Gebhard Thoma

Novartis · Chemistry

Suitable human models for the development and characterization of topical compounds for inflammatory skin diseases such as atopic dermatitis are not readily available to date. We describe here the development of a translational model involving healthy human skin mimicking major aspects of AD and its application for the characterization of topical J...

LYS006 is a novel, highly potent and selective, new‐generation leukotriene A4 hydrolase (LTA4H) inhibitor in clinical development for the treatment of neutrophil‐driven inflammatory diseases. We describe the complex pharmacokinetic to pharmacodynamic (PD) relationship in blood, plasma, and skin of LYS006‐treated nonclinical species and healthy huma...

We present a novel concept for the design of supersoft topical drugs. Enzymatic cleavage of the carbonate ester of the potent pan Janus kinase (JAK) inhibitor 2 releases hydroxypyridine 3. Due to hydroxypyridine-pyridone tautomerism, 3 undergoes a rapid conformational change preventing the compound to assume the bioactive conformation required for...

The JAK kinases JAK1, JAK2, JAK3, and TYK2 play key roles in cytokine signaling. Activation of the JAK/STAT pathways is linked to many diseases involving the immune system, including atopic dermatitis. As systemic JAK inhibitor pharmacology is associated with side effects, topical administration to the skin has been considered to locally restrict t...

Design and optimization of benzo- and pyrido-thiazoles/isothiazoles are reported leading to the discovery of the potent, orally bioavailable Syk inhibitor 5, which was found to be active in a rat PK/PD model. Compound 5 showed acceptable overall kinase selectivity. However, in addition to Syk it also inhibited Aurora kinase in enzymatic and cellula...

We describe the discovery of the selective and potent Syk inhibitor 11, which exhibited favorable PK profiles in rat and dog and was found to be active in a collagen induced arthritis model in rats. Compound 11 was selected for further profiling but, unfortunately, in GLP toxicological studies it showed liver findings in rat and dog. Nevertheless,...

Jak3, together with Jak1, is involved in signal transduction initiated by cytokines signaling through the common gamma chain which are important in immune homeostasis and immune pathologies. Based on genetic evidence Jak3 has been considered to be an attractive target for immunosuppression. The Jak inhibitor tofacitinib (CP-690,550) which is an app...

We describe two series of Syk inhibitors which potently abrogate Syk kinase function in enzymatic assays, cellular assays and in primary cells in the presence of blood. Introduction of a 7-aminoindole substituent led to derivatives with good kinase selectivity and little or no hERG channel inhibition (3b, 10c).

The structure-activity relationship of highly potent special ergolines which selectively block the chemokine receptor CXCR3 is reported. The most potent compounds showed IC(50) values below 10nM in both ligand binding and Ca(2+)-mobilization assays. However, these compounds were poorly active in an assay that measures receptor occupancy in blood. I...

CXCL10 is one of the key chemokines involved in trafficking of autoaggressive T cells to the islets of Langerhans during the autoimmune destruction of beta cells in type 1 diabetes (T1D). Blockade of CXCL10 or genetic deletion of its receptor CXCR3 results in a reduction of T1D in animal models. As an alternative to the use of neutralizing monoclon...

Genetic deficiency of Jak3 leads to abrogation of signal transduction through the common gamma chain (γc) and thus to immunodeficiency suggesting that specific inhibition of Jak3 kinase may result in immunosuppression. Jak1 cooperates with Jak3 in signaling through γc-containing receptors. Unexpectedly, a Jak3-selective inhibitor was less efficient...

Antagonism of CXCR4 disrupts the interaction between the CXCR4 receptor on hematopoietic stem cells (HSCs) and the CXCL12 expressed by stromal cells in the bone marrow, which subsequently results in the shedding of HSCs to the periphery. Because of their profound immunomodulatory effects, HSCs have emerged as a promising therapeutic strategy for au...

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.

We describe a synthetic approach toward the rapid modification of phenyl-indolyl maleimides and the discovery of potent Jak3 inhibitor 1 with high selectivity within the Jak kinase family. We provide a rationale for this unprecedented selectivity based on the X-ray crystal structure of an analogue of 1 bound to the ATP-binding site of Jak3. While e...

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.

Pig-to-human xenotransplantation of islet cells or of vascularized organs would offer a welcome treatment alternative for the ever-increasing number of patients with end-stage organ failure who are waiting for a suitable allograph. The main hurdle are preexisting antibodies, most of which are specific for 'Linear-B', carbohydrate epitopes terminate...

