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1.
ACS Med Chem Lett ; 14(12): 1760-1766, 2023 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-38116421

RESUMO

A high-throughput fragment-based screen has been employed to discover a series of quinazolinone inositol hexakisphosphate kinase (IP6K) inhibitors. IP6Ks have been studied for their role in glucose homeostasis, metabolic disease, fatty liver disease, chronic kidney disease, blood coagulation, neurological development, and psychiatric disease. IP6Ks phosphorylate inositol hexakisphosphate (IP6) to form pyrophosphate 5-diphospho-1,2,3,4,6-pentakisphosphate (IP7). Molecular docking studies and investigation of structure-activity relationships around the quinazolinone core resulted in compounds with submicromolar potency and interesting selectivity for IP6K1 versus the closely related IP6K2 and IP6K3 isoforms.

2.
Behav Processes ; 212: 104941, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37673291

RESUMO

Attention is a cognitive domain often disrupted in neuropsychiatric disorders and continuous performance tests (CPTs) are common clinical assays of attention. In CPTs, participants produce a behavioral response to target stimuli and refrain from responding to non-target stimuli. Performance in CPTs is measured as the ability to discriminate between targets and non-targets. Rodent versions of CPTs (rCPTs) have been validated with both anatomical and pharmacological studies, providing a translational platform for understanding attention function. In humans, stimulus degradation, the inclusion of visual noise in the image to reduce resolution, in CPTs impairs performance. Reduced image contrast, changes in the relative luminescence of elements in the image, has been used in rCPTs to test similar constructs, but, to our knowledge, reduced image resolution has not been tested in an rCPT. In this study, we tested multiple levels of stimulus degradation in a touchscreen version of the rCPT in mice. We found that stimulus degradation significantly decreased performance in males and females. Specifically, we found decreased stimulus discrimination and increases in hit reaction time and reaction time variability. These findings are in line with the effects of stimulus degradation in human studies. These data extend the utility and translational value of the family of rCPTs by demonstrating that stimulus degradation in the form of reduced image resolution produces qualitatively similar behavioral responses in mice as those in previous human studies.

3.
Biomolecules ; 13(9)2023 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-37759717

RESUMO

Inositol is a unique biological small molecule that can be phosphorylated or even further pyrophosphorylated on each of its six hydroxyl groups. These numerous phosphorylation states of inositol along with the kinases and phosphatases that interconvert them comprise the inositol phosphate signaling pathway. Inositol hexakisphosphate kinases, or IP6Ks, convert the fully mono-phosphorylated inositol to the pyrophosphate 5-IP7 (also denoted IP7). There are three isoforms of IP6K: IP6K1, 2, and 3. Decades of work have established a central role for IP6Ks in cell signaling. Genetic and pharmacologic manipulation of IP6Ks in vivo and in vitro has shown their importance in metabolic disease, chronic kidney disease, insulin signaling, phosphate homeostasis, and numerous other cellular and physiologic processes. In addition to these peripheral processes, a growing body of literature has shown the role of IP6Ks in the central nervous system (CNS). IP6Ks have a key role in synaptic vesicle regulation, Akt/GSK3 signaling, neuronal migration, cell death, autophagy, nuclear translocation, and phosphate homeostasis. IP6Ks' regulation of these cellular processes has functional implications in vivo in behavior and CNS anatomy.

4.
Biomolecules ; 13(5)2023 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-37238737

RESUMO

Obesity and nonalcoholic fatty liver disease (NAFLD) are global health concerns, and thus, drugs for the long-term treatment of these diseases are urgently needed. We previously discovered that the inositol pyrophosphate biosynthetic enzyme IP6K1 is a target in diet-induced obesity (DIO), insulin resistance, and NAFLD. Moreover, high-throughput screening (HTS) assays and structure-activity relationship (SAR) studies identified LI-2242 as a potent IP6K inhibitor compound. Here, we tested the efficacy of LI-2242 in DIO WT C57/BL6J mice. LI-2242 (20 mg/kg/BW daily, i.p.) reduced body weight in DIO mice by specifically reducing the accumulation of body fat. It also improved glycemic parameters and reduced hyperinsulinemia. LI-2242-treated mice displayed reduced the weight of various adipose tissue depots and an increased expression of metabolism- and mitochondrial-energy-oxidation-inducing genes in these tissues. LI-2242 also ameliorated hepatic steatosis by reducing the expression of genes that enhance lipid uptake, lipid stabilization, and lipogenesis. Furthermore, LI-2242 enhances the mitochondrial oxygen consumption rate (OCR) and insulin signaling in adipocytes and hepatocytes in vitro. In conclusion, the pharmacologic inhibition of the inositol pyrophosphate pathway by LI-2242 has therapeutic potential in obesity and NAFLD.


