Dirk Leysen

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Medicinal chemist with 35 years of experience with drug research and early development. Academia, Pharma, biotech, start-up experience.Since few year applying background in medicinal chemistry in the field of waste- / surface water treatment to remove / recycle chemicals and APIs. Personal focus on health aspects, (bio)chemistry, micro pollutants and endocrine disruptors.Adagio: using chemistry to restore chemical damage.

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Papers by Dirk Leysen

5-CARBOXAMIDO Substitued Thiazole Derivatives That Interact with Ion Channels, in Particular with Ion Channels from the KV Family

Predicting Residual Adsorbable Organic Halides Concentrations in Industrial Wastewater Using Typical Wastewater Parameters

Water, 2020

The aim of this study was to predict the residual adsorbable organic halides (AOX) concentration ... more The aim of this study was to predict the residual adsorbable organic halides (AOX) concentration in an industrial wastewater using conventional, easy-to-measure wastewater parameters. In a pilot test unit, the wastewater was subjected to ozonation at various intensities, resulting in an AOX-removal and hence varying AOX concentrations. In first instance, the parameters used for modeling were selected using Pearson and Spearman correlations. Secondly, multiple linear regression (MLR) was used as a modeling tool to predict both the soluble and total AOX concentration in wastewater samples. To prevent overfitting, a 10-fold cross-validation was carried out. It was found that both the soluble and the total AOX concentration can be predicted using typical wastewater parameters. The measured parameters were pH, chloride concentration, Water-Soluble Organic Carbon concentration (WSOC), UV-VIS spectrum, turbidity, and Solids Removable by Filtration (SRF). Out of these parameters, the follow...

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Heterocyclic amides as inhibitors of ROCK

A compound of the formula I, or its stereoisomer, tautomer, racemic, salt, osolvate hydrate: ** F... more A compound of the formula I, or its stereoisomer, tautomer, racemic, salt, osolvate hydrate: ** Formula ** in which: R1 is selected from the group comprising hydrogen, alkyl or cycloalkyl; Ar is selected from the group comprising: ** Formula ** where X is selected from Y is an aryl or heteroaryl substituted with a substituent selected from the group consisting of -C (> = O) -SR22, -C (> = O) -NR3R4, carbon, -O -alkenyl of 2 to 8 carbon atoms, carbon atoms or alkenyl of 2 to 8 carbon atoms; where -O-alkyl of 1 to 6 carbon atoms, 8 carbon atoms, -S-alkenyl of 2 to 8 carbon atoms, alkenyl of 2 to 8 carbon atoms are each independently substituted with a substituent selected from the group consisting of R3 is selected from the group consisting of hydrogen, alkenyl of 2 to 8 carbon atoms, substituted with O-Het2 or - S-Het3; or alkyl of 1 to 20 carbon atoms, optionally substituted substituents, each independently selected from the group consisting of aryl, heteroaryl, cycloalkenyl o...

14,15-METHYLENE Substituted Beta-Androgens

Dérivés d'azétidine et de pyrrolidine

Androgen 7-alpha alkyl orally active

A compound of structural formula where: R1 is O, (H, H), (H, OR), NOR, with R being hydrogen, (1-... more A compound of structural formula where: R1 is O, (H, H), (H, OR), NOR, with R being hydrogen, (1-6C) alkyl or (1-6C) alkyl; R2 is alkyl (C2-3), isopropyl, 1-alkenyl (C2-3), isopropenyl, 1, 2-propadienyl or 1-alkynyl (2-3C), each optionally substituted by halogen; or R2 is cyclopropyl or cyclopropenyl, each optionally substituted by (1-2C) alkyl or halogen; R3 is hydrogen, (1-2C) alkyl or ethenyl; R4 is (1-2C) alkyl; R5 is hydrogen or acyl (C1-15), and the dotted lines indicate optional bonds; with the proviso that the compound is not (7a, 17 /) - 7-ethyl-17-hydroxyestr-4-en-3-one (7a-ethyl-19-nortestosterone) or a carboxylic ester thereof and that is not (7a, 17 /) - 17- (acetyloxy) -7-propilestr-4-en-3-one (7-ethyl-19-nortestosterone apropil).

