RESUMO
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%).
RESUMO
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.
Assuntos
Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Quinases Associadas a Receptores de Interleucina-1/antagonistas & inibidores , Pirimidinas/síntese química , Pirimidinas/farmacologia , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/farmacologia , Linhagem Celular , Ensaios de Triagem em Larga Escala , Humanos , Lipopolissacarídeos/farmacologia , Relação Estrutura-Atividade , Especificidade por Substrato , Receptor 4 Toll-Like/antagonistas & inibidoresRESUMO
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.
Assuntos
Analgésicos/farmacologia , Gânglios Espinais/efeitos dos fármacos , Canal de Sódio Disparado por Voltagem NAV1.7/química , Neuralgia/tratamento farmacológico , Bloqueadores dos Canais de Sódio/farmacologia , Nervos Espinhais/efeitos dos fármacos , Compostos de Espiro/farmacologia , Analgésicos/química , Animais , Estrutura Molecular , Técnicas de Patch-Clamp , Quinoxalinas/química , Ratos , Bloqueadores dos Canais de Sódio/química , Compostos de Espiro/química , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Descoberta de Drogas , Canal de Sódio Disparado por Voltagem NAV1.7/metabolismo , Quinoxalinas/farmacologia , Bloqueadores dos Canais de Sódio/farmacologia , Compostos de Espiro/farmacologia , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Quinoxalinas/síntese química , Quinoxalinas/química , Bloqueadores dos Canais de Sódio/síntese química , Bloqueadores dos Canais de Sódio/química , Compostos de Espiro/síntese química , Compostos de Espiro/química , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Compostos Heterocíclicos com 3 Anéis/química , Pirimidinonas/química , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Tiofenos/química , Administração Oral , Animais , Dor Crônica/tratamento farmacológico , Modelos Animais de Doenças , Compostos Heterocíclicos com 3 Anéis/síntese química , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Humanos , Pirimidinonas/síntese química , Pirimidinonas/uso terapêutico , Ratos , Receptores de Glutamato Metabotrópico/metabolismo , Relação Estrutura-Atividade , Tiofenos/síntese química , Tiofenos/uso terapêuticoRESUMO
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.
Assuntos
Dor/tratamento farmacológico , Antagonistas do Receptor Purinérgico P2X/síntese química , Purinas/síntese química , Receptores Purinérgicos P2X7/química , Animais , Humanos , Antagonistas do Receptor Purinérgico P2X/química , Antagonistas do Receptor Purinérgico P2X/uso terapêutico , Purinas/química , Purinas/uso terapêutico , Ratos , Receptores Purinérgicos P2X7/metabolismo , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Analgésicos/síntese química , Desenho de Fármacos , Dor , Antagonistas do Receptor Purinérgico P2/síntese química , Administração Oral , Analgésicos/química , Animais , Modelos Animais de Doenças , Humanos , Estrutura Molecular , Dor/tratamento farmacológico , Antagonistas do Receptor Purinérgico P2/química , Ratos , Receptores Purinérgicos P2X7/metabolismo , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Imidazóis/química , Dor/tratamento farmacológico , Receptor CB2 de Canabinoide/agonistas , Administração Oral , Animais , Doença Crônica , Humanos , Imidazóis/farmacocinética , Imidazóis/uso terapêutico , Ratos , Receptor CB1 de Canabinoide/agonistas , Receptor CB1 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/metabolismo , Relação Estrutura-AtividadeRESUMO
A series of N-8 substituted analogs based upon the spiropiperidine core of the original lead compound 1 was synthesized. This lead has been elaborated to compounds to give compounds 2 and 3 (R=H) that exhibited high NOP binding affinity as well as selectivity against other known opioid receptors. These two series have been further functionalized at the amido nitrogen. The synthesis and structure-activity relationship (SAR) of these and related compounds are discussed.
Assuntos
Piperidinas/síntese química , Piperidinas/farmacologia , Receptores Opioides/efeitos dos fármacos , Compostos de Espiro/síntese química , Compostos de Espiro/farmacologia , Animais , Sítios de Ligação , Capsaicina/farmacologia , Técnicas de Química Combinatória , Tosse/induzido quimicamente , Modelos Animais de Doenças , Desenho de Fármacos , Cobaias , Estrutura Molecular , Piperidinas/química , Receptores Opioides/metabolismo , Compostos de Espiro/química , Relação Estrutura-Atividade , Receptor de NociceptinaRESUMO
Orphanin FQ/nociceptin (OFQ/N) is the endogenously occurring peptide ligand for the nociceptin opioid receptor (NOP) that produces anxiolytic-like effects in mice and rats. The present study assessed the anxiolytic-like activity of 8-[bis(2-methylphenyl)-methyl]-3-phenyl-8-azabicyclo[3.2.1]octan-3-ol (SCH 221510), a novel potent piperidine NOP agonist (EC(50) = 12 nM) that binds with high affinity (K(i) = 0.3 nM) and functional selectivity (>50-fold over the mu-, kappa-, and delta-opioid receptors). The anxiolytic-like activity and side-effect profile of SCH 221510 were assessed in a variety of models and the benzodiazepine, chlordiazepoxide (CDP), was included for comparison. The effects of chronic dosing of SCH 221510 were also assessed. Furthermore, the specificity of the anxiolytic-like effect of SCH 221510 was investigated with the NOP receptor antagonist 1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one (J-113397) and the opioid receptor antagonist naltrexone. Like CDP (1-30 mg/kg i.p.), SCH 221510 (1-30 mg/kg p.o.) produced anxiolytic-like effects in the elevated plus-maze (rat and gerbil), Vogel conflict (rat), conditioned lick suppression (rat), fear-potentiated startle (rat), and pup separation-induced vocalization (guinea pig) assays. In the Vogel conflict, the anxiolytic-like effect of SCH 221510 (10 mg/kg) was attenuated by J-113397 (3-10 mg/kg p.o.), but not naltrexone (3-30 mg/kg i.p.). Additionally, the anxiolytic-like effects of SCH 221510 did not change appreciably following 14-day b.i.d. dosing in rats (10 mg/kg). Furthermore, unlike CDP, SCH 221510 (3-30 mg/kg) produced anxiolytic-like activity at doses that did not disrupt overt behavior. Collectively, these data suggest that NOP agonists such as SCH 221510 may have an anxiolytic-like profile similar to benzodiazepines, with a reduced side-effect liability.
