Discovery of 2-[[2-Ethyl-6-[4-[2-(3-hydroxyazetidin-1-yl)-2-oxoethyl]piperazin-1-yl]-8-methylimidazo[1,2-a]pyridin-3-yl]methylamino]-4-(4-fluorophenyl)thiazole-5-carbonitrile (GLPG1690), a First-in-Class Autotaxin Inhibitor Undergoing Clinical Evaluation for the Treatment of Idiopathic Pulmonary Fibrosis.

Autotaxin is a circulating enzyme with a major role in the production of lysophosphatic acid (LPA) species in blood. A role for the autotaxin/LPA axis has been suggested in many disease areas including pulmonary fibrosis. Structural modifications of the known autotaxin inhibitor lead compound 1, to attenuate hERG inhibition, remove CYP3A4 time-dependent inhibition, and improve pharmacokinetic properties, led to the identification of clinical candidate GLPG1690 (11).

Around the macrolide - Impact of 3D structure of macrocycles on lipophilicity and cellular accumulation.

The aim of this study was to investigate lipophilicity and cellular accumulation of rationally designed azithromycin and clarithromycin derivatives at the molecular level. The effect of substitution site and substituent properties on a global physico-chemical profile and cellular accumulation of investigated compounds was studied using calculated structural parameters as well as experimentally determined lipophilicity. In silico models based on the 3D structure of molecules were generated to investigate conformational effect on studied properties and to enable prediction of lipophilicity and cellular accumulation for this class of molecules based on non-empirical parameters.

Quantification of malondialdehyde by HPLC-FL - application to various biological samples.

Malondialdehyde (MDA) is stabile product of lipid peroxidation (LPO), and therefore MDA is frequently used as a biomarker of LPO. To determine MDA level in various biological samples (human plasma, fish liver tissue and cells in culture), we used an HPLC method with fluorescent detection based on 2-thiobarbituric acid (TBA) assay. The method was validated by the use of spiked pooled plasma samples.

A comparison of in vitro ADME properties and pharmacokinetics of azithromycin and selected 15-membered ring macrolides in rodents.

The purpose of this study was to evaluate the impact of structural modifications on the 15-membered macrolactone ring and/or substituents on the in vitro ADME properties and in vivo pharmacokinetic (PK) profile for selected derivatives in rodents in comparison to azithromycin. Azithromycin and seven selected 15-membered macrolide derivatives, modified either by removal of the sugar moieties, replacement of the amine with a lactam, or addition of lipophilic substituents, were screened in several in vitro ADME assays and in vivo PK studies in rodents. In vitro ADME profiling included assessment of passive permeability and P-gp substrate, metabolic stability in liver microsomes and hepatocytes, as well as CYP direct inhibition measurements.

Macrolactonolides: a novel class of anti-inflammatory compounds.

A new concept in design of safe glucocorticoid therapy was introduced by conjugating potent glucocorticoid steroids with macrolides (macrolactonolides). These compounds were synthesized from various steroid 17β-carboxylic acids and 9a-N-(3-aminoalkyl) derivatives of 9-deokso-9a-aza-9a-homoeritromicin A and 3-descladinosyl-9-deokso-9a-aza-9a-homoeritromicin A using stable alkyl chain. Combining property of macrolides to preferentially accumulate in immune cells, especially in phagocyte cells, with anti-inflammatory activity of classic steroids, we designed molecules which showed good anti-inflammatory activity in ovalbumin (OVA) induced asthma in rats.

Investigating the barriers to bioavailability of macrolide antibiotics in the rat.

The aim of this study was to compare the roles of gastrointestinal absorption and hepatic extraction as barriers to oral bioavailability for macrolide antibiotics erythromycin, clarithromycin, roxithromycin and telithromycin. In this study, the in vitro metabolic stability in rat liver microsomes and hepatocytes, as well as the in vivo pharmacokinetics in rats were determined following intravenous, intraportal, oral and intraduodenal routes of administration. Pharmacokinetic parameters were calculated for each compound for each route of administration.

Intensity of macrolide anti-inflammatory activity in J774A.1 cells positively correlates with cellular accumulation and phospholipidosis.

Some macrolide antibiotics were reported to inhibit interleukin-6 (IL6) and prostaglandin-E2 (PGE(2)) production by bacterial lipopolysaccharide (LPS) stimulated J774A.1 cells. Macrolides are also known to accumulate in cells and some were proven inducers of phospholipidosis.

Modeling cellular pharmacokinetics of 14- and 15-membered macrolides with physicochemical properties.

Macrolides with 14- and 15-membered ring are characterized by high and extensive tissue distribution, as well as good cellular accumulation and retention. Since macrolide structures do not fit the Lipinski rule of five, macrolide pharmacokinetic properties cannot be successfully predicted by common models based on data for small molecules. Here we describe the development of the first models for macrolide cellular pharmacokinetics.

Determination of aqueous stability and degradation products of series of coumarin dimers.

The stability in aqueous solution of five classes of coumarin dimers (I-V, compounds 1-29) was studied by HPLC-MS/MS at various pH values. The relationship between chemical structure and stability is discussed. It was found that dimeric compounds with strong electron withdrawing groups (EWGs) on the α-carbon to the bridging C-atom are stable at all pH values, whereas other derivatives undergo retro-Michael addition at rates which are also affected by the substituents on the aromatic rings.