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
A high throughput screening campaign identified aryl 1,4-diazepane compounds as potent and selective cannabinoid receptor 2 agonists as compared to cannabinoid receptor 1. This class of compounds suffered from poor drug-like parameters as well as low microsomal stability and poor solubility. Structure-activity relationships are described with a focus on improving the drug-like parameters resulting in compounds with improved solubility and permeability.
Assuntos
Azepinas/química , Receptor CB2 de Canabinoide/agonistas , Azepinas/farmacologia , Células CACO-2 , Permeabilidade da Membrana Celular , Ensaios de Triagem em Larga Escala , Humanos , Microssomos Hepáticos/metabolismo , Receptor CB1 de Canabinoide/agonistas , Receptor CB1 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/metabolismo , Solubilidade , Relação Estrutura-AtividadeRESUMO
A high-throughput screening campaign has identified 1,4-diazepane compounds which are potent Cannabinoid receptor 2 agonists with excellent selectivity against the Cannabinoid receptor 1. This class of compounds suffered from low metabolic stability. Following various strategies, compounds with a good stability in liver microsomes and rat PK profile have been identified.
Assuntos
Azepinas/farmacologia , Receptor CB2 de Canabinoide/agonistas , Animais , Azepinas/química , Microssomos Hepáticos/metabolismo , Ratos , Ratos WistarRESUMO
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.