Jan Kelder

Polar Molecular Surface as a Dominating Determinant for Oral Absorption and Brain Penetration of Drugs

AbstractPurpose. To study oral absorption and brain penetration as a function of polar molecular surface area. Methods. Measured brain penetration data of 45 drug molecules were investigated. The dynamic polar surface areas were calculated and correlated with the brain penetration data. Also the static polar surface areas of 776 orally administered CNS drugs that have reached at least Phase II efficacy studies were calculated. The same was done for a series of 1590 orally administered non-CNS drugs that have reached at least Phase II efficacy studies. Results. A linear relationship between brain penetration and dynamic polar surface area (Å2) was found (n = 45, R = 0.917, F1,43 = 229). Brain penetration decreases with increasing polar surface area. A clear difference between the distribution of the polar surface area of the 776 CNS and 1590 non-CNS drugs was found. It was deduced that orally active drugs that are transported passively by the transcellular route should not exceed a polar surface area of about 120 Å2. They can be tailored to brain penetration by decreasing the polar surface to <60−70 Å2. This conclusion is supported by the inverse linear relationship between experimental brain penetration data and the dynamic polar surface area of 45 drug molecules. Conclusions. The polar molecular surface area is a dominating determinant for oral absorption and brain penetration of drugs that are transported by the transcellular route. This property should be considered in the early phase of drug screening.

Use of physicochemical calculation of pKa and CLogP to predict phospholipidosis-inducing potential: A case study with structurally related piperazines

Several cationic amphiphilic compounds are known to induce phospholipidosis, a condition primarily characterized by excessive accumulation of phospholipids in different cell types, giving the affected cells a finely foamy appearance. Excessive storage of lamellar membranous intralysosomal inclusion bodies is the hallmark for phospholipidosis on the electron microscopic level. In case of alveolar phospholipidosis, foamy macrophages accumulate within the alveolar spaces of the lung. Based on such findings in a one-year toxicity study with gepirone in rats, we studied the molecular properties of this compound and compounds suspected of being phospholipidosis inducers by means of physicochemical calculations. Physicochemical molecular calculations of molecular weight, ClogP (partition coefficient octanol/water), logD at pH 7.4, and pKa were performed, for the cationic amphiphilic compounds chlorpromazine, amiodarone, imipramine, propranolol and fluoxetine, and for the structurally related compounds 1-phenylpiperazine (1-PHP), gepirone (and its major metabolites, 3-OH-gepirone and 1-pyrimidinylpiperazine [1-PP]), and buspirone. ClogP and calculated pKa cluster differently for the amphiphilic drugs compared to the chemical series of piperazines. In line with this analysis, lamellar inclusion bodies were found in an in vitro validation experiment in the human monoblastoid cell line U-937, incubated for 96 h at 10 microg/mL with cationic amphiphilic drugs (amiodarone, imipramine, or propranolol). No such lamellar inclusion bodies were seen for any of the compounds from the chemical series of piperazines including gepirone and its metabolites. The data presented support the use of simple physicochemical calculations of ClogP and pKa to discriminate rapidly between compounds suspected of being phospholipidosis inducers. Finally, the discriminative power of these physicochemical ClogP and pKa calculations to predict phospholipidosis-inducing potential was further validated by extension of the set of compounds.

A comparison of the physicochemical and biological properties of mirtazapine and mianserin

Although the chemical structures of the antidepressants mirtazapine and mianserin are closely related there are considerable differences in their biological properties. To find an explanation of this, various physicochemical properties of mirtazapine and mianserin were measured or calculated.

Physicochemical properties and transport of steroids across Caco-2 cells.

AbstractPurpose. The purpose of this work was to study the relevant physicochemical properties for the absorption of steroids. Methods. Various physicochemical properties of steroids were calculated (molecular weight, ClogP, static polar surface area [PSA], etc.). Within this series of steroids, different pharmacological groups were defined. Based on the outcome of this survey, steroids were selected for the Caco-2 permeability study. The apparent permeability coefficients (Papp) were related to the calculated and measured physicochemical properties. Results. Between the defined groups of steroids, ClogP was the most discriminative descriptor. The steroids were well transported over the cell monolayers and the Papp was independent of the concentration and the transport direction. No relationship was found with the PSA; however, the Papp showed a weak inverse correlation with ClogP. Conclusions. The molecular descriptors and Papp values showed that all steroids are well transported. The small differences in the Papp values showed a weak inverse correlation with ClogP: the hydrophilic steroids (ClogP approximately 0-2) tend to diffuse faster over the cell monolayers compared with the more hydrophobic steroids (ClogP approximately 5). The relationship with ClogP suggests that partitioning of steroids between the biologic membrane and the surrounding aqueous phase is one of the main mechanisms for absorption.

