RESUMEN
IRAK4 has been identified as potential therapeutic target for inflammatory and autoimmune diseases. Herein we report the identification and initial SAR studies of a new class of pyrazole containing IRAK4 inhibitors designed to expand chemical diversity and improve off target activity of a previously identified series. These compounds maintain potent IRAK4 activity and desirable ligand efficiency. Rat clearance and a variety of off target activities were also examined, resulting in encouraging data with tractable SAR.
Asunto(s)
Quinasas Asociadas a Receptores de Interleucina-1/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Pirazoles/química , Animales , Sitios de Unión , Cristalografía por Rayos X , Semivida , Humanos , Quinasas Asociadas a Receptores de Interleucina-1/metabolismo , Ligandos , Simulación de Dinámica Molecular , Unión Proteica , Inhibidores de Proteínas Quinasas/metabolismo , Inhibidores de Proteínas Quinasas/farmacocinética , Estructura Terciaria de Proteína , Pirazoles/metabolismo , Pirazoles/farmacocinética , Ratas , Relación Estructura-ActividadRESUMEN
We report the identification and synthesis of a series of aminopyrimidin-4-one IRAK4 inhibitors. Through high throughput screening, an aminopyrimidine hit was identified and modified via structure enabled design to generate a new, potent, and kinase selective pyrimidin-4-one chemotype. This chemotype is exemplified by compound 16, which has potent IRAK4 inhibition activity (IC50 = 27 nM) and excellent kinase selectivity (>100-fold against 99% of 111 tested kinases), and compound 31, which displays potent IRAK4 activity (IC50 = 93 nM) and good rat bioavailability (F = 42%).
RESUMEN
IRAK4 is a critical upstream kinase in the IL-1R/TLR signaling pathway. Inhibition of IRAK4 is hypothesized to be beneficial in the treatment of autoimmune related disorders. A screening campaign identified a pyrazole class of IRAK4 inhibitors that were determined by X-ray crystallography to exhibit an unusual binding mode. SAR efforts focused on the identification of a potent and selective inhibitor with good aqueous solubility and rodent pharmacokinetics. Pyrazole C-3 piperidines were well tolerated, with N-sulfonyl analogues generally having good rodent oral exposure but poor solubility. N-Alkyl piperidines exhibited excellent solubility and reduced exposure. Pyrazoles possessing N-1 pyridine and fluorophenyl substituents were among the most active. Piperazine 32 was a potent enzyme inhibitor with good cellular activity. Compound 32 reduced the in vivo production of proinflammatory cytokines and was orally efficacious in a mouse antibody induced arthritis disease model of inflammation.
RESUMEN
IRAK4 plays a key role in TLR/IL-1 signaling. Previous efforts identified a series of aminopyrimidine IRAK4 inhibitors that possess good potency, but modest kinase selectivity. Exploration of substituents at the C-2 and C-5 positions generated compounds that maintained IRAK4 potency and improved kinase selectivity. Additionally, it was found that the pyrimidine core could be replaced with a pyridine and still retain potency and kinase selectivity. The optimization efforts led to compound 26 which had an IRAK4 IC50 of 0.7 nM, an IC50 of 55 nM on THP-1 cells stimulated with LPS, a TLR4 agonist, and greater than 100-fold selectivity versus 96% of a panel of 306 kinases.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Quinasas Asociadas a Receptores de Interleucina-1/antagonistas & inhibidores , Pirimidinas/síntesis química , Pirimidinas/farmacología , Antiinflamatorios no Esteroideos/síntesis química , Antiinflamatorios no Esteroideos/farmacología , Línea Celular , Ensayos Analíticos de Alto Rendimiento , Humanos , Lipopolisacáridos/farmacología , Relación Estructura-Actividad , Especificidad por Sustrato , Receptor Toll-Like 4/antagonistas & inhibidoresRESUMEN
Interleukin receptor-associated kinase 4 (IRAK4) is a critical element of the Toll-like/interleukin-1 receptor inflammation signaling pathway. A screening campaign identified a novel diaminopyrimidine hit that exhibits weak IRAK4 inhibitory activity and a ligand efficiency of 0.25. Hit-to-lead activities were conducted through independent SAR studies of each of the four pyrimidine substituents. Optimal activity was observed upon removal of the pyrimidine C-4 chloro substituent. The intact C-6 carboribose is required for IRAK4 inhibition. Numerous heteroaryls were tolerated at the C-5 position, with azabenzothiazoles conferring the best activities. Aminoheteroaryls were preferred at the C-2 position. These studies led to the discovery of inhibitors 35, 36, and 38 that exhibit nanomolar inhibition of IRAK4, improved ligand efficiencies, and modest kinase selectivities.
