RESUMEN
Ingenol derivatives with varying degrees of oxidation were prepared by two-phase terpene synthesis. This strategy has allowed access to analogues that cannot be prepared by semisynthesis from natural ingenol. Complex ingenanes resulting from divergent C-H oxidation of a common intermediate were found to interact with protein kinase C in a manner that correlates well with the oxidation state of the ingenane core. Even though previous work on ingenanes has suggested a strong correlation between potential to activate PKCδ and induction of neutrophil oxidative burst, the current study shows that the potential to activate PKCßII is of key importance while interaction with PKCδ is dispensable. Thus, key modifications of the ingenane core allowed PKC isoform selectivity wherein PKCδ-driven activation of keratinocytes is strongly reduced or even absent while PKCßII-driven activation of neutrophils is retained.
Asunto(s)
Diterpenos/química , Diterpenos/farmacología , Proteína Quinasa C/metabolismo , Diterpenos/metabolismo , Activación Enzimática/efectos de los fármacos , Isoenzimas/química , Isoenzimas/metabolismo , Conformación Molecular , Oxidación-Reducción , Proteína Quinasa C/químicaRESUMEN
The synthesis and functionalization of amines are fundamentally important in a vast range of chemical contexts. We present an amine synthesis that repurposes two simple feedstock building blocks: olefins and nitro(hetero)arenes. Using readily available reactants in an operationally simple procedure, the protocol smoothly yields secondary amines in a formal olefin hydroamination. Because of the presumed radical nature of the process, hindered amines can easily be accessed in a highly chemoselective transformation. A screen of more than 100 substrate combinations showcases tolerance of numerous unprotected functional groups such as alcohols, amines, and even boronic acids. This process is orthogonal to other aryl amine syntheses, such as the Buchwald-Hartwig, Ullmann, and classical amine-carbonyl reductive aminations, as it tolerates aryl halides and carbonyl compounds.
RESUMEN
This manuscript concludes the Structure Activity Relationship (SAR) on the pyridazinone scaffold and identifies a compound with subnanomolar p38α activity and 24h coverage in the rat arthritis efficacy model.
Asunto(s)
Proteína Quinasa 14 Activada por Mitógenos/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Piridazinas/síntesis química , Piridazinas/farmacología , Piridinas/síntesis química , Piridinas/farmacología , Animales , Perros , Relación Dosis-Respuesta a Droga , Haplorrinos , Humanos , Proteína Quinasa 14 Activada por Mitógenos/metabolismo , Estructura Molecular , Inhibidores de Proteínas Quinasas/administración & dosificación , Piridazinas/administración & dosificación , Piridinas/administración & dosificación , Ratas , Relación Estructura-ActividadRESUMEN
The development and synthesis of potent p38α MAP kinase inhibitors containing a pyridazinone platform is described. Evolution of the p38α selective pyridopyridazin-6-one series from the p38α/ß dual inhibitor 2H-quinolizin-2-one series will be discussed in full detail.
Asunto(s)
Proteína Quinasa 14 Activada por Mitógenos/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/síntesis química , Piridazinas/química , Animales , Sitios de Unión , Dominio Catalítico , Simulación por Computador , Proteína Quinasa 14 Activada por Mitógenos/metabolismo , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacocinética , Estructura Terciaria de Proteína , Piridazinas/síntesis química , Piridazinas/farmacocinética , Ratas , Relación Estructura-ActividadRESUMEN
The development and synthesis of potent p38alpha MAP kinase inhibitors containing a 2H-quinolizin-2-one platform is described. Evolution of the 2H-quinolizin-2-one series from an early lead to solving off target activity and pharmacokinetic issues is also discussed.
Asunto(s)
Antiinflamatorios/síntesis química , Inhibidores de Proteínas Quinasas/síntesis química , Quinolizinas/química , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidores , Animales , Antiinflamatorios/química , Antiinflamatorios/farmacocinética , Línea Celular , Perros , Haplorrinos , Humanos , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacocinética , Quinolizinas/síntesis química , Quinolizinas/farmacocinética , Ratas , Relación Estructura-Actividad , Factor de Necrosis Tumoral alfa/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
Polyfunctionalized pyrazolo[3,4-c]pyridines were readily prepared by the annulation of alkynes with tert-butyl 4-iodopyrazolocarboximines. The reaction was found to be catalyzed by both NiBr2(PPh3)2/Zn or PdCl2(PhCN)2 to yield complex heterocycles in good to moderate yields. Annulation using nickel catalysis was found to be regio-random, implying that steric control in nickel-catalyzed alkyne insertion has limitations based on the character of the Ni-C bond in the pre-insertion complex.
Asunto(s)
Alquinos/química , Níquel/química , Pirazoles/química , Piridinas/química , Catálisis , Estructura Molecular , Paladio/química , EstereoisomerismoRESUMEN
p38 inhibitors based on 3,4-dihydropyrido[4,3-d]pyrimidazin-2-one template were synthesized and their SAR explored. Benchmark compounds 30, 35, and 36 were found to be potent against the enzyme. Crystal structure of p38 in complex with 30 indicated a key pi-stacking interaction with the pendant tyrosine residue-35 in the glycine-rich loop.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Piridazinas/síntesis química , Piridazinas/farmacología , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidores , Sitios de Unión , Diseño de Fármacos , Glicina/química , Relación Estructura-Actividad , Tirosina/químicaRESUMEN
A new sub-class of p38 inhibitors represented by 7-amino-naphthyridone have been discovered. Benchmark compound 16 potently inhibited p38 in vitro, was functionally active, and displayed excellent pharmacokinetic profiles in two animal species. Compound 16 reduced inflammation in animal disease models at EC(50) doses as low as 0.2mpk.
