RESUMEN
Chronic non-healing wounds impose a huge burden on patients and health care providers. In spite of improvements in standards of care there are no effective and safe treatments that promote new tissue formation and wound closure in ailments such as diabetic foot ulcer, pressure ulcer, venous leg ulcer or digital ulcer in systemic sclerosis. Endothelial dysfunction, which associates with impaired endogenous nitric oxide formation is assumed to be a main disease mechanism in chronic, non-healing wounds in diabetic and elderly patients as well as in digital ulcers in systemic sclerosis. Topadur Pharma has invented small molecular weight nitric oxide-releasing PDE5 inhibitors, which by modulating a key enzyme system of intracellular signaling may address chronic non-healing wounds. The promising first drug candidate TOP-N53 is currently in early clinical development. Here we describe for the first time the design of TOP-N53 and the synthesis of the clinical GMP batch.
Asunto(s)
Pie Diabético , Cicatrización de Heridas , Anciano , Pie Diabético/tratamiento farmacológico , HumanosRESUMEN
We report a new late-stage functionalization of small peptides and cyclopeptides relying on the Negishi cross-coupling of readily prepared iodotyrosine- or iodophenylalanine-containing peptides with aryl-, heteroaryl-, and alkylzinc pivalates or halides. In silico and in vitro determinations of membrane permeability parameters of the modified cyclopeptides showed that in most cases, the solubility was improved by the introduction of polar pyridyl units while the cell-membrane permeability was maintained.
RESUMEN
A fragment library consisting of 3D-shaped, natural product-like fragments was assembled. Library construction was mainly performed by natural product degradation and natural product diversification reactions and was complemented by the identification of 3D-shaped, natural product like fragments available from commercial sources. In addition, during the course of these studies, novel rearrangements were discovered for Massarigenin C and Cytochalasin E. The obtained fragment library has an excellent 3D-shape and natural product likeness, covering a novel, unexplored and underrepresented chemical space in fragment based drug discovery (FBDD).
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Productos Biológicos/química , Citocalasinas/química , Lactonas/química , Bibliotecas de Moléculas Pequeñas/química , Compuestos de Espiro/química , Productos Biológicos/síntesis química , Cristalografía por Rayos X , Citocalasinas/síntesis química , Descubrimiento de Drogas , Lactonas/síntesis química , Modelos Moleculares , Estructura Molecular , Bibliotecas de Moléculas Pequeñas/síntesis química , Compuestos de Espiro/síntesis químicaRESUMEN
We report a general preparation of arylated bicyclo[1.1.1]pentanes through the opening of [1.1.1]propellane with various arylmagnesium halides. After transmetalation with ZnCl2 and Negishi cross-coupling with aryl and heteroaryl halides, bis-arylated bicyclo[1.1.1]pentanes are obtained. These bis-arylated bicyclo[1.1.1]pentanes may be considered as bioisosteres of internal alkynes. Bioisosteres of tazarotene and the metabotropic glutamate receptor 5 (mGluR5) antagonist 2-methyl-6-(phenylethynyl)pyridine were prepared and their physicochemical properties were evaluated.
RESUMEN
We report a multi-objective deâ novo design study driven by synthetic tractability and aimed at the prioritization of computer-generated 5-HT2B receptor ligands with accurately predicted target-binding affinities. Relying on quantitative bioactivity models we designed and synthesized structurally novel, selective, nanomolar, and ligand-efficient 5-HT2B modulators with sustained cell-based effects. Our results suggest that seamless amalgamation of computational activity prediction and molecular design with microfluidics-assisted synthesis enables the swift generation of small molecules with the desired polypharmacology.
Asunto(s)
Ligandos , Receptor de Serotonina 5-HT2B/química , Aminas/síntesis química , Aminas/química , Diseño Asistido por Computadora , Diseño de Fármacos , Humanos , Microfluídica , Unión Proteica , Receptor de Serotonina 5-HT2B/metabolismo , Antagonistas del Receptor de Serotonina 5-HT2/química , Antagonistas del Receptor de Serotonina 5-HT2/metabolismoRESUMEN
The use of flow photochemistry and its apparent superiority over batch has been reported by a number of groups in recent years. To rigorously determine whether flow does indeed have an advantage over batch, a broad range of synthetic photochemical transformations were optimized in both reactor modes and their yields and productivities compared. Surprisingly, yields were essentially identical in all comparative cases. Even more revealing was the observation that the productivity of flow reactors varied very little to that of their batch counterparts when the key reaction parameters were matched. Those with a single layer of fluorinated ethylene propylene (FEP) had an average productivity 20% lower than that of batch, whereas three-layer reactors were 20% more productive. Finally, the utility of flow chemistry was demonstrated in the scale-up of the ring-opening reaction of a potentially explosive [1.1.1] propellane with butane-2,3-dione.
