RESUMEN
With the emergence and rapid spreading of NDM-1 and existence of clinically relevant VIM-1 and IMP-1, discovery of pan inhibitors targeting metallo-beta-lactamases (MBLs) became critical in our battle against bacterial infection. Concurrent with our fragment and high-throughput screenings, we performed a knowledge-based search of known metallo-beta-lactamase inhibitors (MBLIs) to identify starting points for early engagement of medicinal chemistry. A class of compounds exemplified by 11, discovered earlier as B. fragilis metallo-beta-lactamase inhibitors, was selected for in silico virtual screening. From these efforts, compound 12 was identified with activity against NDM-1 only. Initial exploration on metal binding design followed by structure-guided optimization led to the discovery of a series of compounds represented by 23 with a pan MBL inhibition profile. In in vivo studies, compound 23 in combination with imipenem (IPM) robustly lowered the bacterial burden in a murine infection model and became the lead for the invention of MBLI clinical candidates.
Asunto(s)
Infecciones Bacterianas , Inhibidores de beta-Lactamasas , Animales , Ratones , Inhibidores de beta-Lactamasas/farmacología , Inhibidores de beta-Lactamasas/uso terapéutico , Inhibidores de beta-Lactamasas/química , Imipenem/farmacología , Imipenem/uso terapéutico , beta-Lactamasas/metabolismo , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Antibacterianos/química , Pruebas de Sensibilidad MicrobianaRESUMEN
We report the discovery and hit-to-lead optimization of a structurally novel indazole series of CYP11B2 inhibitors. Benchmark compound 34 from this series displays potent inhibition of CYP11B2, high selectivity versus related steroidal and hepatic CYP targets, and lead-like physical and pharmacokinetic properties. On the basis of these and other data, the indazole series was progressed to lead optimization for further refinement.
Asunto(s)
Antihipertensivos/farmacología , Citocromo P-450 CYP11B2/antagonistas & inhibidores , Hipertensión/tratamiento farmacológico , Indazoles/farmacología , Animales , Antihipertensivos/síntesis química , Antihipertensivos/farmacocinética , Inhibidores de la Aromatasa/síntesis química , Inhibidores de la Aromatasa/farmacocinética , Inhibidores de la Aromatasa/farmacología , Línea Celular , Cricetulus , Inhibidores del Citocromo P-450 CYP2D6/síntesis química , Inhibidores del Citocromo P-450 CYP2D6/farmacocinética , Inhibidores del Citocromo P-450 CYP2D6/farmacología , Humanos , Indazoles/síntesis química , Indazoles/farmacocinética , Macaca mulatta , Masculino , Ratas Sprague-Dawley , Estereoisomerismo , Esteroide 11-beta-Hidroxilasa/antagonistas & inhibidoresRESUMEN
DGAT2 plays a critical role in hepatic triglyceride production, and data suggests that inhibition of DGAT2 could prove to be beneficial in treating a number of disease states. This article documents the discovery and optimization of a selective small molecule inhibitor of DGAT2 as well as pharmacological proof of biology in a mouse model of triglyceride production.
Asunto(s)
Diacilglicerol O-Acetiltransferasa/antagonistas & inhibidores , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Isoquinolinas/química , Isoquinolinas/farmacología , Triglicéridos/metabolismo , Animales , Diacilglicerol O-Acetiltransferasa/metabolismo , Descubrimiento de Drogas , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/farmacocinética , Humanos , Isoquinolinas/administración & dosificación , Isoquinolinas/farmacocinética , Masculino , Ratones , Ratones Endogámicos C57BL , Triglicéridos/sangreRESUMEN
Hit-to-lead efforts resulted in the discovery of compound 19, a potent CYP11B2 inhibitor that displays high selectivity vs related CYPs, good pharmacokinetic properties in rat and rhesus, and lead-like physical properties. In a rhesus pharmacodynamic model, compound 19 displays robust, dose-dependent aldosterone lowering efficacy, with no apparent effect on cortisol levels.
RESUMEN
We report the discovery of a benzimidazole series of CYP11B2 inhibitors. Hit-to-lead and lead optimization studies identified compounds such as 32, which displays potent CYP11B2 inhibition, high selectivity versus related CYP targets, and good pharmacokinetic properties in rat and rhesus. In a rhesus pharmacodynamic model, 32 produces dose-dependent aldosterone lowering efficacy, with no apparent effect on cortisol levels.