Assuntos
Hiperglicemia , Resistência à Insulina , Hepatopatia Gordurosa não Alcoólica , Camundongos , Animais , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Difosfatos/metabolismo , Insulina/metabolismo , Obesidade/etiologia , Obesidade/genética , Dieta , Resistência à Insulina/fisiologia , Hiperglicemia/metabolismo , Lipídeos , Inositol/metabolismo , Camundongos Endogâmicos C57BL , Fígado/metabolismo , Metabolismo dos Lipídeos
5.
J Med Chem ; 66(7): 4273-4274, 2023 04 13.
Artigo em Inglês | MEDLINE | ID: mdl-36989441
6.
ACS Med Chem Lett ; 13(4): 608-614, 2022 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-35450366

RESUMO

RNA polymerase I (Pol I) transcribes ribosomal DNA (rDNA) into the 47S ribosomal RNA (rRNA) precursor. Further processing produces the 28S, 5.8S, and 18S rRNAs that are assembled into mature ribosomes. Many cancers exhibit higher Pol I transcriptional activity, reflecting a need for increased ribosome biogenesis and protein synthesis and making the inhibition of this process an attractive therapeutic strategy. Lead molecule BMH-21 (1) has been established as a Pol I inhibitor by affecting the destruction of RPA194, the Pol I large catalytic subunit. A previous structure-activity relationship (SAR) study uncovered key pharmacophores, but activity was constrained within a tight chemical space. This work details further SAR efforts that have yielded new scaffolds and improved off-target activity while retaining the desired RPA194 degradation potency. Pharmacokinetic profiling was obtained and provides a starting point for further optimization. New compounds present additional opportunities for the development of Pol I inhibitory cancer therapies.

7.
Neurosci Lett ; 740: 135423, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-33069811

RESUMO

Social isolation is a growing public health concern across the lifespan. Specifically, isolation early in life, during critical periods of brain development, increases the risk of psychiatric disorders later in life. Previous studies of isolation models in mice have shown distinct neurological abnormalities in various regions of the brain, but the mechanism linking the experience of isolation to these phenotypes is unclear. In this study, we show that ΔFosB, a long-lived transcription factor associated with neuronal activity, chronic stress, and drug-induced neuroplasticity, is upregulated in the prelimbic/infralimbic (PL/IL) region of the cortex and hippocampus of adult C57BL/6J mice transiently isolated for two weeks post-weaning. Additionally, a related transcription factor, FosB, is also increased in the PL/IL in socially isolated females.In contrast, both ΔFosB and FosB are increased in male mice isolated for six weeks from weaning until tissue collection. These results show that short-term isolation during the critical post-weaning period has long-lasting and sex-dependent effects on gene expression in brain and that FosB/ΔFosB expression provides a potential mechanistic link between post-weaning social isolation and associated neurological abnormalities.


Assuntos
Córtex Cerebral/metabolismo , Hipocampo/metabolismo , Sistema Límbico/metabolismo , Proteínas Proto-Oncogênicas c-fos/biossíntese , Isolamento Social/psicologia , Desmame , Animais , Feminino , Regulação da Expressão Gênica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Córtex Pré-Frontal/metabolismo , Proteínas Proto-Oncogênicas c-fos/genética , Caracteres Sexuais
9.
Psychopharmacology (Berl) ; 237(9): 2695-2707, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32474681