Benzylamines substitues et leur utilisation dans le traitement de la depression

La presente invention se rapporte a certains nouveaux derives de benzylamines de la formule (I) d... more La presente invention se rapporte a certains nouveaux derives de benzylamines de la formule (I) dans laquelle R1 et R2, pouvant etre identiques ou differents, sont chacun selectionnes parmi aryle en C?6-12?, heteroaryle en C2-14, C6-12arylC1-6alkyle, C2-14heteroarylC1-6alkyle (la fraction alkyl, aryl ou heteroaryl pouvant etre eventuellement substituee par un ou plusieurs substituants selectionnes parmi alcoxy en C1-6, alkyle en C1-6, cycloalkyle en C3-6, cycloalcenyle en C4-6, aryle en C6-12, heteroaryle en C2-14, halogene, amino, hydroxy, haloC1-6alkyle, nitro, C1-6alkylthio, sulfonamide, C1-6alkylsulfonyle, hydroxy-C1-6alkyle, C1-8alcoxycarbonyle, carboxyle, carboxyC1-6alkyle, carboxamide et C1-6alkylcarboxamide), hydrogene, alkyle en C1-6, cycloalkyle en C3-6, cycloalcenyle en C4-6, alcenyle en C2-6, alcynyle en C2-6 et C1-6alcoxyC1-6alkyle (les fractions alkyle, cycloalkyle, cycloalcenyle, alcenyle, alcynyle ou alcoxyalkyle pouvant etre eventuellement substituees par un ou plus...

The effect of a local ROCK-inhibitor (AMA0076) combined with Benzalkolium chloride on the introcular pressure

Dérivés de thiazole substitués en position 5 par carboxamide, interagissant avec les canaux potassium dépendants de la famille kv

La presente invention concerne des composes qui interagissent avec des canaux ioniques. En partic... more La presente invention concerne des composes qui interagissent avec des canaux ioniques. En particulier, l’invention concerne des composes ayant la formule structurelle (I), (II), (III) ou (IV), des stereo-isomeres, des tautomeres, des racemiques, des promedicaments, des metabolites de ceux-ci, ou un sel pharmaceutiquement acceptable et/ou un solvate de ceux-ci, ou X, Y1, Y2, R1, n, R3, R8, R9, R10, L1, L2, Ar1 et Ar2 sont definis dans la revendication 1. La presente invention concerne egalement des procedes de preparation desdits composes, des compositions pharmaceutiques comprenant lesdits composes et l’utilisation desdits composes dans des procedes de traitement des corps humain et animal.

Derives de l'azetidine et de la pyrrolidine

L'invention concerne un compose de formule (I), dans laquelle A est un noyau a 5 ou 6 element... more L'invention concerne un compose de formule (I), dans laquelle A est un noyau a 5 ou 6 elements eventuellement insature, qui peut renfermer un heteroatome choisi entre N, O et S et qui peut etre substitue par oxo ou par alkyle C1-C6; R?1, R2 et R3? sont independamment H, alkyle C?1?-C6, alcoxy C1-C6, alcoxy C1-C6-alkyle C1-C6, carbo-alcoxy C1-C6 ou halogene; X est O ou S; et n est 1 ou 2; ou un sel pharmaceutiquement acceptable dudit compose, a l'exception de la 3-(naphth-1-yl-oxy)-pyrrolidine et de la 3-(5,6,7,8-tetrahydro-naphth-1-yl-oxy)-pyrrolidine. Ces composes sont des antidepresseurs et peuvent etre utilises pour traiter ou prevenir les pathologies en rapport avec la serotonine.

ROCK2 in Complex with 1426382-07-1

Chirality in drug design

Pharmacochemistry Library, 1997

Publisher Summary This chapter highlights chirality in drug design. All interactions leading to b... more Publisher Summary This chapter highlights chirality in drug design. All interactions leading to biological effects are of chiral nature, even with achiral ligands. Chirality is not an absolute requirement for potency nor selectivity. Selective 5-hydroxytryptamine (5-HT)2c agonists might be useful antidepressants, whereas 5-HT2c antagonists could be valuable drugs against anxiety. The 5-HT2c and 5-HT2A receptors are closely related; 78% of all amino acids within the transmembrane regions are identical. Therefore 5-HT2c selectivity is hard to obtain. To find new 5-HT2C agonists the active conformation of the natural ligand 5-HT is identified, which is used to perform 3-D database searches. This active conformation is determined by pharmacophore modeling and receptor docking. For the construction of a pharmacophore model, chiral reference compounds are used along with non-chiral ligands such as 5-HT and several phenylpiperazines. The minimum energy conformations are determined by using X-ray analysis and MM287- and ToBaD calculations. These conformations are described by X- and Y-coordinates, which represent the distances between the centre of the aromatic nuclei and the counter-ion A- of the protonated amine.

