RESUMEN
Exploring various cyclization strategies, using a submicromolar pyrazole HTS screening hit 6 as a starting point, a novel indazole based CCR1 antagonist core was discovered. This report presents the design and SAR of CCR1 indazole and azaindazole antagonists leading to the identification of three development compounds, including 19e that was advanced to early clinical trials.
Asunto(s)
Compuestos Aza/farmacología , Indazoles/farmacología , Receptores CCR1/antagonistas & inhibidores , Compuestos Aza/síntesis química , Compuestos Aza/química , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Humanos , Indazoles/síntesis química , Indazoles/química , Estructura Molecular , Receptores CCR1/metabolismo , Relación Estructura-ActividadRESUMEN
A HTS screen for CCR1 antagonists afforded a novel sub-micromolar hit 5 containing a pyrazole core. In this report the design, optimization, and SAR of novel CCR1 antagonists based on a pyrazole core motif is presented. Optimization led to the advanced candidate compounds (S)-16q and (S)-16r with 250-fold improved CCR1 potency, excellent off-target selectivity and attractive drug-like properties.
Asunto(s)
Amidas/farmacología , Descubrimiento de Drogas , Pirazoles/farmacología , Receptores CCR1/antagonistas & inhibidores , Amidas/química , Relación Dosis-Respuesta a Droga , Humanos , Estructura Molecular , Pirazoles/química , Receptores CCR1/metabolismo , Relación Estructura-ActividadRESUMEN
The mechanism of intramolecular transfer dehydrogenation catalyzed by [Cp*M(VTMS)2] (1, M=Rh, 2, M=Co, Cp* = C5Me5, VTMS = vinyltrimethylsilane) complexes has been studied using vinyl silane protected alcohols as substrates. Deuterium-labeled substrates have been synthesized and the regioselectivity of H/D transfers investigated using 1H and 2H NMR spectroscopy. The labeling studies establish a regioselective pathway consisting of alkene directed α C-H activation, 2,1 alkene insertion, and finally ß-hydride elimination to give silyl enol ether products.
RESUMEN
Poor solubility and cationic amphiphilic drug-likeness were liabilities identified for a lead series of S1P3-sparing, S1P1 agonists originally developed from a high-throughput screening campaign. This work describes the subsequent optimization of these leads by balancing potency, selectivity, solubility and overall molecular charge. Focused SAR studies revealed favorable structural modifications that, when combined, produced compounds with overall balanced profiles. The low brain exposure observed in rat suggests that these compounds would be best suited for the potential treatment of peripheral autoimmune disorders.
Asunto(s)
Oxadiazoles/farmacología , Receptores de Lisoesfingolípidos/agonistas , Tiadiazoles/farmacología , Animales , Encéfalo/metabolismo , Ácido Glutámico/metabolismo , Células Hep G2 , Humanos , Enlace de Hidrógeno , Cinética , Oxadiazoles/sangre , Oxadiazoles/síntesis química , Ratas , Solubilidad , Relación Estructura-Actividad , Tiadiazoles/sangre , Tiadiazoles/síntesis químicaRESUMEN
A class of α-methyltryptamine sulfonamide glucocorticoid receptor (GR) modulators was optimized for agonist activity. The design of ligands was aided by molecular modeling, and key function-regulating pharmacophoric points were identified that are critical in achieving the desired agonist effect in cell based assays. Compound 27 was profiled in vitro and in vivo in models of inflammation. Analogs could be rapidly prepared in a parallel approach from aziridine building blocks.
Asunto(s)
Receptores de Glucocorticoides/agonistas , Sulfonamidas/química , Sulfonamidas/farmacología , Triptaminas/química , Triptaminas/farmacología , Animales , Antiinflamatorios/química , Antiinflamatorios/metabolismo , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Artritis/inducido químicamente , Artritis/tratamiento farmacológico , Sitios de Unión , Ratones , Simulación del Acoplamiento Molecular , Unión Proteica/efectos de los fármacos , Estructura Terciaria de Proteína , Receptores de Glucocorticoides/metabolismo , Relación Estructura-Actividad , Sulfonamidas/metabolismo , Sulfonamidas/uso terapéutico , Triptaminas/metabolismo , Triptaminas/uso terapéuticoRESUMEN
A class of arylsulfonamide glucocorticoid receptor agonists that contains a substituted phenyl group as a steroid A-ring mimetic is reported. The structural design and SAR that provide the functional switching of a GR antagonist to an agonist is described. A combination of specific hydrogen bonding and lipophilic elements on the A-ring moiety is required to achieve potent GR agonist activity. This study culminated in the identification of compound 23 as a potent GR agonist with selectivity over the PR and MR nuclear hormone receptors.
Asunto(s)
Receptores de Glucocorticoides/agonistas , Esteroides/química , Sulfonamidas/química , Sulfonamidas/farmacología , Sitios de Unión , Glucocorticoides/química , Enlace de Hidrógeno , Ligandos , Simulación del Acoplamiento Molecular , Unión Proteica/efectos de los fármacos , Estructura Terciaria de Proteína , Receptores de Glucocorticoides/metabolismo , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/metabolismoRESUMEN
An uHTS campaign was performed to identify selective inhibitors of PKC-theta. Initial triaging of the hit set based on selectivity and historical analysis led to the identification of 2,4-diamino-5-nitropyrimidines as potent and selective PKC-theta inhibitors. A homology model and initial SAR is presented demonstrating that a 2-arylalkylamino substituent in conjunction with suitable 4-diamino substituent are essential for achieving selectivity over many kinases. Additional hit to lead profiling is presented on selected compounds.
Asunto(s)
Isoenzimas/antagonistas & inhibidores , Proteína Quinasa C/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/química , Pirimidinas/farmacología , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/enzimología , Linfocitos T CD4-Positivos/inmunología , Humanos , Interleucina-2/metabolismo , Modelos Moleculares , Estructura Molecular , Conformación Proteica , Proteína Quinasa C-theta , Relación Estructura-ActividadRESUMEN
While 1,2-diheteroatom-substituted alkenes represent useful synthetic building blocks, there are no simple, general procedures available for preparation of such compounds. We describe here a simple catalytic procedure based on rhodium C-H bond activation for the synthesis of diheteroatom alkenes of the type R(3)SiOCH=CHG (G = -OR, -NRR').