RESUMO

RATIONALE: Cognitive impairment is a primary feature of many neuropsychiatric disorders and there is a need for new therapeutic options. Catechol-O-methyltransferase (COMT) inhibitors modulate cortical dopaminergic function and have been proposed as potential cognitive enhancers. Unfortunately, currently available COMT inhibitors are not good candidates due to either poor blood-brain barrier penetration or severe toxicity. OBJECTIVES: To address the need for safe, brain-penetrant COMT inhibitors, we tested multiple novel compounds in a set of preclinical in vivo efficacy assays in rats to determine their ability to inhibit COMT function and viability as potential clinical candidates. METHODS: We measured the change in concentration of dopamine (DA) metabolites in cerebrospinal fluid (CSF) from the cisterna magna and extracellular fluid (ECF) from the frontal cortex produced by our novel compounds. Additionally, we tested the effects of our brain-penetrant COMT inhibitors in an attentional set-shifting assay (ASST). We benchmarked the performance of the novel COMT inhibitors to the effects produced by the known COMT inhibitor tolcapone. RESULTS: We found that multiple COMT inhibitors, exemplified by LIBD-1 and LIBD-3, significantly modulated dopaminergic function measured as decreases in homovanillic acid (HVA) and increases in 3,4-Dihydroxyphenylacetic acid (DOPAC), two DA metabolites, in CSF and the frontal cortex. Additionally, we found that LIBD-1 significantly improved cognitive flexibility in the ASST, an effect previously reported following tolcapone administration. CONCLUSIONS: These results demonstrate that LIBD-1 is a novel COMT inhibitor with promising in vivo activity and the potential to serve as a new therapy for cognitive impairment.


Assuntos
Inibidores de Catecol O-Metiltransferase/farmacologia , Catecol O-Metiltransferase/metabolismo , Cognição/efeitos dos fármacos , Dopamina/metabolismo , Lobo Frontal/efeitos dos fármacos , Lobo Frontal/metabolismo , Ácido 3,4-Di-Hidroxifenilacético/metabolismo , Animais , Cognição/fisiologia , Feminino , Ácido Homovanílico/metabolismo , Masculino , Microdiálise/métodos , Ratos , Ratos Sprague-Dawley , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologia
10.
Front Behav Neurosci ; 14: 73, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32508604

RESUMO

Effort-related choice (ERC) tasks allow animals to choose between high-value reinforcers that require high effort to obtain and low-value/low-effort reinforcers. Dopaminergic neuromodulation regulates ERC behavior. The enzyme catechol-O-methyltransferase (COMT) metabolizes synaptically-released dopamine. COMT is the predominant regulator of dopamine turnover in regions of the brain with low levels of dopamine transporters (DATs), including the prefrontal cortex (PFC). Here, we evaluated the effects of the COMT inhibitor tolcapone on ERC performance in a touchscreen-based fixed-ratio/concurrent chow task in male mice. In this task, mice were given the choice between engaging in a fixed number of instrumental responses to acquire a strawberry milk reward and consuming standard lab chow concurrently available on the chamber floor. We found no significant effects of tolcapone treatment on either strawberry milk earned or chow consumed compared to vehicle treatment. In contrast, we found that haloperidol decreased instrumental responding for strawberry milk and increased chow consumption as seen in previously published studies. These data suggest that COMT inhibition does not significantly affect effort-related decision making in a fixed-ratio/concurrent chow task in male mice.

11.
Nat Commun ; 11(1): 462, 2020 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-31974374

RESUMO

Human induced pluripotent stem cells (hiPSCs) are a powerful model of neural differentiation and maturation. We present a hiPSC transcriptomics resource on corticogenesis from 5 iPSC donor and 13 subclonal lines across 9 time points over 5 broad conditions: self-renewal, early neuronal differentiation, neural precursor cells (NPCs), assembled rosettes, and differentiated neuronal cells. We identify widespread changes in the expression of both individual features and global patterns of transcription. We next demonstrate that co-culturing human NPCs with rodent astrocytes results in mutually synergistic maturation, and that cell type-specific expression data can be extracted using only sequencing read alignments without cell sorting. We lastly adapt a previously generated RNA deconvolution approach to single-cell expression data to estimate the relative neuronal maturity of iPSC-derived neuronal cultures and human brain tissue. Using many public datasets, we demonstrate neuronal cultures are maturationally heterogeneous but contain subsets of neurons more mature than previously observed.


