RESUMO
Traf2- and Nck-interacting kinase (TNIK) is a serine/threonine kinase highly expressed in the brain and enriched in the postsynaptic density of glutamatergic synapses in the mammalian brain. Accumulating genetic evidence and functional data have implicated TNIK as a risk factor for psychiatric disorders. However, the endogenous substrates of TNIK in neurons are unknown. Here, we describe a novel selective small molecule inhibitor of the TNIK kinase family. Using this inhibitor, we report the identification of endogenous neuronal TNIK substrates by immunoprecipitation with a phosphomotif antibody followed by mass spectrometry. Phosphorylation consensus sequences were defined by phosphopeptide sequence analysis. Among the identified substrates were members of the delta-catenin family including p120-catenin, δ-catenin, and armadillo repeat gene deleted in velo-cardio-facial syndrome (ARVCF), each of which is linked to psychiatric or neurologic disorders. Using p120-catenin as a representative substrate, we show TNIK-induced p120-catenin phosphorylation in cells requires intact kinase activity and phosphorylation of TNIK at T181 and T187 in the activation loop. Addition of the small molecule TNIK inhibitor or knocking down TNIK by two shRNAs reduced endogenous p120-catenin phosphorylation in cells. Together, using a TNIK inhibitor and phosphomotif antibody, we identify endogenous substrates of TNIK in neurons, define consensus sequences for TNIK, and suggest signaling pathways by which TNIK influences synaptic development and function linked to psychiatric and neurologic disorders.
Assuntos
Sequência Consenso/fisiologia , Neurônios/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Sequência de Aminoácidos , Animais , Células COS , Células Cultivadas , Chlorocebus aethiops , Feminino , Quinases do Centro Germinativo , Células HEK293 , Humanos , Masculino , Dados de Sequência Molecular , Fragmentos de Peptídeos/genética , Fragmentos de Peptídeos/metabolismo , Fosforilação/fisiologia , Ratos , Especificidade por Substrato/fisiologiaRESUMO
Herein we describe design strategies that led to the discovery of novel pyridopyrazine-1,6-dione γ-secretase modulators (GSMs) incorporating an indole motif as a heterocyclic replacement for a naphthyl moiety that was present in the original lead 9. Tactics involving parallel medicinal chemistry and in situ monomer synthesis to prepare focused libraries are discussed. Optimized indole GSM 29 exhibited good alignment of in vitro potency and physicochemical properties, and moderate reduction of brain Aß42 was achieved in a rat efficacy model when dosed orally at 30mg/kg. Labeling experiments using a clickable, indole-derived GSM photoaffinity probe demonstrated that this series binds to the presenilin N-terminal fragment (PS1-NTF) of the γ-secretase complex.
Assuntos
Secretases da Proteína Precursora do Amiloide/efeitos dos fármacos , Descoberta de Drogas , Indóis/farmacologia , Presenilinas/efeitos dos fármacos , Pirazinas/química , Animais , Indóis/química , RatosRESUMO
Leucine rich repeat kinase 2 (LRRK2) has been genetically linked to Parkinson's disease (PD). The most common mutant, G2019S, increases kinase activity, thus LRRK2 kinase inhibitors are potentially useful in the treatment of PD. We herein disclose the structure, potential ligand-protein binding interactions, and pharmacological profiling of potent and highly selective kinase inhibitors based on a triazolopyridazine chemical scaffold.
Assuntos
Compostos Heterocíclicos com 2 Anéis/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/química , Piridazinas/farmacologia , Triazóis/farmacologia , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Compostos Heterocíclicos com 2 Anéis/síntese química , Compostos Heterocíclicos com 2 Anéis/química , Humanos , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Proteínas Serina-Treonina Quinases/metabolismo , Estrutura Terciária de Proteína/efeitos dos fármacos , Piridazinas/síntese química , Piridazinas/química , Relação Estrutura-Atividade , Triazóis/síntese química , Triazóis/químicaRESUMO
Herein, we describe the design and synthesis of γ-secretase modulator (GSM) clinical candidate PF-06648671 (22) for the treatment of Alzheimer's disease. A key component of the design involved a 2,5-cis-tetrahydrofuran (THF) linker to impart conformational rigidity and lock the compound into a putative bioactive conformation. This effort was guided using a pharmacophore model since crystallographic information was not available for the membrane-bound γ-secretase protein complex at the time of this work. PF-06648671 achieved excellent alignment of whole cell in vitro potency (Aß42 IC50 = 9.8 nM) and absorption, distribution, metabolism, and excretion (ADME) parameters. This resulted in favorable in vivo pharmacokinetic (PK) profile in preclinical species, and PF-06648671 achieved a human PK profile suitable for once-a-day dosing. Furthermore, PF-06648671 was found to have favorable brain availability in rodent, which translated into excellent central exposure in human and robust reduction of amyloid ß (Aß) 42 in cerebrospinal fluid (CSF).
