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1.
Bioorg Med Chem Lett ; 29(16): 2265-2269, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31257087

RESUMO

An X-ray crystal structure of one of our previously discovered RORγt inverse agonists bound to the RORγt ligand binding domain revealed that the cyclohexane carboxylic acid group of compound 2 plays a significant role in RORγt binding, forming four hydrogen bonding and ionic interactions with RORγt. SAR studies centered around the cyclohexane carboxylic acid group led to identification of several structurally diverse and more potent compounds, including new carboxylic acid analogues 7 and 20, and cyclic sulfone analogues 34 and 37. Notably, compounds 7 and 20 were found to maintain the desirable pharmacokinetic profile of 2.

2.
ACS Med Chem Lett ; 9(7): 673-678, 2018 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-30034599

RESUMO

Screening of a small set of nonselective lipase inhibitors against endothelial lipase (EL) identified a potent and reversible inhibitor, N-(3-(3,4-dichlorophenyl)propyl)-3-hydroxy-1-methyl-2-oxo-1,2-dihydropyridine-4-carboxamide (5; EL IC50 = 61 nM, ELHDL IC50 = 454 nM). Deck mining identified a related hit, N-(3-(3,4-dichlorophenyl)propyl)-4-hydroxy-1-methyl-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxamide (6a; EL IC50 = 41 nM, ELHDL IC50 = 1760 nM). Both compounds were selective against lipoprotein lipase (LPL) but nonselective versus hepatic lipase (HL). Optimization of compound 6a for EL inhibition using HDL as substrate led to N-(4-(3,4-dichlorophenyl)butan-2-yl)-1-ethyl-4-hydroxy-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxamide (7c; EL IC50 = 148 nM, ELHDL IC50 = 218 nM) having improved PK over compound 6a, providing a tool molecule to test for the ability to increase HDL-cholesterol (HDL-C) levels in vivo using a reversible EL inhibitor. Compound 7c did not increase HDL-C in vivo despite achieving plasma exposures targeted on the basis of enzyme activity and protein binding demonstrating the need to develop more physiologically relevant in vitro assays to guide compound progression for in vivo evaluation.

3.
J Med Chem ; 60(12): 5193-5208, 2017 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-28541707

RESUMO

PI3Kδ plays an important role controlling immune cell function and has therefore been identified as a potential target for the treatment of immunological disorders. This article highlights our work toward the identification of a potent, selective, and efficacious PI3Kδ inhibitor. Through careful SAR, the successful replacement of a polar pyrazole group by a simple chloro or trifluoromethyl group led to improved Caco-2 permeability, reduced Caco-2 efflux, reduced hERG PC activity, and increased selectivity profile while maintaining potency in the CD69 hWB assay. The optimization of the aryl substitution then identified a 4'-CN group that improved the human/rodent correlation in microsomal metabolic stability. Our lead molecule is very potent in PK/PD assays and highly efficacious in a mouse collagen-induced arthritis model.


Assuntos
Artrite Experimental/tratamento farmacológico , Avaliação Pré-Clínica de Medicamentos/métodos , Inibidores Enzimáticos/farmacologia , Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Relação Estrutura-Atividade , Animais , Antígenos CD/metabolismo , Antígenos de Diferenciação de Linfócitos T/metabolismo , Células CACO-2/efeitos dos fármacos , Células CACO-2/imunologia , Cães , Canal de Potássio ERG1/metabolismo , Inibidores Enzimáticos/química , Feminino , Humanos , Doenças do Sistema Imunitário/tratamento farmacológico , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Lectinas Tipo C/metabolismo , Masculino , Camundongos Endogâmicos BALB C , Pirazóis/química , Pirazóis/metabolismo , Pirazóis/farmacologia , Coelhos
4.
Bioorg Med Chem Lett ; 27(4): 855-861, 2017 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-28108251

RESUMO

As demonstrated in preclinical animal models, the disruption of PI3Kδ expression or its activity leads to a decrease in inflammatory and immune responses. Therefore, inhibition of PI3Kδ may provide an alternative treatment for autoimmune diseases, such as RA, SLE, and respiratory ailments. Herein, we disclose the identification of 7-(3-(piperazin-1-yl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine derivatives as highly potent, selective and orally bioavailable PI3Kδ inhibitors. The lead compound demonstrated efficacy in an in vivo mouse KLH model.


Assuntos
Aminas/química , Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Aminas/metabolismo , Aminas/uso terapêutico , Animais , Doenças Autoimunes/tratamento farmacológico , Sítios de Ligação , Cristalografia por Raios X , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Humanos , Camundongos , Microssomos Hepáticos/metabolismo , Simulação de Acoplamento Molecular , Fosfatidilinositol 3-Quinases/metabolismo , Piperazina , Piperazinas/química , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/metabolismo , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/uso terapêutico , Relação Estrutura-Atividade , Triazinas/química
5.
ACS Med Chem Lett ; 7(9): 831-4, 2016 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-27660686

RESUMO

A new series of phenylquinazoline inhibitors of Kv 1.5 is disclosed. The series was optimized for Kv 1.5 potency, selectivity versus hERG, pharmacokinetic exposure, and pharmacodynamic potency. 5-Phenyl-N-(pyridin-2-ylmethyl)-2-(pyrimidin-5-yl)quinazolin-4-amine (13k) was identified as a potent and ion channel selective inhibitor with robust efficacy in the preclinical rat ventricular effective refractory period (VERP) model and the rabbit atrial effective refractory period (AERP) model.

