RESUMEN
Sphingosine-1-phosphate (S1P) binds to a family of sphingosine-1-phosphate G-protein-coupled receptors (S1P1-5). The interaction of S1P with these S1P receptors has a fundamental role in many physiological processes in the vascular and immune systems. Agonist-induced functional antagonism of S1P1 has been shown to result in lymphopenia. As a result, agonists of this type hold promise as therapeutics for autoimmune disorders. The previously disclosed differentiated S1P1 modulator BMS-986104 (1) exhibited improved preclinical cardiovascular and pulmonary safety profiles as compared to earlier full agonists of S1P1; however, it demonstrated a long pharmacokinetic half-life (T1/2 18 days) in the clinic and limited formation of the desired active phosphate metabolite. Optimization of this series through incorporation of olefins, ethers, thioethers, and glycols into the alkyl side chain afforded an opportunity to reduce the projected human T1/2 and improve the formation of the active phosphate metabolite while maintaining efficacy as well as the improved safety profile. These efforts led to the discovery of 12 and 24, each of which are highly potent, biased agonists of S1P1. These compounds not only exhibited shorter in vivo T1/2 in multiple species but are also projected to have significantly shorter T1/2 values in humans when compared to our first clinical candidate. In models of arthritis, treatment with 12 and 24 demonstrated robust efficacy.
Asunto(s)
Compuestos Bicíclicos con Puentes/síntesis química , Compuestos Bicíclicos con Puentes/farmacología , Proproteína Convertasas/efectos de los fármacos , Serina Endopeptidasas/efectos de los fármacos , Animales , Artritis Experimental/tratamiento farmacológico , Enfermedades Autoinmunes/tratamiento farmacológico , Biotransformación , Compuestos Bicíclicos con Puentes/efectos adversos , Líquido del Lavado Bronquioalveolar , Quimiotaxis de Leucocito/efectos de los fármacos , Evaluación Preclínica de Medicamentos , Semivida , Humanos , Enfermedades Pulmonares/inducido químicamente , Enfermedades Pulmonares/patología , Masculino , Miocitos Cardíacos/efectos de los fármacos , Fosforilación , Ratas , Ratas Endogámicas Lew , Relación Estructura-ActividadRESUMEN
The identification of small molecule inhibitors of IRAK4 for the treatment of autoimmune diseases has been an area of intense research. We discovered novel 4,6-diaminonicotinamides which potently inhibit IRAK4. Optimization efforts were aided by X-ray crystal structures of inhibitors bound to IRAK4. Structure activity relationship (SAR) studies led to the identification of compound 29 which exhibited sub-micromolar potency in a LTA stimulated cellular assay.
Asunto(s)
Diseño de Fármacos , Quinasas Asociadas a Receptores de Interleucina-1/antagonistas & inhibidores , Niacinamida/química , Inhibidores de Proteínas Quinasas/química , Sitios de Unión , Cristalografía por Rayos X , Evaluación Preclínica de Medicamentos , Humanos , Concentración 50 Inhibidora , Quinasas Asociadas a Receptores de Interleucina-1/metabolismo , Janus Quinasa 3/química , Janus Quinasa 3/metabolismo , Conformación Molecular , Simulación de Dinámica Molecular , Niacinamida/metabolismo , Inhibidores de Proteínas Quinasas/metabolismo , Estructura Terciaria de Proteína , Relación Estructura-ActividadRESUMEN
An empirical approach to improve the microsomal stability and CYP inhibition profile of lead compounds 1a and 1b led to the identification of 5 (BMS-341) as a dissociated glucocorticoid receptor modulator. Compound 5 showed significant improvements in pharmacokinetic properties and, unlike compounds 1a-b, displayed a linear, dose-dependent pharmacokinetic profile in rats. When tested in a chronic model of adjuvant-induced arthritis in rat, the ED50 of 5 (0.9 mg/kg) was superior to that of both 1a and 1b (8 and 17 mg/kg, respectively).