Asunto(s)
Descubrimiento de Drogas , Quinasas Asociadas a Receptores de Interleucina-1/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/farmacología , Relación Dosis-Respuesta a Droga , Humanos , Quinasas Asociadas a Receptores de Interleucina-1/metabolismo , Modelos Moleculares , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Pirimidinas/síntesis química , Pirimidinas/química , Relación Estructura-ActividadRESUMEN
A series of pyrrolo-benzo-1,4-diazine analogs have been synthesized to improve the profile of the previous lead compound 1. The syntheses, structure-activity relationships, and selected pharmacokinetic data of these analogs are described. The optimization efforts allowed the identification of 33, a quinoline amide exhibiting potent Na(v)1.7 inhibitory activity and moderate selectivity over Na(v)1.5. Compound 33 displayed anti-nociceptive oral efficacy in a rat CFA inflammatory pain model at 100 mpk and in a rat spinal nerve ligation neuropathic pain model with an EC50 75 µM.
Asunto(s)
Analgésicos/farmacología , Ganglios Espinales/efectos de los fármacos , Canal de Sodio Activado por Voltaje NAV1.7/química , Neuralgia/tratamiento farmacológico , Bloqueadores de los Canales de Sodio/farmacología , Nervios Espinales/efectos de los fármacos , Compuestos de Espiro/farmacología , Analgésicos/química , Animales , Estructura Molecular , Técnicas de Placa-Clamp , Quinoxalinas/química , Ratas , Bloqueadores de los Canales de Sodio/química , Compuestos de Espiro/química , Relación Estructura-ActividadRESUMEN
A series of pyrrolo-benzo-1,4-diazine analogs have been synthesized and displayed potent Nav1.7 inhibitory activity and moderate selectivity over Nav1.5. The syntheses, structure-activity relationships, and selected pharmacokinetic data of these analogs are described. Compound 41 displayed anti-nociceptive efficacy in the rat CFA pain model at 100 mpk oral dosing.
Asunto(s)
Descubrimiento de Drogas , Canal de Sodio Activado por Voltaje NAV1.7/metabolismo , Quinoxalinas/farmacología , Bloqueadores de los Canales de Sodio/farmacología , Compuestos de Espiro/farmacología , Relación Dosis-Respuesta a Droga , Humanos , Estructura Molecular , Quinoxalinas/síntesis química , Quinoxalinas/química , Bloqueadores de los Canales de Sodio/síntesis química , Bloqueadores de los Canales de Sodio/química , Compuestos de Espiro/síntesis química , Compuestos de Espiro/química , Relación Estructura-ActividadRESUMEN
High throughput screening identified the pyridothienopyrimidinone 1 as a ligand for the metabotropic glutamate receptor 1 (mGluR1=10 nM). Compound 1 has an excellent in vivo profile; however, it displays unfavorable pharmacokinetic issues and metabolic stability. Therefore, using 1 as a template, novel analogues (10i) were prepared. These analogues displayed improved oral exposure and activity in the Spinal Nerve Ligation (SNL) pain model.
Asunto(s)
Compuestos Heterocíclicos con 3 Anillos/química , Pirimidinonas/química , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores , Tiofenos/química , Administración Oral , Animales , Dolor Crónico/tratamiento farmacológico , Modelos Animales de Enfermedad , Compuestos Heterocíclicos con 3 Anillos/síntesis química , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Humanos , Pirimidinonas/síntesis química , Pirimidinonas/uso terapéutico , Ratas , Receptores de Glutamato Metabotrópico/metabolismo , Relación Estructura-Actividad , Tiofenos/síntesis química , Tiofenos/uso terapéuticoRESUMEN
The identification of potent and orally active dihydroimidazoisoquinolines as PDE 10A inhibitors is reported. The SAR development led to the discovery of compound 35 as a potent, selective, and orally active PDE10A inhibitor. Compound 35 inhibited MK-801-induced hyperactivity at 3mg/kg and displayed a 10-fold separation between the minimal effective doses for inhibition of MK-801-induced hyperactivity and hypolocomotion in rats.
