RESUMO
The optimization efforts that led to a novel series of methyl substituted 1-(5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanones that are potent rat and human P2X7 antagonists are described. These efforts resulted in the discovery of compounds with good drug-like properties that are capable of high P2X7 receptor occupancy in rat following oral administration, including compounds 7n (P2X7 IC50 = 7.7 nM) and 7u (P2X7 IC50 =7 .7 nM). These compounds are expected to be useful tools for characterizing the effects of P2X7 antagonism in models of depression and epilepsy, and several of the compounds prepared are candidates for effective P2X7 PET tracers.
Assuntos
Antagonistas do Receptor Purinérgico P2X/química , Pirazinas/química , Receptores Purinérgicos P2X7/química , Triazóis/química , Animais , Meia-Vida , Humanos , Microssomos/metabolismo , Ligação Proteica , Antagonistas do Receptor Purinérgico P2X/metabolismo , Antagonistas do Receptor Purinérgico P2X/farmacocinética , Ratos , Receptores Purinérgicos P2X7/metabolismo , Relação Estrutura-AtividadeRESUMO
The use of P2X7 antagonists to treat inflammatory disorders has garnered considerable interest in recent years. An increasing number of literature reports support the role of P2X7 in inflammatory pathways of the peripheral and central nervous systems (CNSs). A number of CNS indications such as neuropsychiatric and neurodegenerative disorders and neuropathic pain have been linked to a neuroinflammatory response, and clinical studies have shown that inflammatory biomarkers can be mitigated by modulating P2X7. Recent scientific and patent literature describing novel P2X7 antagonists has indicated their use in CNS disorders. In addition, several reports have disclosed the results of administering P2X7 antagonists in pre-clinical models of CNS disease or investigating brain uptake. This review describes small molecule P2X7 antagonists that have first appeared in the literature since 2009 and have potential therapeutic utility in the CNS, or for which new data have emerged implicating their use in CNS indications.
Assuntos
Doenças do Sistema Nervoso Central/tratamento farmacológico , Antagonistas do Receptor Purinérgico P2X/uso terapêutico , Animais , Ensaios Clínicos como Assunto , Modelos Animais de Doenças , Humanos , Doenças Neurodegenerativas/tratamento farmacológicoRESUMO
Leukotrienes (LT's) are known to play a physiological role in inflammatory immune response. Leukotriene A(4) hydrolase (LTA(4)H) is a cystolic enzyme that stereospecifically catalyzes the transformation of LTA(4) to LTB(4). LTB(4) is a known pro-inflammatory mediator. This paper describes the identification and synthesis of substituted benzofurans as LTH(4)H inhibitors. The benzofuran series demonstrated reduced mouse and human whole blood LTB(4) levels in vitro and led to the identification one analog for advanced profiling. Benzofuran 28 showed dose responsive target engagement and provides a useful tool to explore a LTA(4)H inhibitor for the treatment of inflammatory diseases, such as asthma and inflammatory bowel disease (IBD).
Assuntos
Benzofuranos/química , Inibidores Enzimáticos/química , Epóxido Hidrolases/antagonistas & inibidores , Animais , Benzofuranos/farmacologia , Relação Dose-Resposta a Droga , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Humanos , Concentração Inibidora 50 , Camundongos , Estrutura Molecular , Ratos , Ratos Sprague-DawleyRESUMO
Herein, we describe a series of substituted 1H-((1,2,3-triazol-4-yl)methoxy)pyrimidines as potent GluN2B negative allosteric modulators. Exploration of several five- and six-membered heterocycles led to the identification of O-linked pyrimidine analogues that possessed a balance of potency and desirable ADME profiles. Due to initial observations of metabolic saturation, early metabolite identification studies were conducted on compound 18, and the results drove further iterative optimization efforts to avoid the formation of undesired saturating metabolites. The comprehensive investigation of substitution on the pyrimidine moiety of the 1H-1,2,3-triazol-4-yl)methoxy)pyrimidines allowed for the identification of compound 31, which demonstrated high GluN2B receptor affinity, improved solubility, and a clean cardiovascular profile. Compound 31 was profiled in an ex vivo target engagement study in rats at a 10 mg/kg oral dose and achieved an ED50 of 1.7 mg/kg.
Assuntos
Encéfalo , Pirimidinas , Receptores de N-Metil-D-Aspartato , Animais , Ratos , Encéfalo/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Relação Estrutura-AtividadeRESUMO
Previously, benzthiazole containing LTA(4)H inhibitors were discovered that were potent (1-3), but were associated with the potential for a hERG liability. Utilizing medicinal chemistry first principles (e.g., introducing rigidity, lowering cLogD) a new benzthiazole series was designed, congeners of 1-3, which led to compounds 7a, 7c, 12a-d which exhibited LTA(4)H IC(50)=3-6 nM and hERG Dofetilide Binding IC(50)=8.9-> >10 µM.