The special ergoline 1 is a highly potent, selective antagonist of the chemokine receptor CXCR3. The surprising selectivity of this LSD-related compound can be explained by different electronic and steric properties of the ergoline core structure caused by the urea portion of the molecule. Discovery, biopharmaceutical properties and first derivativ...

Chemokine receptors have gained attention as potential targets for novel therapeutic strategies. We investigated the mechanisms of allograft rejection in chemokine receptor Cxcr3-deficient mice using a model of acute heart allograft rejection in the strain combination BALB/c to C57BL/6. Allograft survival was minimally prolonged in Cxcr3-deficient...

Introduction of polar groups in a series of potent CCR5 antagonists which are very likely to adversely affect the conduction system in the heart led to the identification of NIBR-1282 which did not show adverse effects when tested in an isolated rabbit heart ex vivo model. Administration of NIBR-1282 in combination with a non-efficacious dose of Cs...

Polyvalent carbohydrate-protein interactions occur frequently in biology, particularly in recognition events on cellular membranes. Collectively, they can be much stronger than corresponding monovalent interactions, rendering it difficult to control them with individual small molecules. Artificial macromolecules have been used as polyvalent ligands...

The synthesis of the first polylysine conjugates that present different carbohydrate ligands in a multivalent format is reported. Glycopolymers 3c and 3d have been prepared with a highly predictable composition as indicated by H-1 NMR. They function as multivalent E-selectin inhibitors but their potencies are not superior compared to previously-des...

The chemokine receptor CCR5 plays an important role in inflammatory and autoimmune disorders as well as in transplant rejection by affecting the trafficking of effector T cells and monocytes to diseased tissues. Antagonists of CCR5 are believed to be of potential therapeutic value for the disorders mentioned above and HIV infection. Here we report...

Selectins mediate leukocyte rolling and may represent good anti-inflammatory drug targets. Detailed knowledge regarding the structure of selectin ligands has permitted development of selectin antagonists with varying specificities and activity. Efficacy of monovalent selectin antagonists may be increased by presenting them on a polymer backbone. We...

The simplified sialyl Lewisx mimic 5 containing a D-arabinose, a 3-cyclohexyl-2-hydroxypropanoate, and a tetrahydropyran building block instead of L-fucose, sialic acid, and N-acetylglucosamine, respectively was synthesized. Compound 5 was 10-fold more potent than sLex in a static E-selectin binding assay and showed at 50 μM 75% inhibition in a dyn...

Preformed and elicited Ab's against the Galalpha1,3Gal terminating carbohydrate chains (alphaGal Ab's) are the primary cause of hyperacute and acute vascular xenograft rejection in pig-to-primate transplantation. alphaGal Ab's are produced by long-lived Ab-producing cells that are not susceptible to pharmacological immunosuppression. We reasoned th...

Naive Th cells, bearing receptors for cutaneous antigens, become activated in skin-draining lymph nodes and express cutaneous lymphocyte antigen (CLA), which confers to these cells the capacity to migrate into the skin to exert their normal effector functions. In the case of atopic dermatitis (AD), allergen-specific Th2 cells generate exacerbated r...

Preformed and elicited Ab's against the Galalpha1,3Gal terminating carbohydrate chains (alphaGal Ab's) are the primary cause of hyperacute and acute vascular xenograft rejection in pig-to-primate transplantation. alphaGal Ab's are produced by long-lived Ab-producing cells that are not susceptible to pharmacological immunosuppression. We reasoned th...

Naive Th cells, bearing receptors for cutaneous antigens, become activated in skin‐draining lymph nodes and express cutaneous lymphocyte antigen (CLA), which confers to these cells the capacity to migrate into the skin to exert their normal effector functions. In the case of atopic dermatitis (AD), allergen‐specific Th2 cells generate exacerbated r...

G.T. thanks Prof. M. Reza Ghadiri for the opportunity of a sabbatical stay in his laboratory at the Scripps Research Institute. We also would like to thank Mr. Klaus Menninger for his assistance in the monkey experiment.

Von der Größe hängt es ab: Durch Selbstorganisation von Glycodendrimeren, die sowohl einen Liganden als auch eine selbstorganisierende Gruppe enthalten, werden nichtkovalente Nanopartikel gebildet. Optimale Partikelgrößen werden mit der zweiten und dritten Generation erreicht, größere Dendrimerspezies zeigen weniger effiziente Selbstorganisation. E...

Eine Mischung aus Zufall, Spürsinn und rationalem Design führte zu 1, dem derzeit wirksamsten E-Selectin-Inhibitor. 1 wurde in einer zehnstufigen Synthese in einer Gesamtausbeute von >25 % erhalten. In einem statischen Assay war 1 hundertmal wirksamer als Sialyl-Lewisx. In einem noch aussagekräftigeren Fluss-Assay, der die dynamischen In-vivo-Bedin...

