ISSN print edition: 0366-6352 ISSN electronic edition: 1336-9075 Registr. No.: MK SR 9/7 Published monthly

Acidity, lipophilicity, solubility, absorption, and polar surface area of some ACE inhibitors

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Comenius University, Odbojárov 10, SK-832 32 Bratislava, Slovakia

E-mail: remko@fpharm.uniba.sk

Received: 29 September 2006  Revised: 15 November 2006  Accepted: 22 November 2006

Abstract: Computational chemical methods have been used to correlate the molecular properties of the 10 ACE inhibitors (captopril, enalapril, perindopril, lisinopril, ramipril, trandolapril, quinapril, fosinopril, benazepril, and cilazapril) and some of their active metabolites (enalaprilat, perindoprilat, ramiprilat, trandolaprilat, quinaprilat, fosinoprilat, benazeprilat, and cilazaprilat). The computed pK _a values correlate well with the available experimental values. In the dicarboxylic ACE inhibitors, the carboxyalkyl carboxylate group of the ACE inhibitors studied is more acidic than the C-terminal carboxylate. However, at physiological pH = 7.4 both carboxyl groups of ACE inhibitors are completely ionized and the dicarboxyl-containing ACE inhibitors behave as strong acids. The available experimental partition coefficients of these ACE inhibitors investigated are well reproduced by the neural network-based ALOGPs and the fragment-based KoWWiN methods. All parent drugs (and prodrugs), with the exception of fosinopril, are compounds with low lipophilicity. Calculated pK _a, lipophilicity, solubility, absorption, and polar surface area of the most effective ACE inhibitors for the prevention of myocardial infarction, perindopril and ramipril, were found similar. Therefore, it is probable that the experimentally observed differences in the survival benefits in the first year after acute myocardial infarction in patients 65 years of age or older correlate closely to the physicochemical and pharmacokinetic characteristics of the specific ACE inhibitor that is used.

Full paper is available at www.springerlink.com.

DOI: 10.2478/s11696-007-0010-y

Chemical Papers 61 (2) 133–141 (2007)