Asunto(s)
Reacción de Cicloadición/instrumentación , Fotoquímica/instrumentación , Reacción de Cicloadición/economía , Diseño de Equipo , Procesos Fotoquímicos , Fotoquímica/economía , Politetrafluoroetileno/análogos & derivados , Politetrafluoroetileno/química , Rayos UltravioletaRESUMEN
Pyrrolo[2,3-f]isoquinoline based amino acids, tetracyclic lactams and cyclic ketone analogues are described as novel MK2 inhibitors with IC(50) as low as 5nM and good selectivity profiles against a number of related kinases including ERK, p38alpha and JNKs. TNFalpha release was suppressed from human peripheral blood mononuclear cells (hPBMCs), and a representative compound inhibited LPS induced TNFalpha release in mice illustrating the potential of this series to provide orally active MK2 inhibitors.
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Compuestos Heterocíclicos de 4 o más Anillos/química , Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Administración Oral , Aminoácidos/síntesis química , Aminoácidos/química , Aminoácidos/farmacología , Animales , Sitios de Unión , Cristalografía por Rayos X , Compuestos Heterocíclicos de 4 o más Anillos/síntesis química , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Humanos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Isoquinolinas/química , Cetonas/síntesis química , Cetonas/química , Cetonas/farmacología , Lactamas/síntesis química , Lactamas/química , Lactamas/farmacología , Ratones , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/metabolismo , Pirroles/química , Relación Estructura-Actividad , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
New, selective 3-aminopyrazole based MK2-inhibitors were discovered by scaffold hopping strategy. The new derivatives proved to inhibit intracellular phosphorylation of hsp27 as well as LPS-induced TNFalpha release in cells. In addition, selected derivative 14e also inhibited LPS-induced TNFalpha release in vivo.
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Descubrimiento de Drogas , Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Pirazoles/química , Línea Celular Tumoral , Células Cultivadas , Cristalografía por Rayos X , Descubrimiento de Drogas/métodos , Humanos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Conformación Proteica , Proteínas Serina-Treonina Quinasas/metabolismo , Pirazoles/metabolismo , Pirazoles/farmacologíaRESUMEN
Spirocyclopropane- and spiroazetidine-substituted tetracycles 13D-E and 16A are described as orally active MK2 inhibitors. The spiroazetidine derivatives are potent MK2 inhibitors with IC(50)<3 nM and inhibit the release of TNFalpha (IC(50)<0.3 microM) from hPBMCs and hsp27 phosphorylation in anisomycin stimulated THP-1 cells. The spirocyclopropane analogues are less potent against MK2 (IC(50)=0.05-0.23 microM), less potent in cells (IC(50)<1.1 microM), but show good oral absorption. Compound 13E (100mg/kg po; bid) showed oral activity in rAIA and mCIA, with significant reduction of swelling and histological score.
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Ácido Azetidinocarboxílico/química , Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Administración Oral , Animales , Ácido Azetidinocarboxílico/síntesis química , Ácido Azetidinocarboxílico/farmacología , Azetidinas/química , Sitios de Unión , Línea Celular , Cristalografía por Rayos X , Ciclopropanos/química , Ciclopropanos/farmacología , Proteínas de Choque Térmico HSP27/metabolismo , Humanos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Ratones , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/metabolismo , Compuestos de Espiro/química , Relación Estructura-Actividad , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Bruton's tyrosine kinase (BTK) is a member of the TEC kinase family and is selectively expressed in a subset of immune cells. It is a key regulator of antigen receptor signaling in B cells and of Fc receptor signaling in mast cells and macrophages. A BTK inhibitor will likely have a positive impact on autoimmune diseases which are caused by autoreactive B cells and immune-complex driven inflammation. We report the design, optimization, and characterization of potent and selective covalent BTK inhibitors. Starting from the selective reversible inhibitor 3 binding to an inactive conformation of BTK, we designed covalent irreversible compounds by attaching an electrophilic warhead to reach Cys481. The first prototype 4 covalently modified BTK and showed an excellent kinase selectivity including several Cys-containing kinases, validating the design concept. In addition, this compound blocked FcγR-mediated hypersensitivity in vivo. Optimization of whole blood potency and metabolic stability resulted in compounds such as 8, which maintained the excellent kinase selectivity and showed improved BTK occupancy in vivo.
RESUMEN
Pyrrolo-pyrimidones of the general structure 1 were synthesized and evaluated for their potential as MK2 inhibitors. Potent derivatives were discovered which inhibit MK2 in the nanomolar range and show potent inhibition of cytokine release from LPS-stimulated monocytes. These derivatives were shown to inhibit phosphorylation of hsp27, a downstream target of MK2 and are modestly selective in a panel of 28 kinases.
