RESUMEN
Small molecule toll-like receptor (TLR) 7 agonists have gathered considerable interest as promising therapeutic agents for applications in cancer immunotherapy. Herein, we describe the development and optimization of a series of novel TLR7 agonists through systematic structure-activity relationship studies focusing on modification of the phenylpiperidine side chain. Additional refinement of ADME properties culminated in the discovery of compound 14, which displayed nanomolar reporter assay activity and favorable drug-like properties. Compound 14 demonstrated excellent in vivo pharmacokinetic/pharmacodynamic profiles and synergistic antitumor activity when administered in combination with aPD1 antibody, suggesting opportunities of employing 14 in immuno-oncology therapies with immune checkpoint blockade agents.
RESUMEN
Inhibition of the bromodomain and extra-terminal (BET) family of adaptor proteins is an attractive strategy for targeting transcriptional regulation of key oncogenes, such as c-MYC. Starting with the screening hit 1, a combination of structure-activity relationship and protein structure-guided drug design led to the discovery of a differently oriented carbazole 9 with favorable binding to the tryptophan, proline, and phenylalanine (WPF) shelf conserved in the BET family. Identification of an additional lipophilic pocket and functional group optimization to optimize pharmacokinetic (PK) properties culminated in the discovery of 18 (BMS-986158) with excellent potency in binding and functional assays. On the basis of its favorable PK profile and robust in vivo activity in a panel of hematologic and solid tumor models, BMS-986158 was selected as a candidate for clinical evaluation.
Asunto(s)
Antineoplásicos/farmacología , Carbazoles/farmacología , Descubrimiento de Drogas , Fenilalanina/farmacología , Prolina/farmacología , Triptófano/farmacología , Administración Oral , Antineoplásicos/administración & dosificación , Antineoplásicos/química , Carbazoles/administración & dosificación , Carbazoles/química , Proteínas de Ciclo Celular/antagonistas & inhibidores , Proteínas de Ciclo Celular/metabolismo , Relación Dosis-Respuesta a Droga , Humanos , Estructura Molecular , Fenilalanina/administración & dosificación , Fenilalanina/química , Prolina/administración & dosificación , Prolina/química , Relación Estructura-Actividad , Factores de Transcripción/antagonistas & inhibidores , Factores de Transcripción/metabolismo , Triptófano/administración & dosificación , Triptófano/químicaRESUMEN
Substituted benzyloxy aryl compound 2 was identified as an RORγt agonist. Structure based drug design efforts resulted in a potent and selective tricyclic compound 19 which, when administered orally in an MC38 mouse tumor model, demonstrated a desired pharmacokinetic profile as well as a dose-dependent pharmacodynamic response. However, no perceptible efficacy was observed in this tumor model at the doses investigated.
Asunto(s)
Compuestos de Bencilo/farmacología , Compuestos Heterocíclicos/farmacología , Receptores de Ácido Retinoico/agonistas , Animales , Compuestos de Bencilo/química , Relación Dosis-Respuesta a Droga , Femenino , Compuestos Heterocíclicos/química , Ratones , Ratones Endogámicos C57BL , Estructura Molecular , Relación Estructura-Actividad , Receptor de Ácido Retinoico gammaRESUMEN
Structure-activity relationships in a series of (2-oxo-1,4-benzodiazepin-3-yl)-succinamides identified highly potent inhibitors of γ-secretase mediated signaling of Notch1/2/3/4 receptors. On the basis of its robust in vivo efficacy at tolerated doses in Notch driven leukemia and solid tumor xenograft models, 12 (BMS-906024) was selected as a candidate for clinical evaluation.
RESUMEN
This Letter describes synthesis, SAR, and biological activity of (2-oxo-1,4-benzodiazepin-3-yl)-succinamides as inhibitors of γ-secretase mediated signaling of Notch receptors. Optimization of this series led to the identification of BMS-871 (compound 30) which displayed robust in vivo efficacy in Notch-dependent leukemia and solid tumor xenograft models.
Asunto(s)
Antineoplásicos/administración & dosificación , Antineoplásicos/farmacología , Benzodiazepinonas/administración & dosificación , Benzodiazepinonas/farmacología , Receptores Notch/antagonistas & inhibidores , Administración Oral , Animales , Antineoplásicos/química , Benzodiazepinonas/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Ratones , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Estructura Molecular , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/metabolismo , Neoplasias Experimentales/patología , Receptores Notch/metabolismo , Relación Estructura-ActividadRESUMEN
The synthesis, structure-activity relationships (SAR) and biological evaluation of thiazole based tricyclic inhibitors of IKK2 are described. Compound 9 was determined to be orally efficacious in a murine model of rheumatoid arthritis.