6.
Bioorg Med Chem Lett ; 26(17): 4256-60, 2016 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-27476421

RESUMO

Aberrant Class I PI3K signaling is a key factor contributing to many immunological disorders and cancers. We have identified 4-amino pyrrolotriazine as a novel chemotype that selectively inhibits PI3Kδ signaling despite not binding to the specificity pocket of PI3Kδ isoform. Structure activity relationship (SAR) led to the identification of compound 30 that demonstrated efficacy in mouse Keyhole Limpet Hemocyanin (KLH) and collagen induced arthritis (CIA) models.


Assuntos
Aminas/química , Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Triazinas/química , Aminas/metabolismo , Aminas/uso terapêutico , Animais , Artrite/tratamento farmacológico , Artrite/metabolismo , Artrite/patologia , Sítios de Ligação , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Concentração Inibidora 50 , Camundongos , Simulação de Acoplamento Molecular , Fosfatidilinositol 3-Quinases/metabolismo , Ligação Proteica , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/metabolismo , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/uso terapêutico , Estrutura Terciária de Proteína , Relação Estrutura-Atividade
7.
Bioorg Med Chem Lett ; 25(21): 4983-4986, 2015 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-25801931

RESUMO

Phenethyl aminoheterocycles like compound 1 were known to be potent I(Kur) blockers although they lacked potency in vivo. Modification of the heterocycle led to the design and synthesis of pseudosaccharin amines. Compounds such as 14, 17d and 21c were found to be potent K(V)1.5 blockers and selective over other cardiac ion channels. These compounds had potent pharmacodynamic activity, however, they also showed off-target activities such as hemodynamic effects.


Assuntos
Aminas/farmacologia , Canal de Potássio Kv1.5/antagonistas & inibidores , Bloqueadores dos Canais de Potássio/farmacologia , Aminas/síntese química , Aminas/química , Animais , Pressão Sanguínea/efeitos dos fármacos , Cicloexanos/química , Cicloexanos/farmacologia , Relação Dose-Resposta a Droga , Humanos , Canal de Potássio Kv1.5/metabolismo , Camundongos , Estrutura Molecular , Bloqueadores dos Canais de Potássio/síntese química , Bloqueadores dos Canais de Potássio/química , Coelhos , Ratos , Compostos de Espiro/química , Compostos de Espiro/farmacologia , Relação Estrutura-Atividade
8.
Chem Res Toxicol ; 24(11): 2044-54, 2011 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-21939268

RESUMO

Acylfulvenes (AFs), a class of semisynthetic analogues of the sesquiterpene natural product illudin S, are cytotoxic toward cancer cells. The minor structural changes between illudin S and AFs translate to an improved therapeutic window in preclinical cell-based assays and xenograft models. AFs are, therefore, unique tools for addressing the chemical and biochemical basis of cytotoxic selectivity. AFs elicit cytotoxic responses by alkylation of biological targets, including DNA. While AFs are capable of direct alkylation, cytosolic reductive bioactivation to an electrophilic intermediate is correlated with enhanced cytotoxicity. Data obtained in this study illustrate chemical aspects of the process of AF activation. By tracking reaction mechanisms with stable isotope-labeled reagents, enzymatic versus chemical activation pathways for AF were compared for reactions involving the NADPH-dependent enzyme prostaglandin reductase 1 (PTGR1) or sodium borohydride, respectively. These two processes resulted in isomeric products that appear to give rise to similar patterns of DNA modification. The chemically activated isomer has been newly isolated and chemically characterized in this study, including an assessment of its relative stereochemistry and stability at varying pH and under bioassay conditions. In mammalian cancer cells, this chemically activated analogue was shown to not rely on further cellular activation to significantly enhance cytotoxic potency, in contrast to the requirements of AF. On the basis of this study, we anticipate that the chemically activated form of AF will serve as a useful chemical probe for evaluating biomolecular interactions independent of enzyme-mediated activation.