Novel Roflumilast analogs as soft PDE4 inhibitors

Bioorganic & Medicinal Chemistry Letters, 2014

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ChemInform Abstract: Monoamine Re‐Uptake Inhibiting 1‐(2‐((Phenoxyphenyl)methoxy)ethyl) piperazines as Potential Antidepressants

ChemInform, 2010

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was e... more ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

A new cleavage strategy for the solid-phase synthesis of secondary amines

Tetrahedron Letters, 1997

... 97)005029 00404039 97 17.00 + 0.00 A New Cleavage Strategy for the SolidPhase Synthesis of Se... more

Synthesis of C(2)Halomethyl Substituted Derivatives of 2,3-Dihydro-1,3-benzoxaz-4-ones

Synthetic Communications, 1993

Abstract In the pursuit of biologically active compounds we required as a key intermediate 2,3-di... more Abstract In the pursuit of biologically active compounds we required as a key intermediate 2,3-dihydro- 1,3-benzoxaz-bones having a halomethylene moiety at C(2), i.e. 3 (R2 = H or alkyl, R3 = CH2X). The standard procedure for the preparation of this class of compounds is the condensation of salicylamide derivatives 1 with the proper aldehyde1-5 and ketone5,6. Usually, hydrochloric acid or sulphuric acid is used as catalyst and the water formed is cocornmittently removed using a dehydrating agent or by azeotropic destillation7. These procedures did not serve our purpose as the required α-substituted aldehyde or ketone as such is unstable under the conditions employed. Here we report that employment of acetals and ketals 2 affords the desired compound 3; yields are appreciable when the proper reaction conditions are used.

Structure–activity relationship study of human liver microsomes-catalyzed hydrolysis rate of ester prodrugs of MENT by comparative molecular field analysis (CoMFA)

Steroids, 2003

A series of MENT esters (3-71) was designed, prepared and tested to study the structure-activity ... more A series of MENT esters (3-71) was designed, prepared and tested to study the structure-activity relationship (SAR) of the hydrolysis rate with human liver microsomes of these prodrugs. Compounds were obtained covering a wide range of metabolic stability. The results are useful for the proper selection of prodrugs for different pharmaceutical formulations to deliver the potent and prostate-sparing androgen MENT. The MENT esters can especially be administered for male hormone replacement therapy and male contraception. Comparative molecular field analysis (CoMFA) was applied to a dataset of 28 esters, for which ED50 values could be obtained. The CoMFA model where the electrostatic and H-bond molecular fields were combined turned out to be most predictive. Despite the limited size of the dataset, CoMFA can help to rationalize the SAR of the ester hydrolysis rate of ester prodrugs of MENT.

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Tibolone is not converted by human aromatase to 7α-methyl-17α-ethynylestradiol (7α-MEE)

Steroids, 2003

To exclude that aromatization plays a role in the estrogenic activity of tibolone, we studied the... more To exclude that aromatization plays a role in the estrogenic activity of tibolone, we studied the effect tibolone and metabolites on the aromatization of androstenedione and the aromatization of tibolone and its metabolites to 7␣-methyl-17␣-ethynylestradiol (7␣-MEE) by human recombinant aromatase. Testosterone (T), 17␣-methyltestosterone (MT), 19-nortestosterone (Nan), 7␣-methyl-19-nortestosterone (MENT) and norethisterone (NET) were used as reference compounds. Sensitive in vitro bioassays with steroid receptors were used to monitor the generation of product and the reduction of substrate. LC-MSMS without derivatization was used for structural confirmation. A 10 times excess of tibolone and its metabolites did not inhibit the conversion of androstenedione to estrone by human recombinant aromatase as determined by estradiol receptor assay whereas T, MT, Nan, and MENT inhibited the conversion for 75, 53, 85 and 67%, respectively. Tibolone, 3␣-and 3␤-hydroxytibolone were not converted by human aromatase whereas the estrogenic activity formed with the 4-isomer suggests a conversion rate of 0.2% after 120 min incubation. In contrast T, MT, Nan, and MENT were completely converted to their A-ring aromates within 15 min while NET could not be aromatized. Aromatization of T, MT, Nan and MENT was confirmed with LC-MSMS. Structure/function analysis indicated that the 17␣-ethynyl-group prevents aromatization of (19-nor)steroids while 7␣-methyl substitution had no effect. Our results with the sensitive estradiol receptor assays show that in contrast to reference compounds tibolone and its metabolites are not aromatized.

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Tibolone is not converted by human aromatase to 7α-methyl-17α-ethynylestradiol (7α-MEE)

Steroids, 2003

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A Comparison of the Physicochemical and Biological Properties of Mirtazapine and Mianserin

Journal of Pharmacy and Pharmacology, 1997

Although the chemical structures of the antidepressants mirtazapine and mianserin are closely rel... more 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. Isosteric replacement of CH in mianserin by N in mirtazapine has profound effects on physicochemical properties. The charge distributions as indicated by NMR and calculated by semi-empirical quantum mechanics differ, not only for the changed aromatic A-ring (as expected), but also in other regions of the molecule. The N5 atom in particular, which is conjugated to the changed aromatic ring, is less negatively charged in mirtazapine than in mianserin. Consequently the oxidation potential of mirtazapine is significantly higher than that of mianserin. Another result of this difference in charge distribution is that the (calculated) dipole-moment vectors of the compounds are oriented roughly perpend...

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5-CARBOXAMIDO Substitued Thiazole Derivatives That Interact with Ion Channels, in Particular with Ion Channels from the KV Family