Asunto(s)
Artritis Reumatoide/tratamiento farmacológico , Quinasa I-kappa B/antagonistas & inhibidores , Imidazoles/química , Inhibidores de Proteínas Quinasas/química , Piridinas/química , Tiazoles/química , Animales , Modelos Animales de Enfermedad , Perros , Evaluación Preclínica de Medicamentos , Femenino , Quinasa I-kappa B/metabolismo , Ratones , Ratones Endogámicos BALB C , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/uso terapéutico , Piridinas/farmacocinética , Piridinas/uso terapéutico , Ratas , Relación Estructura-ActividadRESUMEN
The design and synthesis of a novel series of oxazole-, thiazole-, and imidazole-based inhibitors of IkappaB kinase (IKK) are reported. Biological activity was improved compared to the pyrazolopurine lead, and the expedient synthesis of the new tricyclic systems allowed for efficient exploration of structure-activity relationships. This, combined with an iterative rat cassette dosing strategy, was used to identify compounds with improved pharmacokinetic (PK) profiles to advance for in vivo evaluation.
Asunto(s)
Compuestos Heterocíclicos con 3 Anillos/síntesis química , Quinasa I-kappa B/antagonistas & inhibidores , Imidazoles/síntesis química , Oxazoles/síntesis química , Tiazoles/síntesis química , Animales , Cristalografía por Rayos X , Femenino , Glutatión Transferasa/genética , Glutatión Transferasa/metabolismo , Compuestos Heterocíclicos con 3 Anillos/farmacocinética , Compuestos Heterocíclicos con 3 Anillos/farmacología , Humanos , Quinasa I-kappa B/genética , Imidazoles/farmacocinética , Imidazoles/farmacología , Técnicas In Vitro , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/metabolismo , Lipopolisacáridos/farmacología , Ratones , Ratones Endogámicos BALB C , Microsomas Hepáticos/metabolismo , Oxazoles/farmacocinética , Oxazoles/farmacología , Ratas , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/metabolismo , Relación Estructura-Actividad , Tiazoles/farmacocinética , Tiazoles/farmacología , Factor de Necrosis Tumoral alfa/biosíntesisRESUMEN
In an era of increasing resistance to classical antibacterial agents, the synthetic oxazolidinone series of antibiotics has attracted much interest. Zyvoxtrade mark was the first oxazolidinone to be approved for clinical use against infections caused by multi-drug resistant Gram-positive bacteria. In the course of studies directed toward the discovery of novel antibacterial agents, a new series of synthetic phenyl-isoxazolinone agents that displayed potent activity against Gram-positive bacterial strains was recently discovered at Bristol-Myers Squibb. Extensive investigation of various substitutions on the phenyl ring was then undertaken. We report here, the synthesis and antibacterial activity of a series of biaryl isoxazolinone compounds.
Asunto(s)
Antibacterianos/química , Antibacterianos/farmacología , Isoxazoles/química , Isoxazoles/farmacología , Animales , Haemophilus influenzae/efectos de los fármacos , Ratas , Relación Estructura-ActividadRESUMEN
A series of potential antimicrobial derivatives possessing bioisosteric replacements for the central oxazolidinone ring found in oxazolidinone antibacterials have been prepared. The design concept involved replacement of the requisite sp(3)-hybridized stereogenic center found at the 5-position of the oxazolidinone with a nitrogen atom. The synthesis and antibacterial activity of three such ring systems, the benzisoxazolinones, pyrroles, and isoxazolinones is described.
Asunto(s)
Antibacterianos/síntesis química , Isoxazoles/química , Nitrógeno/química , Oxazolidinonas/química , Oxazolona/análogos & derivados , Oxazolona/química , Antibacterianos/química , Antibacterianos/farmacología , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Isoxazoles/síntesis química , Isoxazoles/farmacología , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Oxazolona/síntesis química , Oxazolona/farmacología , Pirroles/síntesis química , Pirroles/química , Pirroles/farmacología , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
The synthesis and antifungal activity of 5'- and 5'-6'-substituted azasordarin derivatives are described. Modification of the 5'-position led to the discovery of the spirocyclopentyl analogue 7g, which is the first azasordarin to register single-digit MIC values versus Aspergillus spp. Further investigation identified the 5'-i-Pr derivative 7b, which displays superior pharmacokinetic properties compared to other azasordarins.
Asunto(s)
Antifúngicos/química , Antifúngicos/farmacocinética , Compuestos Aza/síntesis química , Compuestos Aza/farmacocinética , Administración Oral , Animales , Antifúngicos/farmacología , Aspergillus/efectos de los fármacos , Compuestos Aza/química , Compuestos Aza/farmacología , Glicósidos/química , Indenos , Inyecciones Intravenosas , Ratones , Pruebas de Sensibilidad Microbiana , Compuestos de Espiro/química , Compuestos de Espiro/farmacocinética , Compuestos de Espiro/farmacología , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Compounds based on sordaricin were prepared via organometallic addition onto a fully protected sordaricin aldehyde. The fungal growth inhibition profiles for these compounds were established and the results are presented here. The synthesis of homologated sordaricin as well as ether and ester derivatives is presented, and structural rearrangement products upon oxidation. These compounds were evaluated as agents to inhibit fungal growth.