Asunto(s)
Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Pirimidinonas/síntesis química , Pirimidinonas/farmacología , Pirroles/síntesis química , Pirroles/farmacología , Artritis Reumatoide/tratamiento farmacológico , Técnicas Químicas Combinatorias , Citocinas/metabolismo , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Proteínas de Choque Térmico HSP27/antagonistas & inhibidores , Proteínas de Choque Térmico HSP27/metabolismo , Humanos , Leucocitos Mononucleares/efectos de los fármacos , Lipopolisacáridos/farmacología , Estructura Molecular , Monocitos/efectos de los fármacos , Fosforilación , Pirimidinonas/química , Pirroles/química , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidoresRESUMEN
Bicycloalkyl groups have been previously described as phenyl group bioisosteres. This article describes the synthesis of new building blocks allowing their introduction into complex molecules, and explores their use as a means to modify the physicochemical properties of drug candidates and improve the quality of imaging agents. In particular, the replacement of an aromatic ring with a bicyclo[1.1.1]pentane-1,3-diyl (BCP) group improves aqueous solubility by at least 50-fold, and markedly decreases nonspecific binding (NSB) as measured by CHI(IAM), the chromatographic hydrophobicity index on immobilized artificial membranes. Structural variations with the bicyclo[2.2.2]octane-1,4-diyl group led to more lipophilic molecules and did not show the same benefits regarding NSB or solubility, whereas substitutions with cubane-1,4-diyl showed improvements for both parameters. These results confirm the potential advantages of both BCP and cubane motifs as bioisosteric replacements for optimizing para-phenyl-substituted molecules.
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Compuestos Bicíclicos con Puentes/química , Membranas Artificiales , Compuestos de Anilina/química , Compuestos Bicíclicos con Puentes/síntesis química , Ácidos Carboxílicos/química , Interacciones Hidrofóbicas e Hidrofílicas , Ligandos , SolubilidadRESUMEN
We report an automated flow chemistry platform that can efficiently perform a wide range of chemistries, including single/multi-phase and single/multi-step, with a reaction volume of just 14 µL. The breadth of compatible chemistries is successfully demonstrated and the desired products are characterized, isolated, and collected online by preparative HPLC/MS/ELSD.
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Química Farmacéutica/instrumentación , Química Farmacéutica/métodos , Descubrimiento de Drogas , Automatización , Cromatografía Líquida de Alta Presión , Técnicas Químicas Combinatorias , Dispersión Dinámica de Luz , Espectrometría de MasasRESUMEN
The NIBR (Novartis Institutes for BioMedical Research) compound collection enrichment and enhancement project integrates corporate internal combinatorial compound synthesis and external compound acquisition activities in order to build up a comprehensive screening collection for a modern drug discovery organization. The main purpose of the screening collection is to supply the Novartis drug discovery pipeline with hit-to-lead compounds for today's and the future's portfolio of drug discovery programs, and to provide tool compounds for the chemogenomics investigation of novel biological pathways and circuits. As such, it integrates designed focused and diversity-based compound sets from the synthetic and natural paradigms able to cope with druggable and currently deemed undruggable targets and molecular interaction modes. Herein, we will summarize together with new trends published in the literature, scientific challenges faced and key approaches taken at NIBR to match the chemical and biological spaces.
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Diseño de Fármacos , Evaluación Preclínica de Medicamentos/métodos , Genómica/métodos , Animales , Inteligencia Artificial , Técnicas Químicas Combinatorias , Humanos , Biblioteca de PéptidosRESUMEN
Novel hydroxamate inhibitors of tumor necrosis factor converting enzyme (TACE) and matrix metalloproteases (MMPs) have been synthesized via the Claisen-Ireland rearrangement. Aryl residues have been introduced to fill the enzyme's P1' specificity pocket. The best compound inhibits MMPs and TACE with nanomolar potency and inhibits the release of TNFalpha from cells with an IC50 of 48 nM. Oral administration to rats inhibits the LPS-induced plasma TNFalpha levels with an ED50 of 1 mg/kg.
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Ácidos Hidroxámicos/síntesis química , Inhibidores de la Metaloproteinasa de la Matriz , Metaloendopeptidasas/antagonistas & inhibidores , Inhibidores de Proteasas/síntesis química , Factor de Necrosis Tumoral alfa/metabolismo , Proteínas ADAM , Proteína ADAM17 , Administración Oral , Animales , Células Cultivadas , Humanos , Ácidos Hidroxámicos/química , Ácidos Hidroxámicos/farmacología , Leucocitos Mononucleares/metabolismo , Masculino , Inhibidores de Proteasas/química , Inhibidores de Proteasas/farmacología , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
[reaction: see text] The synthesis of an indole diazabicyclo[3.2.2]nonedione derivative was achieved in a few steps starting from L-tryptophan. Reduction with borane-THF complex leads to fragmentation of the bicycle and the stereoselective formation of an azepinoindole derivative was observed.
RESUMEN
[formula: see text] The development of a highly diastereoselective addition of the titanium enolate derived from ketone 1 to aldehyde 2 offers an efficient entry to the total synthesis of the epothilone family. The new aldol process is robust and tolerates a wide range of functional groups.
Asunto(s)
Epotilonas/síntesis química , Aldehídos/química , Antineoplásicos/síntesis química , Antineoplásicos/química , Epotilonas/química , Estereoisomerismo , Titanio/químicaRESUMEN
A series of alpha-diazo-beta-ketoesters were reacted with Boc amino acid amides in the presence of rhodium octanoate catalyst. The resulting N-H insertion products were treated with acid, providing the 1,4-azine intermediates, which were oxidized by air to form the corresponding pyrazine-6-one products. The pyrazine-6-ones were further derivatized by N-alkylation or by conversion to the arylpyrazines using sequential bromination and Suzuki coupling reactions. [reaction: see text]