com/iLab2/) was used for determining absorption constant, ka, while Caco-2 permeability and percent of the absorbed molecules (%absorbed) were predicted with pkCSM software (http://biosig.unimelb.edu.au/pkcsm/) for all compounds observed based on their structure. RESULTS: Anisotropic lipophilicity was quantified with retention constants, RM 0 obtained by applying thin-layer reversed-phase chromatography for 13 newly synthesized 1-aryl-3-methyl succinimide derivates. All observed compounds are expected to have favorable Caco-2 permeability except compound 5 with carboxylic group which ionizes in physiological fluids. For all analyzed succinimide derivates short absorption times are expected as well as high ...