Asunto(s)
Hipercinesia/tratamiento farmacológico , Imidazoles/síntesis química , Isoquinolinas/síntesis química , Inhibidores de Fosfodiesterasa/síntesis química , Hidrolasas Diéster Fosfóricas/química , Psicotrópicos/síntesis química , Animales , Área Bajo la Curva , Cristalografía por Rayos X , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 3/química , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 3/metabolismo , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 7/química , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 7/metabolismo , Maleato de Dizocilpina , Haplorrinos , Humanos , Hipercinesia/inducido químicamente , Hipercinesia/enzimología , Imidazoles/administración & dosificación , Imidazoles/farmacocinética , Isoquinolinas/administración & dosificación , Isoquinolinas/farmacocinética , Masculino , Modelos Moleculares , Inhibidores de Fosfodiesterasa/administración & dosificación , Inhibidores de Fosfodiesterasa/farmacocinética , Hidrolasas Diéster Fosfóricas/metabolismo , Psicotrópicos/administración & dosificación , Psicotrópicos/farmacocinética , Ratas , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/enzimología , Relación Estructura-ActividadRESUMEN
High-throughput screening identified a series of pyrazoloquinolines as PDE10A inhibitors. The SAR development led to the discovery of compound 27 as a potent, selective, and orally active PDE10A inhibitor. Compound 27 inhibits MK-801 induced hyperactivity at 3mg/kg with an ED(50) of 4mg/kg and displays a â¼6-fold separation between the ED(50) for inhibition of MK-801 induced hyperactivity and hypolocomotion in rats.
Asunto(s)
Inhibidores Enzimáticos/farmacología , Hidrolasas Diéster Fosfóricas/metabolismo , Pirazolonas/farmacología , Quinolinas/farmacología , Esquizofrenia/tratamiento farmacológico , Administración Oral , Animales , Cristalografía por Rayos X , Maleato de Dizocilpina/antagonistas & inhibidores , Maleato de Dizocilpina/farmacología , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/química , Ensayos Analíticos de Alto Rendimiento , Humanos , Modelos Moleculares , Estructura Molecular , Pirazolonas/administración & dosificación , Pirazolonas/química , Quinolinas/administración & dosificación , Quinolinas/química , Ratas , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
A series of pyrazoloquinolines, possessing (hetero)arylhydroxymethyl substituents at the quinoline C-4 position were evaluated as PDE10A inhibitors. Among these, methylpyrimidyl analogue 15 was identified as having good rodent and monkey exposure, and a MED of 10 mg/kg in an in vivo model.
Asunto(s)
Descubrimiento de Drogas , Inhibidores Enzimáticos/farmacología , Hidrolasas Diéster Fosfóricas/metabolismo , Quinolinas/química , Quinolinas/farmacología , Animales , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacocinética , Haplorrinos , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Concentración 50 Inhibidora , Estructura Molecular , Pirazolonas/síntesis química , Pirazolonas/química , Pirazolonas/farmacocinética , Pirazolonas/farmacología , Quinolinas/síntesis química , Quinolinas/farmacocinética , RatasRESUMEN
A series of fused tricyclic mGluR1 antagonists containing a pyridone ring were synthesized. In vitro, these antagonists were potent against both human and rat isozymes, as well as selective for inhibiting mGluR1 over mGluR5. When dosed orally, several examples were active in vivo in a rat SNL test.
Asunto(s)
Piridonas/síntesis química , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores , Administración Oral , Analgésicos/farmacología , Animales , Células Cultivadas , Ciclización , Humanos , Concentración 50 Inhibidora , Estructura Molecular , Neuralgia/tratamiento farmacológico , Unión Proteica/efectos de los fármacos , Piridonas/química , Piridonas/farmacología , RatasRESUMEN
A series of pyrazoloquinoline analogs have been synthesized and shown to bind to PDE10 with high affinity. From the SAR study and our lead optimization efforts, compounds 16 and 27 were found to possess potent oral antipsychotic activity in the MK-801 induced hyperactive rat model.
Asunto(s)
Antipsicóticos/farmacología , Inhibidores de Fosfodiesterasa/farmacología , Hidrolasas Diéster Fosfóricas/química , Pirazoles/farmacología , Quinolinas/farmacología , Esquizofrenia/tratamiento farmacológico , Administración Oral , Animales , Química Farmacéutica/métodos , Cristalografía por Rayos X/métodos , Modelos Animales de Enfermedad , Maleato de Dizocilpina/farmacología , Diseño de Fármacos , Antagonistas de Aminoácidos Excitadores/farmacología , Humanos , Modelos Químicos , Conformación Molecular , Ratas , Relación Estructura-ActividadRESUMEN
Novel P2X(7) antagonists were developed using a purine scaffold. These compounds were potent and selective at the P2X(7) receptor in human and rodent as well as efficacious in rodent pain models. Compound 15a was identified to have oral potency in several pain models in rodent similar to naproxen, gabapentin and pregabalin. Structure-activity relationship (SAR) development and results of pain models are presented.