Assuntos
Álcool Desidrogenase/metabolismo , Antibióticos Antineoplásicos/química , Boroidretos/química , DNA/metabolismo , Neoplasias/tratamento farmacológico , Sesquiterpenos/química , Compostos de Espiro/química , Alquilação , Animais , Antibióticos Antineoplásicos/metabolismo , Antibióticos Antineoplásicos/farmacologia , Biotransformação , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , DNA/química , Ativação Enzimática/efeitos dos fármacos , Humanos , NADP/metabolismo , Neoplasias/metabolismo , Neoplasias/patologia , Ratos , Sesquiterpenos/metabolismo , Sesquiterpenos/farmacologia , Compostos de Espiro/metabolismo , Compostos de Espiro/farmacologia , Estereoisomerismo , Relação Estrutura-Atividade
9.
Chem Res Toxicol ; 20(10): 1513-9, 2007 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-17900171

RESUMO

Acylfulvenes (AFs) are a class of antitumor agents that exert their cytotoxic effects by forming covalent adducts with biomolecules, including DNA and proteins; clinical trials are ongoing for (-)-(hydroxymethyl)AF. Recently, depurinating DNA adducts N3-AF-deoxyadenosine (dAdo) and N7-AF-deoxyguanosine (dGuo) were identified from reactions of the parent compound, AF, with calf thymus DNA in the presence of the reductase enzyme alkenal/one oxidoreductase (AOR) and cofactor NADPH. We report here the development of a structure-specific quantitative analytical method for evaluating levels of the major base adduct N3-AF-adenine (Ade), which results from depurination of N3-AF-dAdo, and its utilization to further probe the relationship between AOR-mediated bioactivation and adduct formation in a cell-free system. As an internal standard, the isotopomer N3-AF-Ade-d3 was synthesized, and electrospray-ionization mass spectrometry coupled with high-performance liquid chromatography (HPLC-ESI-MS/MS) was used to detect and quantitate the adduct. This method was validated and found to be accurate (R2>or=0.99) and precise (relative standard deviation 5.8-6.4%), with a limit of detection of 2 fmol. DNA samples, to which the stable-isotope-labeled internal standard was added, were subjected to neutral thermal hydrolysis yielding N3-AF-Ade. Adducts were isolated by a simple solid-liquid methanol extraction procedure, and adduct formation was examined in the presence of either high (1-3 micromol) or low (15 nmol) levels of DNA. Absolute amounts of N3-AF-Ade were measured in cell-free reaction mixtures containing varying levels of AOR as the only drug-activating enzyme. The increase in adduct formation (5-100 adducts per 10(5) DNA bases) over a range of enzyme concentrations (1-24 nM of AOR) showed saturation type behavior. This study reports a sensitive HPLC-ESI-MS/MS method for quantitation of the major DNA adduct induced by AF and illustrates a correlation between N3-AF-Ade formation and AOR-mediated enzymatic activation in a cell-free system, thus providing a template for further studies of drug toxicity in cells and in vivo.


Assuntos
Oxirredutases do Álcool/metabolismo , Antineoplásicos Alquilantes/metabolismo , Adutos de DNA/metabolismo , Desoxiadenosinas/metabolismo , Alquilação , Animais , Antineoplásicos Alquilantes/química , Cromatografia Líquida de Alta Pressão , Adutos de DNA/análise , Desoxiadenosinas/química , Ratos , Reprodutibilidade dos Testes , Sesquiterpenos/química , Sesquiterpenos/metabolismo , Espectrometria de Massas por Ionização por Electrospray , Compostos de Espiro/química , Compostos de Espiro/metabolismo
10.
J Med Chem ; 49(8): 2593-9, 2006 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-16610802

RESUMO

Acylfulvenes comprise a family of semisynthetic natural product derivatives with potent antitumor activities. Previous studies indicated that acylfulvenes are bioactivated by NADPH-dependent alkenal/one reductase (AOR), presumably generating intermediates with the capacity to alkylate cellular targets, such as DNA, proteins, and glutathione. This process is thought to induce apoptosis, and the chemical and biochemical pathways involved are topics of current investigation. In this study, four acylfulvene analogues were synthesized: (-)-acylfulvene, (+)-acylfulvene, (-)-(hydroxymethyl)acylfulvene, and (+)-(hydroxymethyl)acylfulvene. These compounds were synthesized by a chiral-resolution method, described for the first time in this report, and by asymmetric synthesis using a method formally demonstrated previously. Cell toxicity studies indicate a positive correlation between AOR level and acylfulvene sensitivity. The absolute configuration of acylfulvene analogues has a significant influence on cytotoxicity. (-)-(Hydroxymethyl)acylfulvene is 25 times more potent than (+)-(hydroxymethyl)acylfulvene in cells transfected with an AOR overexpression vector. Based on kinetic parameters, the rates of AOR-mediated activation are more strongly dependent on acylfulvene substitution than on absolute stereochemistry. These data support the role of AOR-mediated metabolism and indicate the involvement of other stereochemically dictated pathways, such as transport and biomolecule binding, in contributing to the cytotoxicity of acylfulvenes.


Assuntos
Oxirredutases do Álcool/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/toxicidade , Oxirredutases do Álcool/química , Oxirredutases do Álcool/genética , Animais , Antineoplásicos/química , Biotransformação , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Ativação Enzimática , Humanos , Conformação Molecular , Ratos , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Sesquiterpenos/síntese química , Sesquiterpenos/química , Sesquiterpenos/toxicidade , Compostos de Espiro/síntese química , Compostos de Espiro/química , Compostos de Espiro/toxicidade , Estereoisomerismo , Relação Estrutura-Atividade , Transfecção
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