Relation between the molecular electrostatic potential and activity of some FF-MAS related sterol compounds.

Follicular Fluid-Meiosis Activating Sterol (FF-MAS) is a compound important for maturation of gametes in mammals. Therefore, it may serve as a lead compound for a novel method of contraception. We studied the Molecular Electrostatic Potential of a series of active and inactive analogues of FF-MAS. We find that double bond configurations required for activity result in a local negative electrostatic potential which is larger as well as more dense compared to those of inactive molecules. We therefore hypothesize that the interaction energy of the double bond system of the MAS compounds with its receptor substantially contributes to the overall interaction energy. This notion is supported by interaction studies of the electrostatic potential originating from the double bonds in crystal structures of cholesterol and four MAS-derived Delta(8,14) structures synthesized and crystallized by us. In addition, we were able to derive a pharmacophore model that relates the local average ESP and its distance to the 3beta-OH oxygen atom to the activity of the molecules.

Molecular structure of vecuronium bromide, a neuromuscular blocking agent. Crystal structure, molecular mechanics and NMR investigations

The crystal and molecular structure of vecuronium bromide {1-[2β,3α,5α,16β,17β)-3,17-bis(acetyloxy)-2-(piperidin-1-yl)androstan-16-yl]-1-methylpiperidinium bromide}, a potent non-depolarizing neuromuscular blocking agent, has been determined by single-crystal X-ray diffraction analysis. The compound crystallizes in the orthorhombic system, space group P212121. The observed axial conformation of the A ring acetoxy and piperidinyl substituents at positions 2 and 3 of the steroid skeleton is also present in solution, as is indicated by NMR experiments. After protonation of the piperidinyl group at position 2 this conformation changes into an equatorial conformation similar to the one observed in the N-methylated analogue pancuronium bromide. Molecular mechanics calculations have been performed to explain these observations.

Calculated heats of formation of sterol diene isomers compared with synthetic yields of isomerisation reactions of Δ5,7 sterols

Heats of formation of five series of diene sterol isomers were calculated and compared with synthetic yields of acid-catalysed isomerisation reactions starting from Δ5,7 isomers. Calculations were based on molecular mechanics, using the MM3 program package. For each of the five Δ5,7 starting compounds, three possible reaction paths were considered, in which heats of formation were calculated for theoretically possible intermediate double bond isomers. Similar results are found for all five series. The starting compounds are found to have the unfavourable heats of formation compared to all other isomers considered within one series. In general, isomerisation reactions of diene sterols ultimately yield spiro compounds when allowed to proceed for a sufficient amount of time. These compounds are found to have the lowest heats of formation in each series. However, they were not formed in the reactions considered in this paper, because the reactions were stopped after the desired isomer was formed in excess, before the spiro compounds could occur. Most compounds identified as products in the syntheses have a favourable heat of formation compared to the isomers preceding the (most stable) spiro compounds. However, when the reactions were carried out at low temperature, isomers with less favourable heats of formation could be trapped. We show that calculated heats of formation correspond well with synthetic yields and we suggest they can be a useful tool in planning syntheses.

The conformation of the A-ring fragment of neuromuscular blocking agents structurally related to pancuronium. X-Ray structure determinations, molecular mechanics calculations and molecular dynamics simulations

Org 9616 [1-{(2β,3α,5α,16β,17α)-3-acetoxy-17-(1-oxobutoxy)-2-(piperidin-1-yl)androstan-16-yl}-1-methylpiperidinium bromide] is a non-depolarizing neuromuscular blocking agent, structurally related to pancuroniam. The reported crystal structures of the free base and the HBr salt show that the monoquaternary aminosteroid changes from a vecuronium-like conformation with the A-ring substituents in an axial orientation to a pancuroniam-like conformation with the A-ring substituents in an equatorial orientation upon protonation. The conformations observed in the X-ray structures of Org. 9616 and several other neuromuscular blockers, suggest a different conformational behaviour of the piperidino group attached to the A-ring of the steroid skeleton in pancuroniam and protonated veuronium. The conformational flexibilities of the A-ring and substituents in pancuroniam, vecuronium and protonated veuronium are more closely investigated by means of molecular mechanics calculations and molecular dynamics simulations. A model explaining the difference in selectivity between pancuroniam and vecuronium is based on the conformational behaviour of this part of the molecule. The relevance of the presented model for the 3β-methyl analogues of pancuroniam and vecuronium and the 2β-trimethylammonium analogue of pancuroniam is discussed.