Assuntos
Doença de Alzheimer , Secretases da Proteína Precursora do Amiloide , Peptídeos beta-Amiloides , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Secretases da Proteína Precursora do Amiloide/metabolismo , Doença de Alzheimer/tratamento farmacológico , Humanos , Animais , Peptídeos beta-Amiloides/metabolismo , Ratos , Relação Estrutura-Atividade , Camundongos , Masculino , Descoberta de Drogas , Furanos/farmacologia , Furanos/farmacocinética , Furanos/síntese química , Furanos/química , Furanos/uso terapêutico , Ratos Sprague-Dawley , Encéfalo/metabolismoRESUMO
Despite the record-breaking discovery, development and approval of vaccines and antiviral therapeutics such as Paxlovid, coronavirus disease 2019 (COVID-19) remained the fourth leading cause of death in the world and third highest in the United States in 2022. Here, we report the discovery and characterization of PF-07817883, a second-generation, orally bioavailable, SARS-CoV-2 main protease inhibitor with improved metabolic stability versus nirmatrelvir, the antiviral component of the ritonavir-boosted therapy Paxlovid. We demonstrate the in vitro pan-human coronavirus antiviral activity and off-target selectivity profile of PF-07817883. PF-07817883 also demonstrated oral efficacy in a mouse-adapted SARS-CoV-2 model at plasma concentrations equivalent to nirmatrelvir. The preclinical in vivo pharmacokinetics and metabolism studies in human matrices are suggestive of improved oral pharmacokinetics for PF-07817883 in humans, relative to nirmatrelvir. In vitro inhibition/induction studies against major human drug metabolizing enzymes/transporters suggest a low potential for perpetrator drug-drug interactions upon single-agent use of PF-07817883.
Assuntos
Antivirais , Tratamento Farmacológico da COVID-19 , Inibidores de Proteases , SARS-CoV-2 , Humanos , Animais , Camundongos , SARS-CoV-2/efeitos dos fármacos , Antivirais/farmacologia , Antivirais/farmacocinética , Antivirais/uso terapêutico , Antivirais/química , Administração Oral , Inibidores de Proteases/farmacologia , Inibidores de Proteases/farmacocinética , Inibidores de Proteases/uso terapêutico , Inibidores de Proteases/química , Proteases 3C de Coronavírus/antagonistas & inibidores , Proteases 3C de Coronavírus/metabolismo , Ratos , COVID-19/virologiaRESUMO
The structure-based design, synthesis, and biological evaluation of a new pyrazole series of irreversible KAT II inhibitors are described herein. The modification of the inhibitor scaffold of 1 and 2 from a dihydroquinolinone core to a tetrahydropyrazolopyridinone core led to discovery of a new series of potent KAT II inhibitors with excellent physicochemical properties. Compound 20 is the most potent and lipophilically efficient of these new pyrazole analogs, with a k(inact)/K(i) value of 112,000 M(-1)s(-1) and lipophilic efficiency (LipE) of 8.53. The X-ray crystal structure of 20 with KAT II demonstrates key features that contribute to this remarkable potency and binding efficiency.
