title: A Comparative Study of Molecular Structure, pKa, Lipophilicity, Solubility, Absorption and Polar Surface Area of Some Antiplatelet Drugs.
abstract: Theoretical chemistry methods have been used to study the molecular properties of antiplatelet agents (ticlopidine, clopidogrel, prasugrel, elinogrel, ticagrelor and cangrelor) and several thiol-containing active metabolites. The geometries and energies of most stable conformers of these drugs have been computed at the Becke3LYP/6-311++G(d,p) level of density functional theory. Computed dissociation constants show that the active metabolites of prodrugs (ticlopidine, clopidogrel and prasugrel) and drugs elinogrel and cangrelor are completely ionized at pH 7.4. Both ticagrelor and its active metabolite are present at pH = 7.4 in neutral undissociated form. The thienopyridine prodrugs ticlopidine, clopidogrel and prasugrel are lipophilic and insoluble in water. Their lipophilicity is very high (about 2.5-3.5 logP values). The polar surface area, with regard to the structurally-heterogeneous character of these antiplatelet drugs, is from very large interval of values of 3-255 Å². Thienopyridine prodrugs, like ticlopidine, clopidogrel and prasugrel, with the lowest polar surface area (PSA) values, exhibit the largest absorption. A high value of polar surface area (PSA) of cangrelor (255 Å²) results in substantial worsening of the absorption in comparison with thienopyridine drugs.
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Comenius University in Bratislava, Odbojarov 10, SK-832 32 Bratislava, Slovakia. remko@fpharm.uniba.sk.
authors.forename: Milan
authors.initials: M
authors.lastname: Remko
authors.affiliation: Department of Internal Medicine, Faculty of Medicine, Slovak Medical University, Limbová 12, SK-833 03 Bratislava, Slovakia. aremkova@szu.sk.
authors.forename: Anna
authors.initials: A
authors.lastname: Remková
authors.affiliation: Department of Theoretical Chemistry, Zernike Institute for Advanced Materials, University of Groningen, Nijenborgh 4, 9747 AG Groningen, The Netherlands. R.Broer@rug.nl.
authors.forename: Ria
authors.initials: R
authors.lastname: Broer
mesh_terms: D065966:Absorption, Physicochemical; D057927:Hydrophobic and Hydrophilic Interactions; D015394:Molecular Structure; D010975:Platelet Aggregation Inhibitors / Q000737:chemistry*; D012995:Solubility; D013499:Surface Properties
chemical_list: D010975:Platelet Aggregation Inhibitors
keywords: absorption; antiplatelet agents; lipophilicity; molecular structure; pKa; polar surface area; solubility; solvent effect