Acrivastine

Analysis of structure-kinetic relationships (SKR) can contribute to an improved understanding of receptor-ligand interactions. Here, fragment 1 (4-(2-benzylphenoxy)-1-methylpiperidine) was used in different fragment growing approaches to mimic the putative binding mode of the long residence time (RT) ligands olopatadine, acrivastine, and levocetirizine at the histamine H₁ receptor (H₁R). SKR analyses reveal that introduction of a carboxylic acid moiety can increase RT at H₁R up to 11-fold. Ligand efficiency (LE) decreases upon the introduction of the negatively charged group, whereas kinetic efficiency (KE) increases up to 8.5-fold. The olopatadine/acrivastine mimics give up to 15-fold differences in the RT, while the levocetirizine mimics afford similar RTs with only a 3-fold difference. Therefore, the levocetirizine mimics are less sensitive to structural changes. This study illustrates that for H₁R, there are several ways to increase RT but the different strategies differ significantly in SKR.

Zwitterions contain both positively and negatively charged functional groups, resulting in an overall net neutral charge. Nevertheless, the membrane permeability of the zwitterionic form of a compound is assumed to be much lower than the permeability of the uncharged neutral form. Although a significant proportion of pharmaceuticals are zwitterionic, it has not been clear so far whether their permeability is dominated by the permeation of the zwitterionic or the neutral form, since neutral fractions are often quite low as compared to the zwitterionic fraction. This complicates the in silico prediction of the permeability of zwitterionic compounds. In this work, we re-evaluated existing in vitro permeability data from literature measured with Caco-2/MDCK cell assays, using more strict exclusion criteria for effects like diffusion limitation by the aqueous boundary layers, paracellular transport, active transport and retention. Using this re-evaluated data set, we show that extracted intrinsic permeabilities of the neutral fraction are well predicted by the solubility-diffusion model (RMSE = 1.21; n = 18) if the permeability of the zwitterionic species is assumed negligible. Our work thus suggests that only the neutral species is relevant for the membrane permeability of zwitterionic compounds, and that membrane permeability of zwitterionic compounds is indeed predictable by the solubility-diffusion model.