RESUMEN
IRAK4 is responsible for initiating signaling from Toll-like receptors (TLRs) and members of the IL-1/18 receptor family. Kinase-inactive knock-ins and targeted deletions of IRAK4 in mice cause reductions in TLR induced pro-inflammatory cytokines and these mice are resistant to various models of arthritis. Herein we report the identification and optimization of a series of potent IRAK4 inhibitors. Representative examples from this series showed excellent selectivity over a panel of kinases, including the kinases known to play a role in TLR-mediated signaling. The compounds exhibited low nM potency in LPS- and R848-induced cytokine assays indicating that they are blocking the TLR signaling pathway. A key compound (26) from this series was profiled in more detail and found to have an excellent pharmaceutical profile as measured by predictive assays such as microsomal stability, TPSA, solubility, and clogP. However, this compound was found to afford poor exposure in mouse upon IP or IV administration. We found that removal of the ionizable solubilizing group (32) led to increased exposure, presumably due to increased permeability. Compounds 26 and 32, when dosed to plasma levels corresponding to ex vivo whole blood potency, were shown to inhibit LPS-induced TNFα in an in vivo murine model. To our knowledge, this is the first published in vivo demonstration that inhibition of the IRAK4 pathway by a small molecule can recapitulate the phenotype of IRAK4 knockout mice.
Asunto(s)
Indoles/química , Indoles/farmacología , Quinasas Asociadas a Receptores de Interleucina-1/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Quinolinas/química , Quinolinas/farmacología , Animales , Femenino , Humanos , Indoles/farmacocinética , Quinasas Asociadas a Receptores de Interleucina-1/inmunología , Lipopolisacáridos/inmunología , Ratones , Ratones Endogámicos C57BL , Modelos Moleculares , Inhibidores de Proteínas Quinasas/farmacocinética , Quinolinas/farmacocinética , Transducción de Señal/efectos de los fármacosRESUMEN
A series of 5-vinyl-3-pyridinecarbonitriles were synthesized and evaluated as PKCtheta inhibitors. The systematic optimization of 4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-phenylvinyl]-3-pyridinecarbonitrile 3 resulted in the identification of compound 23e as a potent PKCtheta inhibitor with good selectivity over PKCdelta.
Asunto(s)
Isoenzimas/antagonistas & inhibidores , Nitrilos/química , Proteína Quinasa C/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Piridinas/química , Animales , Humanos , Isoenzimas/metabolismo , Microsomas/metabolismo , Nitrilos/síntesis química , Nitrilos/farmacología , Proteína Quinasa C/metabolismo , Proteína Quinasa C-delta/antagonistas & inhibidores , Proteína Quinasa C-delta/metabolismo , Proteína Quinasa C-theta , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Piridinas/síntesis química , Piridinas/farmacología , Ratas , Relación Estructura-ActividadRESUMEN
PKCtheta is a serine/threonine kinase involved in the regulation of IL2 production in T cells. It has recently become an attractive therapeutic target for a variety of immunological disorders. We describe the optimization of the enzymatic and cellular potency of a series of 5-vinyl-3-pyridinecarbonitrile inhibitors of PKCtheta. A binding model was developed that explains much of the SAR observed for this series, including the enzymatic potency observed for 19. An analysis of functional potency against various physiochemical parameters suggests that cellular potency is correlated with LogD(7.4), but not with cLogP, PAMPA permeability, or TPSA.
Asunto(s)
Isoenzimas/antagonistas & inhibidores , Nitrilos/síntesis química , Proteína Quinasa C/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/síntesis química , Piridinas/síntesis química , Compuestos de Vinilo/síntesis química , Animales , Simulación por Computador , Concentración 50 Inhibidora , Isoenzimas/metabolismo , Cinética , Espectroscopía de Resonancia Magnética , Ratones , Ratones Endogámicos C57BL , Modelos Moleculares , Nitrilos/química , Nitrilos/farmacología , Proteína Quinasa C/metabolismo , Proteína Quinasa C-theta , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Piridinas/química , Piridinas/farmacología , Espectrometría de Masa por Ionización de Electrospray , Relación Estructura-Actividad , Compuestos de Vinilo/química , Compuestos de Vinilo/farmacologíaRESUMEN
Inhibition of spleen tyrosine kinase has attracted much attention as a mechanism for the treatment of cancers and autoimmune diseases such as asthma, rheumatoid arthritis, and systemic lupus erythematous. We report the structure-guided optimization of pyridazine amide spleen tyrosine kinase inhibitors. Early representatives of this scaffold were highly potent and selective but mutagenic in an Ames assay. An approach that led to the successful identification of nonmutagenic examples, as well as further optimization to compounds with reduced cardiovascular liabilities is described. Select pharmacokinetic and in vivo efficacy data are presented.
Asunto(s)
Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Piridazinas/síntesis química , Piridazinas/farmacología , Bazo/enzimología , Amidas/síntesis química , Amidas/farmacología , Animales , Biología Computacional , Simulación por Computador , Diseño de Fármacos , Canales de Potasio Éter-A-Go-Go/efectos de los fármacos , Humanos , Técnicas In Vitro , Ratones , Microsomas Hepáticos/metabolismo , Modelos Moleculares , Conformación Molecular , Mutagénesis/efectos de los fármacos , Pruebas de Mutagenicidad , Inhibidores de Proteínas Quinasas/farmacocinética , Piridazinas/farmacocinética , Ratas , Bazo/efectos de los fármacos , Relación Estructura-Actividad , Difracción de Rayos XRESUMEN
We describe the discovery of several pyrrolopyrazines as potent and selective Syk inhibitors and the efforts that eventually led to the desired improvements in physicochemical properties and human whole blood potencies. Ultimately, our mouse model revealed unexpected toxicity that precluded us from further advancing this series.
Asunto(s)
Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Pirazinas/síntesis química , Pirroles/síntesis química , Animales , Linfocitos B/efectos de los fármacos , Linfocitos B/enzimología , Proteínas Sanguíneas/metabolismo , Cristalografía por Rayos X , Humanos , Ratones , Microsomas Hepáticos/metabolismo , Modelos Moleculares , Estructura Molecular , Unión Proteica , Pirazinas/farmacología , Pirazinas/toxicidad , Pirroles/farmacología , Pirroles/toxicidad , Relación Estructura-Actividad , Quinasa SykRESUMEN
Tertiary aryl squaramides were synthesized by using copper catalyzed C-N bond-formation with L-proline as the ligand. Symmetrical diaryl squaramides could be prepared in a one-pot reaction by using excess aryl bromide with varying yields. Unsymmetrical derivatives were prepared by sequential arylation. Yields of the diarylated products were highly sensitive to steric effects.