Asunto(s)
Dolor/tratamiento farmacológico , Antagonistas del Receptor Purinérgico P2X/síntesis química , Purinas/síntesis química , Receptores Purinérgicos P2X7/química , Animales , Humanos , Antagonistas del Receptor Purinérgico P2X/química , Antagonistas del Receptor Purinérgico P2X/uso terapéutico , Purinas/química , Purinas/uso terapéutico , Ratas , Receptores Purinérgicos P2X7/metabolismo , Relación Estructura-ActividadRESUMEN
Cough continues to be one of the top reasons why patients seek medical attention from health care providers. The prescription antitussive market is dominated by opioids, such as codeine that produces inconsistent efficacy and is often accompanied by significant side effect liabilities. Consequently, cough represents an unmet medical need and an underserved market. Yet, against the backdrop of increasing cough research, the development of novel treatments has been exceptionally challenging with dextromethorphan being the last US drug approved for cough almost a half century ago. We support the position that an unambiguous and actionable 'road map' that clearly delineates the pathway forward for new cough suppressants from basic research to and beyond clinical proof-of-concept studies will be an important aspect for future success of this pharmacological class of drug. Pivotal to the establishment of such a road map will be the review of lessons learned from antitussive agents that have been recently progressed to proof-of-concept trials. In the present commentary, we briefly discuss observations and challenges pertaining to SCH 486757, a selective orally active NOP agonist that has recently advanced to human antitussive testing.
Asunto(s)
Antitusígenos/farmacología , Compuestos de Azabiciclo/farmacología , Tos/tratamiento farmacológico , Pirimidinas/farmacología , Animales , Antitusígenos/administración & dosificación , Antitusígenos/uso terapéutico , Compuestos de Azabiciclo/administración & dosificación , Compuestos de Azabiciclo/uso terapéutico , Ensayos Clínicos como Asunto , Codeína/administración & dosificación , Codeína/farmacología , Dextrometorfano/administración & dosificación , Dextrometorfano/farmacología , Modelos Animales de Enfermedad , Perros , Evaluación Preclínica de Medicamentos , Cobayas , Humanos , Péptidos Opioides/agonistas , Péptidos Opioides/metabolismo , Pirimidinas/administración & dosificación , Pirimidinas/uso terapéutico , Ratas , Receptores Opioides/agonistas , NociceptinaRESUMEN
The endogenous opioid-like peptide, nociceptin, produces anxiolytic-like effects that are mediated via the nociceptin (NOP) receptor. Similarly, synthetic, non-peptide NOP agonists produce robust anxiolytic-like effects although these effects are limited by marked side effects. In the present studies, the effects of a novel NOP receptor agonist, SCH 655842, were examined in rodent models sensitive to anxiolytic drugs and tests measuring potential adverse affects. Oral administration of SCH 655842 produced robust, anxiolytic-like effects in three species, i.e., rat, guinea pig, and mouse. Specifically, SCH 655842 was effective in rat conditioned lick suppression (3-10 mg/kg) and fear-potentiated startle (3-10 mg/kg) tests, a guinea pig pup vocalization test (1-3 mg/kg), as well as in mouse Geller-Seifter (30 mg/kg) and marble burying (30 mg/kg) tests. The anxiolytic-like effect of SCH 655842 in the conditioned lick suppression test was attenuated by the NOP antagonist, J-113397. In mice, SCH 655842 reduced locomotor activity and body temperature at doses similar to the anxiolytic-like dose and these effects were absent in NOP receptor knockout mice. In rats, SCH 655842 did not produce adverse behavioral effects up to doses of 70-100 mg/kg. Pharmacokinetic studies in the rat confirmed dose-related increases in plasma and brain levels of SCH 655842 across a wide oral dose range. Taken together, SCH 655842 may represent a NOP receptor agonist with improved tolerability compared to other members of this class although further studies are necessary to establish whether this extends to higher species.