Asunto(s)
Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/farmacocinética , Naftiridinas/administración & dosificación , Naftiridinas/farmacocinética , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidores , Administración Oral , Animales , Sitios de Unión , Disponibilidad Biológica , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/química , Humanos , Técnicas In Vitro , Lipopolisacáridos/farmacología , Macaca mulatta , Masculino , Ratones , Ratones Endogámicos BALB C , Microsomas Hepáticos/efectos de los fármacos , Estructura Molecular , Monocitos/efectos de los fármacos , Naftiridinas/química , Ratas , Ratas Sprague-Dawley , Estereoisomerismo , Relación Estructura-Actividad , Factor de Necrosis Tumoral alfa/antagonistas & inhibidoresRESUMEN
p38 inhibitors based on 3,4-dihydropyrimido[4,5-d]pyrimidin-2-one and 3,4-dihydropyrido[4,3-d]pyrimidin-2-one platforms were synthesized and preliminary SAR explored. Among the pyrimido-pyrimidones the emergence of two sub-types of analogs-C7-amino-pyrimidines such as 24 and C7-amino-piperidines such as 42-characterized with good p38 inhibition and better off-target profiles in terms of ion channel activities was significant. Representative compound 54 in the pyrido-pyrimidone class was found to be equipotent with corresponding analog in the quinazolinone series.
Asunto(s)
Inhibidores Enzimáticos/química , Piridazinas/química , Pirimidinas/química , Pirimidinonas/química , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidores , Química Farmacéutica/métodos , Diseño de Fármacos , Inhibidores Enzimáticos/metabolismo , Inhibidores Enzimáticos/farmacología , Humanos , Concentración 50 Inhibidora , Modelos Químicos , Piridazinas/farmacología , Piridinas/química , Pirimidinas/farmacología , Pirimidinonas/farmacología , Quinazolinas/química , Relación Estructura-Actividad , Proteínas Quinasas p38 Activadas por Mitógenos/químicaRESUMEN
[reaction: see text] 1,3-Diketones were synthesized directly from ketones and acid chlorides and were then converted in situ into pyrazoles by the addition of hydrazine. This method is extremely fast, general, and chemoselective, allowing for the synthesis of previously inaccessible pyrazoles and synthetically demanding pyrazole-containing fused rings.
Asunto(s)
Cloruros/química , Técnicas Químicas Combinatorias , Cetonas/química , Cetonas/síntesis química , Pirazoles/síntesis química , Hidrazinas/química , Estructura MolecularRESUMEN
The initial disclosure of tri-substituted imidazole-based drug molecules such as 1 for inhibition of p38 MAP kinase by SmithKline Beecham (SB) sparked an effort in this area at Merck and other pharmaceutical research establishments. Although analogs in this class have shown good inhibitory properties against p38 MAP kinase, their selectivity profile were modest and left much room for improvement. Attempts to discover newer compounds with improved selectivity over the prototypical SB compound 203580 (1), led to the discovery of a new sub-class of p38 inhibitors typified by compound 18 at Merck. Although this benchmark compound was potent, highly selective and orally efficacious it was burdened with compound related adverse effects in dogs that has delayed further development. In 1999, a new class of p38 inhibitors represented by clinical candidate VX-745 (26), was disclosed by Vertex Pharmaceuticals. This compound displayed unprecedented selectivity due to its unique mode of binding to the active site in p38 MAP kinase. Inspired by the exquisite selectivity profile of VX-745 [26] a scaffold re-design was initiated at Merck which resulted in the discovery of the quinazolinone, pyrimido-pyrimidone, pyrido-pyrimidone, quinolinone and naphthyridinone based p38 inhibitors.
Asunto(s)
Diseño de Fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidores , Sitios de Unión , Imidazoles/química , Imidazoles/farmacología , Piridazinas/química , Piridazinas/farmacología , Pirimidinas/química , Pirimidinas/farmacología , Pirimidinonas/síntesis química , Pirimidinonas/farmacología , Relación Estructura-ActividadRESUMEN
Development for a class of potent 3,4-dihydropyrido(3,2-d)pyrimidone inhibitors of p38a MAP kinase is described. Modification of N-1 aryl and C-6 arylsulfide in 3,4-dihydropyrido(3,2-d)pyrimidone analogues for the interaction with the hydrophobic pockets in p38 active site is also discussed.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Proteínas Quinasas Activadas por Mitógenos/antagonistas & inhibidores , Pirimidinonas/síntesis química , Inhibidores Enzimáticos/farmacología , Cinética , Estructura Molecular , Pirimidinonas/farmacología , Relación Estructura-Actividad , Proteínas Quinasas p38 Activadas por MitógenosRESUMEN
A new class of p38 antagonists based on 3,4-dihydropyrido[3,2,-d]pyrimidine scaffold has been developed. These inhibitors exhibit unprecedented selectivity towards p38 over other very closely related kinases. Compounds 25, 33, and 34 were identified as benchmark analogues for follow-up studies. They show good potency for enzyme inhibition and excellent functional activity.