Assuntos
Compostos Aza/farmacologia , Benzotiazóis/farmacologia , Inibidores Enzimáticos/farmacologia , Epóxido Hidrolases/antagonistas & inibidores , Animais , Compostos Aza/síntese química , Compostos Aza/química , Benzotiazóis/síntese química , Benzotiazóis/química , Relação Dose-Resposta a Droga , Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Epóxido Hidrolases/metabolismo , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Humanos , Camundongos , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
Selective inhibitors of the GluN2B subunit of N-methyl-d-aspartate receptors in the ionotropic glutamate receptor superfamily have been targeted for the treatment of mood disorders. We sought to identify structurally novel, brain penetrant, GluN2B-selective inhibitors suitable for evaluation in a clinical setting in patients with major depressive disorder. We identified a new class of negative allosteric modulators of GluN2B that contain a 1,3-dihydro-imidazo[4,5-b]pyridin-2-one core. This series of compounds had poor solubility properties and poor permeability, which was addressed utilizing two approaches. First, a series of structural modifications was conducted which included replacing hydrogen bond donor groups. Second, enabling formulation development was undertaken in which a stable nanosuspension was identified for lead compound 12. Compound 12 was found to have robust target engagement in rat with an ED70 of 1.4 mg/kg. The nanosuspension enabled sufficient margins in preclinical toleration studies to nominate 12 for progression into advanced good laboratory practice studies.
Assuntos
Antipsicóticos/síntese química , Desenho de Fármacos , Imidazóis/química , Piridinas/química , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Regulação Alostérica , Animais , Antipsicóticos/farmacocinética , Antipsicóticos/uso terapêutico , Encéfalo/metabolismo , Cães , Avaliação Pré-Clínica de Medicamentos , Meia-Vida , Humanos , Imidazóis/farmacocinética , Imidazóis/uso terapêutico , Masculino , Transtornos do Humor/tratamento farmacológico , Transtornos do Humor/patologia , Nanoestruturas/química , Permeabilidade/efeitos dos fármacos , Piridinas/farmacocinética , Piridinas/uso terapêutico , Ratos , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/genética , Receptores de N-Metil-D-Aspartato/metabolismo , Solubilidade , Relação Estrutura-AtividadeRESUMO
Herein, we disclose a series of selective GluN2B negative allosteric modulators containing a 1H-pyrrolo[3,2-b]pyridine core. Lead optimization efforts included increasing brain penetration as well as decreasing cytochrome P450 inhibition and hERG channel binding. The series was also optimized to reduce metabolic turnover in human and rat. Compounds 9, 25, 30, and 34 have good in vitro GluN2B potency and good predicted absorption, but moderate to high projected clearance. They were assessed in vivo to determine their target engagement. All four compounds achieved >75% receptor occupancy after an oral dose of 10 mg/kg in rat. Compound 9 receptor occupancy was measured in a dose-response experiment, and its ED50 was found to be 2.0 mg/kg.
RESUMO
The total synthesis of aigialomycin D was carried out using a nickel-catalyzed ynal macrocyclization as a key step. This key step allowed macrocycle assembly and formation of a disubstituted alkene and a secondary hydroxyl stereocenter in a single step, although the stereocenter was formed unselectively. An interesting side reaction involving five-membered-ring synthesis by an aldehyde/styrene cyclization was observed when macrocyclization of an alkynyl silane was attempted. A mechanistic basis for this surprising process is provided.
Assuntos
Alcenos/síntese química , Alcinos/química , Macrolídeos/síntese química , Níquel/química , Alcenos/química , Catálise , Ciclização , Fungos/química , Macrolídeos/química , Estrutura MolecularRESUMO
A single pot dipolar cycloaddition reaction/Cope elimination sequence was developed to access novel 1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridine P2X7 antagonists that contain a synthetically challenging chiral center. The structure-activity relationships of the new compounds are described. Two of these compounds, (S)-(2-fluoro-3-(trifluoromethyl)phenyl)(1-(5-fluoropyrimidin-2-yl)-6-methyl-1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)methanone (compound 29) and (S)-(3-fluoro-2-(trifluoromethyl)pyridin-4-yl)(1-(5-fluoropyrimidin-2-yl)-6-methyl-1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)methanone (compound 35), were found to have robust P2X7 receptor occupancy at low doses in rat with ED50 values of 0.06 and 0.07 mg/kg, respectively. Compound 35 had notable solubility compared to 29 and showed good tolerability in preclinical species. Compound 35 was chosen as a clinical candidate for advancement into phase I clinical trials to assess safety and tolerability in healthy human subjects prior to the initiation of proof of concept studies for the treatment of mood disorders.
Assuntos
Desenho de Fármacos , Antagonistas do Receptor Purinérgico P2X/síntese química , Antagonistas do Receptor Purinérgico P2X/farmacologia , Piridinas/síntese química , Piridinas/farmacologia , Receptores Purinérgicos P2X7/metabolismo , Animais , Reação de Cicloadição , Cães , Humanos , Masculino , Camundongos , Modelos Moleculares , Conformação Molecular , Antagonistas do Receptor Purinérgico P2X/química , Antagonistas do Receptor Purinérgico P2X/farmacocinética , Piridinas/química , Piridinas/farmacocinética , Ratos , Estereoisomerismo , Distribuição TecidualRESUMO
[reaction: see text] A new nickel-catalyzed method for the reductive aldol addition of acrylates and aldehydes has been developed. An unexpected requirement for an aryl iodide additive was found in the process, and the effect was shown to be linked to an initiation step.
RESUMO
Novel 5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine P2X7 antagonists were optimized to allow for good blood-brain barrier permeability and high P2X7 target engagement in the brain of rats. Compound 25 (huP2X7 IC50 = 9 nM; rat P2X7 IC50 = 42 nM) achieved 80% receptor occupancy for 6 h when dosed orally at 10 mg/kg in rats as measured by ex vivo radioligand binding autoradiography. Structure-activity relationships within this series are described, as well as in vitro ADME results. In vivo pharmacokinetic data for key compounds is also included.