Eine Mischung aus Zufall, Spürsinn und rationalem Design führte zu 1, dem derzeit wirksamsten E-Selectin-Inhibitor. 1 wurde in einer zehnstufigen Synthese in einer Gesamtausbeute von >25 % erhalten. In einem statischen Assay war 1 hundertmal wirksamer als Sialyl-Lewisx. In einem noch aussagekräftigeren Fluss-Assay, der die dynamischen In-vivo-Bedin...

Organisation zahlt sich aus: Die sterische Abstoßung zwischen Fucose und dem Methylsubstituenten am benachbarten Tetrahydropyran reduziert den Abstand zwischen Galactose und Fucose in dem E-Selectin-Antagonisten 1, verglichen mit dem Abstand in ähnlichen Verbindungen ohne Methylsubstituenten. Die Konformation von 1 in Lösung ähnelt der von 1, gebun...

Organisation zahlt sich aus: Die sterische Abstoßung zwischen Fucose und dem Methylsubstituenten am benachbarten Tetrahydropyran reduziert den Abstand zwischen Galactose und Fucose in dem E-Selectin-Antagonisten 1, verglichen mit dem Abstand in ähnlichen Verbindungen ohne Methylsubstituenten. Die Konformation von 1 in Lösung ähnelt der von 1, gebun...

It pays to be organized: Steric repulsion between fucose and the methyl substituent of the adjacent tetrahydropyran reduces the distance between galactose and fucose in the E-selectin antagonist 1 compared to the distance in closely related compounds that lack the methyl group. This effect causes a solution conformation of 1 that already resembles...

The synthesis of the highly potent E-selectin inhibitor 5 is described. Sialyl Lewis X mimic 5 was rationally designed by combining two previously disclosed beneficial sLe(x) modifications in a single molecule. The compound was found to be 30-fold more potent than sLe(x) in a static, cell-free equilibrium assay. Furthermore, compound 5 was highly a...

It pays to be organized: Steric repulsion between fucose and the methyl substituent of the adjacent tetrahydropyran reduces the distance between galactose and fucose in the E-selectin antagonist 1 compared to the distance in closely related compounds that lack the methyl group. This effect causes a solution conformation of 1 that already resembles...

Selectin-dependent rolling is the earliest observable event in the recruitment of leukocytes to inflamed tissues. Several glycoproteins decorated with sialic acid, fucose, and/or sulfate have been shown to bind the selectins. The best-characterized selectin ligand is P-selectin glycoprotein-1 (PSGL-1) that supports P-selectin- dependent rolling in...

Selectin-dependent rolling is the earliest observable event in the recruitment of leukocytes to inflamed tissues. Several glycoproteins decorated with sialic acid, fucose, and/or sulfate have been shown to bind the selectins. The best-characterized selectin ligand is P-selectin glycoprotein-1 (PSGL-1) that supports P-selectin– dependent rolling in...

In the search for drugs that could control excessive leukocyte extravasation, we now report on modifications of the already known potent E-selectin antagonist 3 containing a cyclohexyllactic acid residue and a glucal-derived building block. Thus, we describe the synthesis and biological evaluation of a series of derivatives 6 with modified glucal-d...

An early step of the inflammatory response-the rolling of leukocytes on activated endothelial cells-is mediated by selectin/carbohydrate interactions. The tetrasaccharide sialyl Lewis(x) (sLe(x)) 1 is a ligand for E-, P-, and L-selectin and, therefore, serves as a lead structure to develop analogues which allow the control of acute and chronic infl...

Glycopolymers are useful macromolecules with a non-carbohydrate backbone for presenting saccharides in a multivalent form. Here, a new methodology is described which allows easy access to water-soluble, biodegradable glycopolymers with both predeterminable composition and molecular weight distribution. Thus, chloroacetylation of commercially availa...

A protocol for the functionalization of polyaspartimide (PAI) with carbohydrates containing an amino funtion at the reducing end to give biodegradable neoglycoconjugates such as 4 is presented. Scope and limitation of the strategy with respect to the preparation of multivalent sialyl Lewisx5 are discussed.

The relation of the solution and bioactive conformation of sialyl Lewis x (sLe(x)) has been addressed by chemical means. To mimic the preferred solution conformation of sLe(x) 1, the more rigid analog 2 has been designed and synthesized. The sialic acid residue of 1 was replaced by a carboxylic acid function which is fixed in the equatorial positio...

Cited By (since 1996): 10, Export Date: 21 April 2012, Source: Scopus