Assuntos
Diferenciação Celular/genética , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes Induzidas/fisiologia , Células-Tronco Neurais/fisiologia , Transcriptoma , Algoritmos , Animais , Astrócitos/citologia , Células Cultivadas , Córtex Cerebral/citologia , Técnicas de Cocultura , Bases de Dados Genéticas , Regulação da Expressão Gênica , Humanos , Modelos Neurológicos , Células-Tronco Neurais/citologia , Neurônios/citologia , Neurônios/fisiologia , Ratos
12.
ACS Chem Neurosci ; 10(10): 4221-4226, 2019 10 16.
Artigo em Inglês | MEDLINE | ID: mdl-31491076

RESUMO

The male rat adrenal pheochromocytoma cell-derived PC12 cell line can synthesize and release catecholamine neurotransmitters, and it has been widely used as a model system in cell biology and toxicology research. Catechol-O-methyltransferase (COMT) is involved in the inactivation of the catecholamine neurotransmitters, and it is particularly important for the regulation of dopamine. In this study, we explored the feasibility of using PC12 cells as an in vitro drug screening platform to compare the activity of multiple COMT inhibitors. Incubation of PC12 cells with tolcapone, a highly potent and selective COMT inhibitor, increased the concentrations of dopamine and its metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) while reducing the metabolites 3-methoxytyramine (3-MT) and homovanillic acid (HVA) in the cell culture medium. LIBD-3, a novel, non-nitrocatechol COMT inhibitor, produced similar effects compared to tolcapone. LIBD-4, a less potent inhibitor, exhibited the expected right-shift in functional inhibition in the assay. These results match the known in vivo effects of COMT inhibition in rodents. Together, these data support the continued use of PC12 cells as an in vitro screen that bridges cell-free enzyme assays and more costly in vivo assays.


Assuntos
Inibidores de Catecol O-Metiltransferase/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Dopamina/metabolismo , Animais , Avaliação Pré-Clínica de Medicamentos , Células PC12 , Ratos
13.
Bioorg Med Chem Lett ; 29(19): 126628, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31445853

RESUMO

Inositol hexakisphosphate kinases (IP6Ks) have been increasingly studied as therapeutically interesting enzymes. IP6K isoform specific knock-outs have been used to successfully explore inositol pyrophosphate physiology and related pathologies. A pan-IP6K inhibitor, N2-(m-trifluorobenzyl)-N6-(p-nitrobenzyl) purine (TNP), has been used to confirm phenotypes observed in genetic knock-out experiments; however, it suffers by having modest potency and poor solubility making it difficult to handle for in vitro applications in the absence of DMSO. Moreover, TNP's pan-IP6K inhibitory profile does not inform which IP6K isoform is responsible for which phenotypes. In this report we describe a series of purine-based isoform specific IP6K1 inhibitors. The lead compound was identified after multiple rounds of SAR and has been found to selectively inhibit IP6K1 over IP6K2 or IP6K3 using biochemical and biophysical approaches. It also boasts increased solubility and IP6K1 potency over TNP. These new compounds are useful tools for additional assay development and exploration of IP6K1 specific biology.


Assuntos
Fosfotransferases (Aceptor do Grupo Fosfato)/antagonistas & inibidores , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Humanos , Isoformas de Proteínas , Relação Estrutura-Atividade
14.
ACS Med Chem Lett ; 10(5): 687-689, 2019 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-31097980

RESUMO

Medicinal chemists have increasing opportunities to transition from the pharmaceutical industry to academic medical centers interested in translational research. This Viewpoint highlights some of the differences between these two cultures and strategies to succeed in academic drug discovery.

15.
ACS Med Chem Lett ; 10(11): 1573-1578, 2019 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-32038769

RESUMO

A series of bicyclic pyridones were identified as potent inhibitors of catechol O-methyltransferase (COMT). Substituted benzyl groups attached to the basic nitrogen of the core scaffold gave the most potent inhibitors within this series. Rat pharmacokinetic studies showed medium to high levels of clearance for this series, but with high free fraction due to remarkably low levels of protein and tissue binding. In rat biomarker studies, levels of unbound drug exposure are seen in the brain, which exceed their respective IC50s, leading to changes in the levels of dopamine metabolites in a manner consistent with COMT inhibition.

