RESUMO
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.
Assuntos
Amidas/farmacologia , Descoberta de Drogas , Pirazóis/farmacologia , Receptores CCR1/antagonistas & inibidores , Amidas/química , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Pirazóis/química , Receptores CCR1/metabolismo , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Compostos Aza/farmacologia , Indazóis/farmacologia , Receptores CCR1/antagonistas & inibidores , Compostos Aza/síntese química , Compostos Aza/química , Relação Dose-Resposta a Droga , Desenho de Fármacos , Humanos , Indazóis/síntese química , Indazóis/química , Estrutura Molecular , Receptores CCR1/metabolismo , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Oxidiazóis/farmacologia , Receptores de Lisoesfingolipídeo/agonistas , Tiadiazóis/farmacologia , Animais , Encéfalo/metabolismo , Ácido Glutâmico/metabolismo , Células Hep G2 , Humanos , Ligação de Hidrogênio , Cinética , Oxidiazóis/sangue , Oxidiazóis/síntese química , Ratos , Solubilidade , Relação Estrutura-Atividade , Tiadiazóis/sangue , Tiadiazóis/síntese químicaRESUMO
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.
RESUMO
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.
Assuntos
Receptores de Glucocorticoides/agonistas , Esteroides/química , Sulfonamidas/química , Sulfonamidas/farmacologia , Sítios de Ligação , Glucocorticoides/química , Ligação de Hidrogênio , Ligantes , Simulação de Acoplamento Molecular , Ligação Proteica/efeitos dos fármacos , Estrutura Terciária de Proteína , Receptores de Glucocorticoides/metabolismo , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/metabolismoRESUMO
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.
Assuntos
Receptores de Glucocorticoides/agonistas , Sulfonamidas/química , Sulfonamidas/farmacologia , Triptaminas/química , Triptaminas/farmacologia , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/metabolismo , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Artrite/induzido quimicamente , Artrite/tratamento farmacológico , Sítios de Ligação , Camundongos , Simulação de Acoplamento Molecular , Ligação Proteica/efeitos dos fármacos , Estrutura Terciária de Proteína , Receptores de Glucocorticoides/metabolismo , Relação Estrutura-Atividade , Sulfonamidas/metabolismo , Sulfonamidas/uso terapêutico , Triptaminas/metabolismo , Triptaminas/uso terapêuticoRESUMO
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.
Assuntos
Isoenzimas/antagonistas & inibidores , Proteína Quinase C/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/química , Pirimidinas/farmacologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/enzimologia , Linfócitos T CD4-Positivos/imunologia , Humanos , Interleucina-2/metabolismo , Modelos Moleculares , Estrutura Molecular , Conformação Proteica , Proteína Quinase C-theta , Relação Estrutura-AtividadeRESUMO
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').