RESUMEN
Disruption of interleukin-13 (IL-13) signaling with large molecule antibody therapies has shown promise in diseases of allergic inflammation. Given that IL-13 recruits several members of the Janus Kinase family (JAK1, JAK2, and TYK2) to its receptor complex, JAK inhibition may offer an alternate small molecule approach to disrupting IL-13 signaling. Herein we demonstrate that JAK1 is likely the isoform most important to IL-13 signaling. Structure-based design was then used to improve the JAK1 potency of a series of previously reported JAK2 inhibitors. The ability to impede IL-13 signaling was thereby significantly improved, with the best compounds exhibiting single digit nM IC50's in cell-based assays dependent upon IL-13 signaling. Appropriate substitution was further found to influence inhibition of a key off-target, LRRK2. Finally, the most potent compounds were found to be metabolically labile, which makes them ideal scaffolds for further development as topical agents for IL-13 mediated diseases of the lungs and skin (for example asthma and atopic dermatitis, respectively).
Asunto(s)
Dermatitis Atópica/genética , Interleucina-13/metabolismo , Janus Quinasa 1/antagonistas & inhibidores , Janus Quinasa 2/antagonistas & inhibidores , Humanos , Transducción de SeñalRESUMEN
The identification of a novel fused triazolo-pyrrolopyridine scaffold, optimized derivatives of which display nanomolar inhibition of Janus kinase 1, is described. Prototypical example 3 demonstrated lower cell potency shift, better permeability in cells and higher oral exposure in rat than the corresponding, previously reported, imidazo-pyrrolopyridine analogue 2. Examples 6, 7 and 18 were subsequently identified from an optimization campaign and demonstrated modest selectivity over JAK2, moderate to good oral bioavailability in rat with overall pharmacokinetic profiles comparable to that reported for an approved pan-JAK inhibitor (tofacitinib).
Asunto(s)
Janus Quinasa 1/antagonistas & inhibidores , Piridinas/farmacología , Animales , Cristalografía por Rayos X , Janus Quinasa 1/química , Janus Quinasa 2/antagonistas & inhibidores , Janus Quinasa 2/química , Cinética , Modelos Moleculares , Piridinas/química , Pirroles/química , Pirroles/farmacología , RatasRESUMEN
Addition of the 4-fluorophenylpyrazole group to the previously described 2-azadecalin glucocorticoid receptor (GR) antagonist 1 resulted in significantly enhanced functional activity. SAR of the bridgehead substituent indicated that whereas groups as small as methyl afforded high GR binding, GR functional activity was enhanced by larger groups such as benzyl, substituted ethers, and aminoalkyl derivatives. GR antagonists with binding and functional activity comparable to mifepristone were discovered (e.g., 52: GR binding K(i) 0.7 nM; GR reporter gene functional K(i) 0.6 nM) and found to be highly selective over other steroid receptors. Analogues 43 and 45 had >50% oral bioavailability in the dog.
Asunto(s)
Isoquinolinas/química , Isoquinolinas/farmacología , Pirazoles/química , Pirazoles/farmacología , Receptores de Glucocorticoides/antagonistas & inhibidores , Animales , Compuestos Aza/síntesis química , Compuestos Aza/química , Compuestos Aza/farmacocinética , Compuestos Aza/farmacología , Perros , Isoquinolinas/síntesis química , Isoquinolinas/farmacocinética , Cinética , Pirazoles/síntesis química , Pirazoles/farmacocinética , Ratas , Receptores de Glucocorticoides/metabolismo , Relación Estructura-ActividadRESUMEN
The 2-azadecalin ring system was evaluated as a scaffold for the preparation of glucocorticoid receptor (GR) antagonists. High affinity, selective GR antagonists were discovered based on a hypothetical binding mode related to the steroidal GR antagonist RU-43044. 2-Benzenesulfonyl substituted 8a-benzyl-hexahydro-2H-isoquinolin-6-ones exemplified by (R)-37 had low nanomolar affinity for GR with moderate functional activity (200 nM) in a reporter gene assay. These compounds were devoid of affinity for other steroidal receptors (ER, AR, MR, and PR). Analogues based on an alternative putative binding mode (CP-like) were found to be inactive.
Asunto(s)
Benceno/química , Hidrógeno/química , Isoquinolinas/química , Isoquinolinas/farmacología , Receptores de Glucocorticoides/antagonistas & inhibidores , Azufre/química , Isoquinolinas/síntesis química , Estructura Molecular , Unión Proteica , Receptores de Glucocorticoides/metabolismo , Relación Estructura-Actividad , Sulfonamidas/químicaRESUMEN
A virtual screening approach comprising a 3-D similarity search based on known GR modulators was used to identify a novel series of non-steroidal glucocorticoid receptor (GR) antagonists. Optimization of the initial hit to provide potent compounds which exhibit good selectivity against other steroidal nuclear hormone receptors is described.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Antidepresivos/síntesis química , Glucocorticoides/química , Receptores de Glucocorticoides/metabolismo , Animales , Antidepresivos/farmacología , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Humanos , Cinética , Modelos Químicos , Conformación Molecular , Ratas , Receptores de Esteroides/metabolismo , Relación Estructura-ActividadRESUMEN
Optimisation of ADS100380, a sub-micromolar HDAC inhibitor identified using a virtual screening approach, led to a series of substituted 5-(1H-pyrazol-3-yl)-thiophene-2-hydroxamic acids (6a-i), that possessed significant HDAC inhibitory activity. Subsequent functionalisation of the pendent phenyl group of compounds 6f and 6g provided analogues 6j-w with further enhanced enzyme and anti-proliferative activity. Compound 6j demonstrated efficacy in a mouse xenograft experiment.