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1.
Bioorg Med Chem Lett ; 29(19): 126628, 2019 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-31445853

RESUMEN

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.


Asunto(s)
Fosfotransferasas (Aceptor del Grupo Fosfato)/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Humanos , Isoformas de Proteínas , Relación Estructura-Actividad
2.
Bioorg Med Chem Lett ; 28(19): 3231-3235, 2018 10 15.
Artículo en Inglés | MEDLINE | ID: mdl-30170942

RESUMEN

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.


Asunto(s)
Inhibidores Enzimáticos/farmacología , Metiltransferasas/antagonistas & inhibidores , Humanos
3.
Bioorg Med Chem Lett ; 28(6): 1043-1049, 2018 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-29486970

RESUMEN

A series of isoquinuclidine benzamides as glycine uptake inhibitors for the treatment of schizophrenia are described. Potency, lipophilicity, and intrinsic human microsomal clearance were parameters for optimization. Potency correlated with the nature of the ortho substituents of the benzamide ring, and reductions in lipophilicity could be achieved through heteroatom incorporation in the benzamide and pendant phenyl moieties. Improvements in human CLint were achieved through changes in ring size and the N-alkyl group of the isoquinuclidine itself, with des-alkyl derivatives (40-41, 44) demonstrating the most robust microsomal stability. Dimethylbenzamide 9 was tested in a mouse MK801 LMA assay and had a statistically significant attenuation of locomotor activity at 3 and 10 µmol/kg compared to control.


Asunto(s)
Benzamidas/farmacología , Compuestos Bicíclicos con Puentes/farmacología , Proteínas de Transporte de Glicina en la Membrana Plasmática/antagonistas & inhibidores , Administración Oral , Animales , Benzamidas/administración & dosificación , Benzamidas/química , Compuestos Bicíclicos con Puentes/administración & dosificación , Compuestos Bicíclicos con Puentes/química , Relación Dosis-Respuesta a Droga , Humanos , Inyecciones Intravenosas , Locomoción/efectos de los fármacos , Masculino , Ratones , Estructura Molecular , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad
4.
J Labelled Comp Radiopharm ; 57(5): 342-9, 2014 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-24700683

RESUMEN

In support of a program to develop an alpha 7 agonist as a treatment for Alzheimer's disease, three drug candidates, 1, 2, and 3, were prepared in labeled forms. Compound 1 was prepared in C-14 labeled form by lithiation of [2,6-(14)C2]2-chloropyridine and subsequent coupling with spirooxirane-2,3'-quinuclidine. When this same coupling was attempted using [3,4,5,6-(2)H4]2-chloropyridine, alcohol [(2)H6]-6 was the major product indicating that the primary isotope effect for the lithiation step was significant enough to shift the reaction pathway. Therefore, an alternate site of labeling was used to prepare [(2)H4]-1. [(13)C5]-2 was prepared in five steps from [(13)C5 ]2-furoic acid, but the C-14 labeled compound used [(14)C2]-1 as the starting material instead. [(14)C2]-3 was prepared in two steps from [carbonyl-(14)C]nicotinic acid.


Asunto(s)
Isótopos de Carbono/química , Isótopos de Carbono/aislamiento & purificación , Niacina/análogos & derivados , Receptor Nicotínico de Acetilcolina alfa 7/antagonistas & inhibidores , Marcaje Isotópico , Radiofármacos/síntesis química
5.
bioRxiv ; 2024 Aug 16.
Artículo en Inglés | MEDLINE | ID: mdl-39211199

RESUMEN

Ribosome biosynthesis is a cancer vulnerability executed by targeting RNA polymerase I (Pol I) transcription. We developed advanced, specific Pol I inhibitors to identify drivers of this sensitivity. By integrating multi-omics features and drug sensitivity data from a large cancer cell panel, we discovered that RPL22 frameshift mutation conferred Pol I inhibitor sensitivity in microsatellite instable cancers. Mechanistically, RPL22 directly interacts with 28S rRNA and mRNA splice junctions, functioning as a splicing regulator. RPL22 deficiency, intensified by 28S rRNA sequestration, promoted the splicing of its paralog RPL22L1 and p53 negative regulator MDM4. Chemical and genetic inhibition of rRNA synthesis broadly remodeled mRNA splicing controlling hundreds of targets. Strikingly, RPL22-dependent alternative splicing was reversed by Pol I inhibition revealing a ribotoxic stress-initiated tumor suppressive pathway. We identify a mechanism that robustly connects rRNA synthesis activity to splicing and reveals their coordination by ribosomal protein RPL22.