Assuntos
Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Pirazóis/farmacologia , Transaminases/antagonistas & inibidores , Domínio Catalítico/efeitos dos fármacos , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Interações Hidrofóbicas e Hidrofílicas/efeitos dos fármacos , Modelos Moleculares , Estrutura Molecular , Pirazóis/síntese química , Pirazóis/química , Relação Estrutura-Atividade , Transaminases/metabolismoRESUMO
Cyclic nucleotides are critical regulators of synaptic plasticity and participate in requisite signaling cascades implicated across multiple neurotransmitter systems. Phosphodiesterase 9A (PDE9A) is a high-affinity, cGMP-specific enzyme widely expressed in the rodent central nervous system. In the current study, we observed neuronal staining with antibodies raised against PDE9A protein in human cortex, cerebellum, and subiculum. We have also developed several potent, selective, and brain-penetrant PDE9A inhibitors and used them to probe the function of PDE9A in vivo. Administration of these compounds to animals led to dose-dependent accumulation of cGMP in brain tissue and cerebrospinal fluid, producing a range of biological effects that implied functional significance for PDE9A-regulated cGMP in dopaminergic, cholinergic, and serotonergic neurotransmission and were consistent with the widespread distribution of PDE9A. In vivo effects of PDE9A inhibition included reversal of the respective disruptions of working memory by ketamine, episodic and spatial memory by scopolamine, and auditory gating by amphetamine, as well as potentiation of risperidone-induced improvements in sensorimotor gating and reversal of the stereotypic scratching response to the hallucinogenic 5-hydroxytryptamine 2A agonist mescaline. The results suggested a role for PDE9A in the regulation of monoaminergic circuitry associated with sensory processing and memory. Thus, PDE9A activity regulates neuronal cGMP signaling downstream of multiple neurotransmitter systems, and inhibition of PDE9A may provide therapeutic benefits in psychiatric and neurodegenerative diseases promoted by the dysfunction of these diverse neurotransmitter systems.
Assuntos
3',5'-AMP Cíclico Fosfodiesterases/antagonistas & inibidores , 3',5'-GMP Cíclico Fosfodiesterases/metabolismo , Colinérgicos/farmacologia , GMP Cíclico/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Inibidores de Fosfodiesterase/farmacologia , 3',5'-AMP Cíclico Fosfodiesterases/genética , 3',5'-AMP Cíclico Fosfodiesterases/metabolismo , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Feminino , Humanos , Macaca fascicularis , Masculino , Memória/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos dos fármacos , Neurotransmissores/farmacologia , Ratos , Ratos Long-Evans , Ratos Wistar , Filtro Sensorial/efeitos dos fármacos , Comportamento Estereotipado/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacosRESUMO
We describe a generalized approach to stereocontrolled synthesis of substituted cyclic hydroxamic acids (3-amino-1-hydroxy-3,4-dihydroquinolinones) by selective reduction of substituted 2-nitrophenylalanine substrates. Compounds in this series have antibacterial properties and have also recently been reported as KAT II inhibitors. The key nitrophenyl alanine intermediates are prepared enantioselectively in excellent yield by phase transfer catalyzed alkylation of the corresponding nitrobenzyl bromides. The scope and limitations of the reductive cyclization transformation have been explored with attention to the effects of substitution pattern and electronics on reaction efficiency and byproduct formation. In addition, a novel activated trifluoroethyl ester cyclization strategy has been developed as an alternate approach to the most sterically demanding systems in this series.
Assuntos
Ácidos Hidroxâmicos/química , Ácidos Hidroxâmicos/síntese química , Nitrocompostos/química , Ciclização , Ésteres , Oxirredução , Fenilalanina/análogos & derivados , Fenilalanina/síntese química , Fenilalanina/química , Acetato de Sódio/química , Especificidade por Substrato , Compostos de Estanho/químicaRESUMO
Utilizing a phenotypic screen, we identified chemical matter that increased astrocytic apoE secretion in vitro. We designed a clickable photoaffinity probe based on a pyrrolidine lead compound and carried out probe-based quantitative chemical proteomics in human astrocytoma CCF-STTG1 cells to identify liver x receptor ß (LXRß) as the target. Binding of the small molecule ligand stabilized LXRß, as shown by cellular thermal shift assay (CETSA). In addition, we identified a probe-modified peptide by mass spectrometry and proposed a model where the photoaffinity probe is bound in the ligand-binding pocket of LXRß. Taken together, our findings demonstrated that the lead chemical matter bound directly to LXRß, and our results highlight the power of chemical proteomic approaches to identify the target of a phenotypic screening hit. Additionally, the LXR photoaffinity probe and lead compound described herein may serve as valuable tools to further evaluate the LXR pathway.