16.
J Med Chem ; 61(21): 9647-9665, 2018 11 08.
Artigo em Inglês | MEDLINE | ID: mdl-30272964

RESUMO

A series of 8-hydroxy quinolines were identified as potent inhibitors of catechol O-methyltransferase (COMT) with selectivity for the membrane-bound form of the enzyme. Small substituents at the 7-position of the quinoline were found to increase metabolic stability without sacrificing potency. Compounds with good pharmacokinetics and brain penetration were identified and demonstrated in vivo modulation of dopamine metabolites in the brain. An X-ray cocrystal structure of compound 21 in the S-COMT active site shows chelation of the active site magnesium similar to catechol-based inhibitors. These compounds should prove useful for treatment of many neurological and psychiatric conditions associated with compromised cortical dopamine signaling.


Assuntos
Inibidores de Catecol O-Metiltransferase/química , Inibidores de Catecol O-Metiltransferase/farmacologia , Catecol O-Metiltransferase/metabolismo , Desenho de Fármacos , Oxiquinolina/química , Oxiquinolina/farmacologia , Animais , Encéfalo/metabolismo , Catecol O-Metiltransferase/química , Inibidores de Catecol O-Metiltransferase/metabolismo , Inibidores de Catecol O-Metiltransferase/farmacocinética , Masculino , Camundongos , Modelos Moleculares , Oxiquinolina/metabolismo , Oxiquinolina/farmacocinética , Conformação Proteica , Ratos , Distribuição Tecidual
17.
Bioorg Med Chem Lett ; 28(19): 3231-3235, 2018 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-30170942

RESUMO

Due to increased interest in As(III) S-adenosylmethionine methyltransferase (AS3MT), a search for chemical probes that can help elucidate function was initiated. A homology model was built based on related enzymes, and virtual screening produced 426 potential hits. Evaluation of these compounds in a functional enzymatic assay revealed several modest inhibitors including an O-substituted 2-amino-3-cyano indole scaffold. Two iterations of near neighbor searches revealed compound 5 as a potent inhibitor of AS3MT with good selectivity over representative methyltransferases DOT1L and NSD2 as well as a representative set of diverse receptors. Compound 5 should prove to be a useful tool to investigate the role of AS3MT and a potential starting point for further optimization.


Assuntos
Inibidores Enzimáticos/farmacologia , Metiltransferases/antagonistas & inibidores , Humanos
18.
J Clin Invest ; 126(11): 4273-4288, 2016 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-27701146

RESUMO

Enhancing energy expenditure (EE) is an attractive strategy to combat obesity and diabetes. Global deletion of Ip6k1 protects mice from diet-induced obesity (DIO) and insulin resistance, but the tissue-specific mechanism by which IP6K1 regulates body weight is unknown. Here, we have demonstrated that IP6K1 regulates fat accumulation by modulating AMPK-mediated adipocyte energy metabolism. Cold exposure led to downregulation of Ip6k1 in murine inguinal and retroperitoneal white adipose tissue (IWAT and RWAT) depots. Adipocyte-specific deletion of Ip6k1 (AdKO) enhanced thermogenic EE, which protected mice from high-fat diet-induced weight gain at ambient temperature (23°C), but not at thermoneutral temperature (30°C). AdKO-induced increases in thermogenesis also protected mice from cold-induced decreases in body temperature. UCP1, PGC1α, and other markers of browning and thermogenesis were elevated in IWAT and RWAT of AdKO mice. Cold-induced activation of sympathetic signaling was unaltered, whereas AMPK was enhanced, in AdKO IWAT. Moreover, beige adipocytes from AdKO IWAT displayed enhanced browning, which was diminished by AMPK depletion. Furthermore, we determined that IP6 and IP6K1 differentially regulate upstream kinase-mediated AMPK stimulatory phosphorylation in vitro. Finally, treating mildly obese mice with the IP6K inhibitor TNP enhanced thermogenesis and inhibited progression of DIO. Thus, IP6K1 regulates energy metabolism via a mechanism that could potentially be targeted in obesity.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Adipócitos Brancos/metabolismo , Tecido Adiposo Branco/metabolismo , Obesidade/metabolismo , Fosfotransferases (Aceptor do Grupo Fosfato)/metabolismo , Termogênese , Proteínas Quinases Ativadas por AMP/genética , Adipócitos Brancos/patologia , Tecido Adiposo Branco/patologia , Animais , Metabolismo Energético/genética , Camundongos , Camundongos Knockout , Obesidade/induzido quimicamente , Obesidade/genética , Obesidade/patologia , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Fosfotransferases (Aceptor do Grupo Fosfato)/genética , Transdução de Sinais/genética , Proteína Desacopladora 1/genética , Proteína Desacopladora 1/metabolismo
19.
Mol Metab ; 5(10): 903-917, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27689003