6.
J Med Chem ; 67(16): 13639-13665, 2024 Aug 22.
Artículo en Inglés | MEDLINE | ID: mdl-39096294

RESUMEN

Inositol hexakisphosphate kinases (IP6Ks) have been studied for their role in glucose homeostasis, metabolic disease, fatty liver disease, chronic kidney disease, neurological development, and psychiatric disease. IP6Ks phosphorylate inositol hexakisphosphate (IP6) to the pyrophosphate, 5-diphosphoinositol-1,2,3,4,6-pentakisphosphate (5-IP7). Most of the currently known potent IP6K inhibitors contain a critical carboxylic acid which limits blood-brain barrier (BBB) penetration. In this work, the synthesis and testing of a variety of carboxylic acid isosteres resulted in several new compounds with improved BBB penetration. The most promising compound has an IP6K1 IC50 of 16 nM with an improved brain/plasma ratio and a favorable pharmacokinetic profile. This series of brain penetrant compounds may be used to investigate the role of IP6Ks in CNS disorders.


Asunto(s)
Barrera Hematoencefálica , Fosfotransferasas (Aceptor del Grupo Fosfato) , Barrera Hematoencefálica/metabolismo , Fosfotransferasas (Aceptor del Grupo Fosfato)/metabolismo , Fosfotransferasas (Aceptor del Grupo Fosfato)/antagonistas & inhibidores , Animales , Humanos , Relación Estructura-Actividad , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Ratones , Masculino , Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacología , Ácidos Carboxílicos/síntesis química , Ratas
7.
Biomolecules ; 13(5)2023 05 20.
Artículo en Inglés | MEDLINE | ID: mdl-37238737

RESUMEN

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.


Asunto(s)
Hiperglucemia , Resistencia a la Insulina , Enfermedad del Hígado Graso no Alcohólico , Ratones , Animales , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/etiología , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Difosfatos/metabolismo , Insulina/metabolismo , Obesidad/etiología , Obesidad/genética , Dieta , Resistencia a la Insulina/fisiología , Hiperglucemia/metabolismo , Lípidos , Inositol/metabolismo , Ratones Endogámicos C57BL , Hígado/metabolismo , Metabolismo de los Lípidos
8.
ACS Med Chem Lett ; 14(12): 1760-1766, 2023 Dec 14.
Artículo en Inglés | MEDLINE | ID: mdl-38116421

RESUMEN

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.

9.
Bioorg Med Chem Lett ; 22(2): 1174-8, 2012 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-22197137

RESUMEN

A series of 4-piperidin-4-ylidenemethyl-benzamide δ-opioid receptor agonists is described with an emphasis on balancing the potency, subtype selectivity and in vitro ADME and safety properties. The three sites impacting SAR are substitutions on the aryl group (R(1)), the piperidine nitrogen (R(2)), and the amide (R(3)). Each region contributes to the balance of properties for δ opioid activity and a desirable CNS profile, and two clinical candidates (20 and 24) were advanced.


Asunto(s)
Benzamidas/farmacología , Sistema Nervioso Central/efectos de los fármacos , Piperidinas/farmacología , Receptores Opioides delta/agonistas , Benzamidas/química , Sistema Nervioso Central/metabolismo , Relación Dosis-Respuesta a Droga , Canales de Potasio Éter-A-Go-Go/antagonistas & inhibidores , Células HEK293 , Humanos , Estructura Molecular , Piperidinas/química , Receptores Opioides delta/metabolismo , Estereoisomerismo , Relación Estructura-Actividad
10.
Bioorg Med Chem Lett ; 22(2): 1169-73, 2012 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-22197139

RESUMEN

A novel series of piperazine derivatives exhibits sub-nanomolar binding and enhanced subtype selectivity as δ-opioid agonists. The synthesis and SAR are described as well as the application of computational models to improve in vitro ADME and safety properties suitable for CNS indications, specifically microsomal clearance, permeability, and hERG channel inhibition.


Asunto(s)
Sistema Nervioso Central/efectos de los fármacos , Piperazinas/farmacología , Receptores Opioides delta/agonistas , Animales , Sistema Nervioso Central/metabolismo , Simulación por Computador , Perros , Relación Dosis-Respuesta a Droga , Canales de Potasio Éter-A-Go-Go/antagonistas & inhibidores , Humanos , Estructura Molecular , Piperazinas/síntesis química , Piperazinas/química , Receptores Opioides delta/metabolismo , Estereoisomerismo , Relación Estructura-Actividad
11.
ACS Pharmacol Transl Sci ; 4(2): 780-789, 2021 Apr 09.
Artículo en Inglés | MEDLINE | ID: mdl-33860201

RESUMEN

Inositol hexakisphosphate kinases (IP6Ks) catalyze pyrophosphorylation of inositol hexakisphosphate (IP6) into inositol 5-diphospho-1,2,3,4,6-pentakisphosphate (IP7), which is involved in numerous areas of cell physiology including glucose homeostasis, blood coagulation, and neurological development. Inhibition of IP6Ks may be effective for the treatment of Type II diabetes, obesity, metabolic complications, thrombosis, and psychiatric disorders. We performed a high-throughput screen (HTS) of 158 410 compounds for IP6K1 inhibitors using a previously developed ADP-Glo Max assay. Of these, 1206 compounds were found to inhibit IP6K1 kinase activity by more than 25%, representing a 0.8% hit rate. Structural clustering analysis of HTS-active compounds, which were confirmed in the dose-response testing using the same kinase assay, revealed diverse clusters that were feasible for future structure-activity relationship (SAR) optimization to potent IP6K inhibitors. Medicinal chemistry SAR efforts in three chemical series identified potent IP6K1 inhibitors which were further validated in an orthogonal LC-MS IP7 analysis. The effects of IP6K1 inhibitors on cellular IP7 levels were further confirmed and were found to correlate with cellular IP6K1 binding measured by a high-throughput cellular thermal shift assay (CETSA).