Assuntos
Apolipoproteínas E/metabolismo , Astrócitos/metabolismo , Receptores X do Fígado/metabolismo , Astrócitos/citologia , Linhagem Celular , Humanos , Ligantes , Ligação Proteica , ProteômicaRESUMO
The worldwide outbreak of COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a global pandemic. Alongside vaccines, antiviral therapeutics are an important part of the healthcare response to countering the ongoing threat presented by COVID-19. Here, we report the discovery and characterization of PF-07321332, an orally bioavailable SARS-CoV-2 main protease inhibitor with in vitro pan-human coronavirus antiviral activity and excellent off-target selectivity and in vivo safety profiles. PF-07321332 has demonstrated oral activity in a mouse-adapted SARS-CoV-2 model and has achieved oral plasma concentrations exceeding the in vitro antiviral cell potency in a phase 1 clinical trial in healthy human participants.
Assuntos
Tratamento Farmacológico da COVID-19 , Lactamas/farmacologia , Lactamas/uso terapêutico , Leucina/farmacologia , Leucina/uso terapêutico , Nitrilas/farmacologia , Nitrilas/uso terapêutico , Prolina/farmacologia , Prolina/uso terapêutico , SARS-CoV-2/efeitos dos fármacos , Inibidores de Protease Viral/farmacologia , Inibidores de Protease Viral/uso terapêutico , Administração Oral , Animais , COVID-19/virologia , Ensaios Clínicos Fase I como Assunto , Coronavirus/efeitos dos fármacos , Modelos Animais de Doenças , Quimioterapia Combinada , Humanos , Lactamas/administração & dosagem , Lactamas/farmacocinética , Leucina/administração & dosagem , Leucina/farmacocinética , Camundongos , Camundongos Endogâmicos BALB C , Testes de Sensibilidade Microbiana , Nitrilas/administração & dosagem , Nitrilas/farmacocinética , Prolina/administração & dosagem , Prolina/farmacocinética , Ensaios Clínicos Controlados Aleatórios como Assunto , Ritonavir/administração & dosagem , Ritonavir/uso terapêutico , SARS-CoV-2/fisiologia , Inibidores de Protease Viral/administração & dosagem , Inibidores de Protease Viral/farmacocinética , Replicação Viral/efeitos dos fármacosRESUMO
Late-stage oxidation using liver microsomes was applied to phosphodiesterase 2 inhibitor 1 to reduce its clearance by cytochrome P450 enzymes, introduce renal clearance, and minimize the risk for victim drug-drug interactions. This approach yielded PF-06815189 (2) with improved physicochemical properties and a mixed metabolic profile. This example highlights the importance of C-H diversification methods to drug discovery.
RESUMO
Computational modeling was used to direct the synthesis of analogs of previously reported phosphodiesterase 2A (PDE2A) inhibitor 1 with an imidazotriazine core to yield compounds of significantly enhanced potency. The analog PF-05180999 (30) was subsequently identified as a preclinical candidate targeting cognitive impairment associated with schizophrenia. Compound 30 demonstrated potent binding to PDE2A in brain tissue, dose responsive mouse brain cGMP increases, and reversal of N-methyl-d-aspartate (NMDA) antagonist-induced (MK-801, ketamine) effects in electrophysiology and working memory models in rats. Preclinical pharmacokinetics revealed unbound brain/unbound plasma levels approaching unity and good oral bioavailability resulting in an average concentration at steady state (Cav,ss) predicted human dose of 30 mg once daily (q.d.). Modeling of a modified release formulation suggested that 25 mg twice daily (b.i.d.) could maintain plasma levels of 30 at or above targeted efficacious plasma levels for 24 h, which became part of the human clinical plan.
Assuntos
Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 2/antagonistas & inibidores , Descoberta de Drogas , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacologia , Animais , Disponibilidade Biológica , Encéfalo/fisiologia , Nucleotídeo Cíclico Fosfodiesterase do Tipo 2/química , Nucleotídeo Cíclico Fosfodiesterase do Tipo 2/metabolismo , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Humanos , Imidazóis/química , Imidazóis/metabolismo , Imidazóis/farmacocinética , Imidazóis/farmacologia , Concentração Inibidora 50 , Memória de Curto Prazo/efeitos dos fármacos , Simulação de Acoplamento Molecular , Conformação ProteicaRESUMO
As part of our effort in identifying phosphodiesterase (PDE) 4B-preferring inhibitors for the treatment of central nervous system (CNS) disorders, we sought to identify a positron emission tomography (PET) ligand to enable target occupancy measurement in vivo. Through a systematic and cost-effective PET discovery process, involving expression level (Bmax) and biodistribution determination, a PET-specific structure-activity relationship (SAR) effort, and specific binding assessment using a LC-MS/MS "cold tracer" method, we have identified 8 (PF-06445974) as a promising PET lead. Compound 8 has exquisite potency at PDE4B, good selectivity over PDE4D, excellent brain permeability, and a high level of specific binding in the "cold tracer" study. In subsequent non-human primate (NHP) PET imaging studies, [18F]8 showed rapid brain uptake and high target specificity, indicating that [18F]8 is a promising PDE4B-preferring radioligand for clinical PET imaging.
Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Inibidores de Fosfodiesterase/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Animais , Córtex Cerebral/metabolismo , Cromatografia Líquida , Descoberta de Drogas , Macaca fascicularis , Ensaio Radioligante , Relação Estrutura-Atividade , Espectrometria de Massas em TandemRESUMO
Phosphodiesterase 2A (PDE2A) inhibitors have been reported to demonstrate in vivo activity in preclinical models of cognition. To more fully explore the biology of PDE2A inhibition, we sought to identify potent PDE2A inhibitors with improved brain penetration as compared to current literature compounds. Applying estimated human dose calculations while simultaneously leveraging synthetically enabled chemistry and structure-based drug design has resulted in a highly potent, selective, brain penetrant compound 71 (PF-05085727) that effects in vivo biochemical changes commensurate with PDE2A inhibition along with behavioral and electrophysiological reversal of the effects of NMDA antagonists in rodents. This data supports the ability of PDE2A inhibitors to potentiate NMDA signaling and their further development for clinical cognition indications.
Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 2/antagonistas & inibidores , Desenho de Fármacos , Inibidores de Fosfodiesterase/química , Inibidores de Fosfodiesterase/farmacologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Cristalografia por Raios X , Nucleotídeo Cíclico Fosfodiesterase do Tipo 2/química , Nucleotídeo Cíclico Fosfodiesterase do Tipo 2/metabolismo , Cães , Haplorrinos , Humanos , Camundongos , Simulação de Acoplamento Molecular , Inibidores de Fosfodiesterase/administração & dosagem , Inibidores de Fosfodiesterase/farmacocinética , RatosRESUMO
Herein we describe the discovery of a novel series of cyclopropyl chromane-derived pyridopyrazine-1,6-dione γ-secretase modulators for the treatment of Alzheimer's disease (AD). Using ligand-based design tactics such as conformational analysis and molecular modeling, a cyclopropyl chromane unit was identified as a suitable heterocyclic replacement for a naphthyl moiety that was present in the preliminary lead 4. The optimized lead molecule 44 achieved good central exposure resulting in robust and sustained reduction of brain amyloid-ß42 (Aß42) when dosed orally at 10 mg kg-1 in a rat time-course study. Application of the unpaced isolated heart Langendorff model enabled efficient differentiation of compounds with respect to cardiovascular safety, highlighting how minor structural changes can greatly impact the safety profile within a series of compounds.
RESUMO
We previously observed a cutaneous type IV immune response in nonhuman primates (NHP) with the mGlu5 negative allosteric modulator (NAM) 7. To determine if this adverse event was chemotype- or mechanism-based, we evaluated a distinct series of mGlu5 NAMs. Increasing the sp3 character of high-throughput screening hit 40 afforded a novel morpholinopyrimidone mGlu5 NAM series. Its prototype, (R)-6-neopentyl-2-(pyridin-2-ylmethoxy)-6,7-dihydropyrimido[2,1-c][1,4]oxazin-4(9H)-one (PF-06462894, 8), possessed favorable properties and a predicted low clinical dose (2 mg twice daily). Compound 8 did not show any evidence of immune activation in a mouse drug allergy model. Additionally, plasma samples from toxicology studies confirmed that 8 did not form any reactive metabolites. However, 8 caused the identical microscopic skin lesions in NHPs found with 7, albeit with lower severity. Holistically, this work supports the hypothesis that this unique toxicity may be mechanism-based although additional work is required to confirm this and determine clinical relevance.