Assuntos
Ansiolíticos/farmacologia , Compostos Azabicíclicos/farmacologia , Comportamento Animal/efeitos dos fármacos , Receptores Opioides/agonistas , Animais , Animais Recém-Nascidos , Ansiolíticos/química , Compostos Azabicíclicos/química , Benzimidazóis/farmacologia , Células CHO , Cricetinae , Cricetulus , Feminino , Gerbillinae , Cobaias , Humanos , Masculino , Estrutura Molecular , Antagonistas de Entorpecentes , Piperidinas/farmacologia , Ligação Proteica , Ratos , Ratos Wistar , Receptores Opioides/metabolismo , Receptor de NociceptinaRESUMO
A series of N-substituted analogs based upon the spiropiperidine core of 1 was synthesized and exhibited high binding affinity to the nociceptin (NOP) receptor. The selectivities against other known opioid receptors were determined.
Assuntos
Piperidinas/síntese química , Receptores Opioides/agonistas , Administração Oral , Animais , Tosse/tratamento farmacológico , Avaliação Pré-Clínica de Medicamentos , Guanosina 5'-O-(3-Tiotrifosfato) , Ligantes , Farmacocinética , Piperidinas/farmacocinética , Piperidinas/farmacologia , Ligação Proteica , Ratos , Receptores Opioides/metabolismo , Compostos de Espiro/síntese química , Compostos de Espiro/farmacocinética , Compostos de Espiro/farmacologia , Relação Estrutura-Atividade , Receptor de NociceptinaRESUMO
A novel series of 3-substituted-8-aryl-[1,2,4]-triazolo[5,1-i]purin-5-amine analogs related to Sch 58261 was synthesized in order to identify potent adenosine A(2A) receptor antagonists with improved selectivity over the A(1) receptor, physiochemical properties, and pharmacokinetic profiles as compared to those of Sch 58261. As a result of structural modifications, numerous analogs with excellent in vitro binding affinities and selectivities were identified. Moreover, compound 27 displayed both superior in vitro and highly promising in vivo profiles.
Assuntos
Antagonistas do Receptor A2 de Adenosina , Fármacos Neuroprotetores/farmacologia , Purinas/síntese química , Purinas/farmacologia , Pirimidinas/farmacologia , Triazóis/síntese química , Triazóis/farmacologia , Antagonistas do Receptor A1 de Adenosina , Fenômenos Químicos , Físico-Química , Indicadores e Reagentes , Espectroscopia de Ressonância Magnética , Relação Estrutura-AtividadeRESUMO
The structure-activity relationship (SAR) exploration using 2-(2-furanyl)-7-phenyl[1,2,4]triazolo-[1,5-c]pyrimidin-5-amine (1) as a template led to the identification of a novel class of potent and selective adenosine A2A receptor (AR) antagonists. However, these compounds were found to be associated with significant hERG activity. This report discusses the strategy and outcome of an expanded SAR focused on addressing the hERG liability. As a result, compounds 21 and 24 possess excellent in vitro profiles, highly promising in vivo profiles, and acceptable levels of hERG channel inhibition.
Assuntos
Antagonistas do Receptor A2 de Adenosina , Pirimidinas/farmacologia , Triazóis/farmacologia , Administração Oral , Animais , Catalepsia/tratamento farmacológico , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Humanos , Estrutura Molecular , Atividade Motora/efeitos dos fármacos , Pirimidinas/química , Pirimidinas/classificação , Pirimidinas/uso terapêutico , Ratos , Relação Estrutura-Atividade , Triazóis/química , Triazóis/uso terapêuticoRESUMO
The structure-activity relationship of this novel class of compounds based on 2-(2-furanyl)-7-phenyl[1,2,4]-triazolo[1,5-c]pyrimidin-5-amine, 1, and its analogs was evaluated for their in vitro and in vivo adenosine A(2A) receptor antagonism. Several compounds displayed oral activity at 3 mg/kg in a rat catalepsy model. Specifically, compound 8g displayed an excellent in vitro profile, as well as a highly promising in vivo profile.
Assuntos
Antagonistas do Receptor A2 de Adenosina , Pirimidinas/farmacologia , Triazóis/farmacologia , Administração Oral , Animais , Catalepsia/tratamento farmacológico , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Masculino , Estrutura Molecular , Pirimidinas/química , Pirimidinas/classificação , Pirimidinas/uso terapêutico , Ratos , Relação Estrutura-Atividade , Triazóis/química , Triazóis/uso terapêuticoRESUMO
In high throughput screening of our file compounds, a novel structure 1 was identified as a potent A(2A) receptor antagonist with no selectivity over the A1 adenosine receptor. The structure-activity relationship investigation using 1 as a template lead to identification of a novel class of compounds as potent and selective antagonists of A(2A) adenosine receptor. Compound 26 was identified to be the most potent A(2A) receptor antagonist (Ki = 0.8 nM) with 100-fold selectivity over the A1 adenosine receptor.