12.
ACS Med Chem Lett ; 10(11): 1573-1578, 2019 Nov 14.
Artículo en Inglés | MEDLINE | ID: mdl-32038769

RESUMEN

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.

13.
J Med Chem ; 61(21): 9647-9665, 2018 11 08.
Artículo en Inglés | MEDLINE | ID: mdl-30272964

RESUMEN

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.


Asunto(s)
Inhibidores de Catecol O-Metiltransferasa/química , Inhibidores de Catecol O-Metiltransferasa/farmacología , Catecol O-Metiltransferasa/metabolismo , Diseño de Fármacos , Oxiquinolina/química , Oxiquinolina/farmacología , Animales , Encéfalo/metabolismo , Catecol O-Metiltransferasa/química , Inhibidores de Catecol O-Metiltransferasa/metabolismo , Inhibidores de Catecol O-Metiltransferasa/farmacocinética , Masculino , Ratones , Modelos Moleculares , Oxiquinolina/metabolismo , Oxiquinolina/farmacocinética , Conformación Proteica , Ratas , Distribución Tisular
14.
Mol Metab ; 5(10): 903-917, 2016 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-27689003

RESUMEN

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.

15.
Oncotarget ; 5(12): 4361-9, 2014 Jun 30.
Artículo en Inglés | MEDLINE | ID: mdl-24952786

RESUMEN

DNA intercalation is a major therapeutic modality for cancer therapeutic drugs. The therapeutic activity comes at a cost of normal tissue toxicity and genotoxicity. We have recently described a planar heterocyclic small molecule DNA intercalator, BMH-21, that binds ribosomal DNA and inhibits RNA polymerase I (Pol I) transcription. Despite DNA intercalation, BMH-21 does not cause phosphorylation of H2AX, a key biomarker activated in DNA damage stress. Here we assessed whether BMH-21 activity towards expression and localization of Pol I marker proteins depends on DNA damage signaling and repair pathways. We show that BMH-21 effects on the nucleolar stress response were independent of major DNA damage associated PI3-kinase pathways, ATM, ATR and DNA-PKcs. However, testing a series of BMH-21 derivatives with alterations in its N,N-dimethylaminocarboxamide arm showed that several derivatives had acquired the property to activate ATM- and DNA-PKcs -dependent damage sensing and repair pathways while their ability to cause nucleolar stress and affect cell viability was greatly reduced. The data show that BMH-21 is a chemically unique DNA intercalator that has high bioactivity towards Pol I inhibition without activation or dependence of DNA damage stress. The findings also show that interference with DNA and DNA metabolic processes can be exploited therapeutically without causing DNA damage.


Asunto(s)
Proteínas de Ciclo Celular/genética , Daño del ADN/genética , Proteínas Supresoras de Tumor/genética , Humanos , Sustancias Intercalantes , Modelos Moleculares , Fosforilación , ARN Polimerasa I , Transducción de Señal
16.
J Med Chem ; 57(11): 4950-61, 2014 Jun 12.
Artículo en Inglés | MEDLINE | ID: mdl-24847734

RESUMEN

RNA polymerase I (Pol I) is a dedicated polymerase that transcribes the 45S ribosomal (r) RNA precursor. The 45S rRNA precursor is subsequently processed into the mature 5.8S, 18S, and 28S rRNAs and assembled into ribosomes in the nucleolus. Pol I activity is commonly deregulated in human cancers. On the basis of the discovery of lead molecule BMH-21, a series of pyridoquinazolinecarboxamides have been evaluated as inhibitors of Pol I and activators of the destruction of RPA194, the Pol I large catalytic subunit protein. Structure-activity relationships in assays of nucleolar stress and cell viability demonstrate key pharmacophores and their physicochemical properties required for potent activation of Pol I stress and cytotoxicity. This work identifies a set of bioactive compounds that potently cause RPA194 degradation that function in a tightly constrained chemical space. This work has yielded novel derivatives that contribute to the development of Pol I inhibitory cancer therapeutic strategies.


Asunto(s)
Amidas/síntesis química , Antineoplásicos/síntesis química , Piridinas/síntesis química , Quinazolinas/síntesis química , ARN Polimerasa I/antagonistas & inhibidores , Amidas/química , Amidas/farmacología , Antineoplásicos/química , Antineoplásicos/farmacología , Línea Celular Tumoral , Nucléolo Celular/metabolismo , Supervivencia Celular/efectos de los fármacos , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Técnicas In Vitro , Microsomas Hepáticos/metabolismo , Piridinas/química , Piridinas/farmacología , Quinazolinas/química , Quinazolinas/farmacología , Relación Estructura-Actividad
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