Asunto(s)
Ansiolíticos/efectos adversos , Ansiolíticos/farmacología , Compuestos de Azabiciclo/efectos adversos , Compuestos de Azabiciclo/farmacología , Receptores Opioides/agonistas , Animales , Ansiolíticos/sangre , Ansiolíticos/farmacocinética , Compuestos de Azabiciclo/sangre , Compuestos de Azabiciclo/farmacocinética , Conducta Animal/efectos de los fármacos , Conducta Animal/fisiología , Temperatura Corporal/efectos de los fármacos , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Condicionamiento Psicológico/efectos de los fármacos , Condicionamiento Psicológico/fisiología , Relación Dosis-Respuesta a Droga , Miedo/efectos de los fármacos , Miedo/fisiología , Femenino , Técnicas de Inactivación de Genes , Cobayas , Masculino , Ratones , Actividad Motora/efectos de los fármacos , Ratas , Receptores Opioides/deficiencia , Receptores Opioides/genética , Prueba de Desempeño de Rotación con Aceleración Constante , Especificidad de la Especie , Vocalización Animal/efectos de los fármacos , Receptor de NociceptinaRESUMEN
Structure-activity relationship (SAR) efforts around our initial lead compound 1 led to the identification of potent P2X(7) receptor antagonists with improved pharmacokinetic profiles. These compounds were potent and selective at the P2X(7) receptor in both human and rodent. Compound (entry 31) exhibited oral efficacy in the rat MIA and CCI pain models.
Asunto(s)
Analgésicos/síntesis química , Diseño de Fármacos , Dolor , Antagonistas del Receptor Purinérgico P2/síntesis química , Administración Oral , Analgésicos/química , Animales , Modelos Animales de Enfermedad , Humanos , Estructura Molecular , Dolor/tratamiento farmacológico , Antagonistas del Receptor Purinérgico P2/química , Ratas , Receptores Purinérgicos P2X7/metabolismo , Relación Estructura-ActividadRESUMEN
A series of 2,4-diphenyl-1H-imidazole analogs have been synthesized and displayed potent human CB2 agonist activity. Many of these analogs showed high functional selectivity over human CB1 receptors. The syntheses, structure-activity relationships, and selected pharmacokinetic data of these analogs are described.
Asunto(s)
Imidazoles/química , Dolor/tratamiento farmacológico , Receptor Cannabinoide CB2/agonistas , Administración Oral , Animales , Enfermedad Crónica , Humanos , Imidazoles/farmacocinética , Imidazoles/uso terapéutico , Ratas , Receptor Cannabinoide CB1/agonistas , Receptor Cannabinoide CB1/metabolismo , Receptor Cannabinoide CB2/metabolismo , Relación Estructura-ActividadRESUMEN
A series of spiro-azetidines and azetidinones has been evaluated as novel blockers of the T-type calcium channel (Ca(V)3.2) which is a new therapeutic target for the potential treatment of both inflammatory and neuropathic pain. Confirmation and optimization of the potency, selectivity and DMPK properties of leads will be described.
Asunto(s)
Azetidinas/química , Bloqueadores de los Canales de Calcio/síntesis química , Canales de Calcio Tipo T/química , Piperidinas/química , Compuestos de Espiro/química , Animales , Azetidinas/síntesis química , Azetidinas/uso terapéutico , Bloqueadores de los Canales de Calcio/química , Bloqueadores de los Canales de Calcio/uso terapéutico , Canales de Calcio Tipo T/metabolismo , Diseño de Fármacos , Humanos , Dolor/tratamiento farmacológico , Unión Proteica , Ratas , Relación Estructura-ActividadRESUMEN
We describe the pharmacological and pharmacokinetic profiles of SCH 486757, a nociceptin/orphanin FQ peptide (NOP) receptor agonist that has recently entered human clinical trials for cough. SCH 486757 selectively binds human NOP receptor (K(i)=4.6+/-0.61nM) over classical opioid receptors. In a guinea pig capsaicin cough model, SCH 486757 (0.01-1mg/kg) suppressed cough at 2, 4, and 6h post oral administration with a maximum efficacy occurring at 4h equivalent to codeine, hydrocodone, dextromethorphan and baclofen. The antitussive effects of SCH 486757 (3.0mg/kg, p.o.) was blocked by the NOP receptor antagonist J113397 (12mg/kg, i.p.) but not by naltrexone (10mg/kg, p.o.). SCH 486757 does not produce tolerance to its antitussive activity after a 5-day BID dosing regimen. After acute and chronic dosing paradigms, SCH 486757 (1mg/kg) inhibited capsaicin-evoked coughing by 46+/-9% and 40+/-11%, respectively. In a feline mechanically-evoked cough model, SCH 486757 produces a maximum inhibition of cough and expiratory abdominal electromyogram amplitude of 59 and 61%, respectively. SCH 486757 did not significantly affect inspiratory electromyogram amplitude. We examined the abuse potential of SCH 486757 (10mg/kg, p.o.) in a rat conditioned place preference procedure which is sensitive to classical drugs of abuse, such as amphetamine and morphine. SCH 486757 was without effect in this model. Finally, SCH 486757 displays a good oral pharmacokinetic profile in the guinea pig, rat and dog. We conclude that SCH 486757 has a favorable antitussive profile in preclinical animal models.