Assuntos
Regulação Alostérica/efeitos dos fármacos , Compostos Heterocíclicos com 3 Anéis/farmacologia , Compostos Heterocíclicos com 3 Anéis/farmacocinética , Piridinas/farmacologia , Piridinas/farmacocinética , Receptor de Glutamato Metabotrópico 5/antagonistas & inibidores , Receptor de Glutamato Metabotrópico 5/metabolismo , Animais , Feminino , Células HEK293 , Compostos Heterocíclicos com 3 Anéis/efeitos adversos , Compostos Heterocíclicos com 3 Anéis/química , Humanos , Masculino , Simulação de Acoplamento Molecular , Piridinas/efeitos adversos , Piridinas/química , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
Significant progress has been made in prospectively designing molecules using the central nervous system multiparameter optimization (CNS MPO) desirability tool, as evidenced by the analysis reported herein of a second wave of drug candidates that originated after the development and implementation of this tool. This simple-to-use design algorithm has expanded design space for CNS candidates and has further demonstrated the advantages of utilizing a flexible, multiparameter approach in drug discovery rather than individual parameters and hard cutoffs of physicochemical properties. The CNS MPO tool has helped to increase the percentage of compounds nominated for clinical development that exhibit alignment of ADME attributes, cross the blood-brain barrier, and reside in lower-risk safety space (low ClogP and high TPSA). The use of this tool has played a role in reducing the number of compounds submitted to exploratory toxicity studies and increasing the survival of our drug candidates through regulatory toxicology into First in Human studies. Overall, the CNS MPO algorithm has helped to improve the prioritization of design ideas and the quality of the compounds nominated for clinical development.
Assuntos
Sistema Nervoso Central/efeitos dos fármacos , Sistema Nervoso Central/metabolismo , Desenho de Fármacos , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Algoritmos , Animais , Transporte Biológico , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Humanos , Permeabilidade/efeitos dos fármacosRESUMO
Strategic replacement of one or more hydrogen atoms with fluorine atom(s) is a common tactic to improve potency at a given target and/or to modulate parameters such as metabolic stability and pKa. Molecular weight (MW) is a key parameter in design, and incorporation of fluorine is associated with a disproportionate increase in MW considering the van der Waals radius of fluorine versus hydrogen. Herein we examine a large compound data set to understand the effect of introducing fluorine on the risk of encountering P-glycoprotein mediated efflux (as measured by MDR efflux ratio), passive permeability, lipophilicity, and metabolic stability. Statistical modeling of the MDR ER data demonstrated that an increase in MW as a result of introducing fluorine atoms does not lead to higher risk of P-gp mediated efflux. Fluorine-corrected molecular weight (MWFC), where the molecular weight of fluorine has been subtracted, was found to be a more relevant descriptor.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/química , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Flúor/química , Flúor/metabolismo , Interações Hidrofóbicas e Hidrofílicas , Estrutura Molecular , Peso Molecular , PermeabilidadeRESUMO
The kynurenine pathway is responsible for the metabolism of more than 95% of dietary tryptophan (TRP) and produces numerous bioactive metabolites. Recent studies have focused on three enzymes in this pathway: indoleamine dioxygenase (IDO1), kynurenine monooxygenase (KMO), and kynurenine aminotransferase II (KAT II). IDO1 inhibitors are currently in clinical trials for the treatment of cancer, and these agents may also have therapeutic utility in neurological disorders, including multiple sclerosis. KMO inhibitors are being investigated as potential treatments for neurodegenerative diseases, such as Huntington's and Alzheimer's diseases. KAT II inhibitors have been proposed in new therapeutic approaches toward psychiatric and cognitive disorders, including cognitive impairment associated with schizophrenia. Numerous medicinal chemistry studies are currently aimed at the design of novel, potent, and selective inhibitors for each of these enzymes. The emerging opportunities and significant challenges associated with pharmacological modulation of these enzymes will be explored in this review.
Assuntos
Cinurenina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Doenças do Sistema Nervoso Central/tratamento farmacológico , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Quinurenina 3-Mono-Oxigenase/antagonistas & inibidores , Transaminases/antagonistas & inibidoresRESUMO
Leucine rich repeat kinase 2 (LRRK2) has been genetically linked to Parkinson's disease (PD) by genome-wide association studies (GWAS). The most common LRRK2 mutation, G2019S, which is relatively rare in the total population, gives rise to increased kinase activity. As such, LRRK2 kinase inhibitors are potentially useful in the treatment of PD. We herein disclose the discovery and optimization of a novel series of potent LRRK2 inhibitors, focusing on improving kinome selectivity using a surrogate crystallography approach. This resulted in the identification of 14 (PF-06447475), a highly potent, brain penetrant and selective LRRK2 inhibitor which has been further profiled in in vivo safety and pharmacodynamic studies.