RESUMO

OBJECTIVE: Obesity and type 2 diabetes (T2D) lead to various life-threatening diseases such as coronary heart disease, stroke, osteoarthritis, asthma, and neurodegeneration. Therefore, extensive research is ongoing to identify novel pathways that can be targeted in obesity/T2D. Deletion of the inositol pyrophosphate (5-IP7) biosynthetic enzyme, inositol hexakisphosphate kinase-1 (IP6K1), protects mice from high fat diet (HFD) induced obesity (DIO) and insulin resistance. Yet, whether this pathway is a valid pharmacologic target in obesity/T2D is not known. Here, we demonstrate that TNP [N2-(m-Trifluorobenzyl), N6-(p-nitrobenzyl)purine], a pan-IP6K inhibitor, has strong anti-obesity and anti-diabetic effects in DIO mice. METHODS: Q-NMR, GTT, ITT, food intake, energy expenditure, QRT-PCR, ELISA, histology, and immunoblot studies were conducted in short (2.5-week)- and long (10-week)-term TNP treated DIO C57/BL6 WT and IP6K1-KO mice, under various diet and temperature conditions. RESULTS: TNP, when injected at the onset of HFD-feeding, decelerates initiation of DIO and insulin resistance. Moreover, TNP facilitates weight loss and restores metabolic parameters, when given to DIO mice. However, TNP does not reduce weight gain in HFD-fed IP6K1-KO mice. TNP specifically enhances insulin sensitivity in DIO mice via Akt activation. TNP decelerates weight gain primarily by enhancing thermogenic energy expenditure in the adipose tissue. Accordingly, TNP's effect on body weight is partly abolished whereas its impact on glucose homeostasis is preserved at thermoneutral temperature. CONCLUSION: Pharmacologic inhibition of the inositol pyrophosphate pathway has strong therapeutic potential in obesity, T2D, and other metabolic diseases.

20.
Bioorg Med Chem Lett ; 26(12): 2952-2956, 2016 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-27133481

RESUMO

A series of N-heterocyclic pyridinone catechol-O-methyltransferase (COMT) inhibitors were synthesized. Physicochemical properties, including ligand lipophilic efficiency (LLE) and clogP, were used to guide compound design and attempt to improve inhibitor pharmacokinetics. Incorporation of heterocyclic central rings provided improvements in physicochemical parameters but did not significantly reduce in vitro or in vivo clearance. Nevertheless, compound 11 was identified as a potent inhibitor with sufficient in vivo exposure to significantly affect the dopamine metabolites homovanillic acid (HVA) and dihydroxyphenylacetic acid (DOPAC), and indicate central COMT inhibition.


Assuntos
Inibidores de Catecol O-Metiltransferase/farmacologia , Catecol O-Metiltransferase/metabolismo , Compostos Heterocíclicos/farmacologia , Piridonas/farmacologia , Animais , Inibidores de Catecol O-Metiltransferase/síntese química , Inibidores de Catecol O-Metiltransferase/química , Relação Dose-Resposta a Droga , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/química , Humanos , Modelos Moleculares , Estrutura Molecular , Piridonas/síntese química , Piridonas/química , Ratos , Relação Estrutura-Atividade
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