Journal of Pharmaceutical Research International

Over the past decade, drug resistance has emerged as a major challenge in the treatment of high blood pressure. This report evaluates new imidazo[4.5-c]pyridin-4-one compounds designed to inhibit the AT1 enzyme, and highlights their therapeutic potential, supported by favourable pharmacological properties. Three-dimensional (3D) models of AT1-IPx complexes were constructed via in situ modifications of the crystal structure of AT1-IP1 (PDB entry code: 4HEE), which acted as the reference compound for a training set of 15 and a validation set of 4 VIPs with established experimental inhibitory potencies IC₅₀^exp. To ascertain the active conformation of IP1-15, we devised a gas-phase quantitative structure-activity relationship (QSAR) model that established a linear correlation between the computed free energies (ΔΔG_com) of AT1-IP complex formation and the experimentally derived pIC₅₀^exp values, where pIC₅₀^exp = − logIC₅₀^exp. Subsequently, we evaluated the Virtual Compound Library (VCL) utilizing Lipinski's Rule of Five and the PH4 model, followed by an assessment of the potency of the novel IP analogues employing the maintained QSAR model. The pharmacokinetic characteristics of the resultant analogues have been assessed. The linear correlation equation obtained for the QSAR model is: pIC₅₀^exp = − 0.0687×ΔΔG_com + 8.035 (R² = 0.94). This relationship shows a strong correlation between the calculated free energies (ΔΔGcom) and the experimental values of pIC₅₀. Additionally, the linear correlation between experimental and predicted values for the pharmacophoric model (PH4) is expressed as follows: pIC₅₀^exp = 0.9316 × pIC₅₀^pre + 0.497 (R² = 0.93). This correlation validates the good predictive power of the developed pharmacophoric model. Lastly, the virtual screening of the IP analogue library found 43 compounds that might work well when taken by oral or through intravenous applications. The best candidate among them had a good pharmacokinetic profile and a preliminary inhibitory power (IC₅₀^pre) of 29.18 pm which was linked to a positive pharmacokinetic profile. This makes it a promising candidate for future experimental studies. The combination of molecular modelling and pharmacophore-based screening of the virtual library has led to the identification of new antihypertensive agents with favourable pharmacokinetic profiles.