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1.
J Med Chem ; 62(21): 9931-9946, 2019 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-31638797

RESUMO

RORγt is an important nuclear receptor that regulates the production of several pro-inflammatory cytokines such as IL-17 and IL-22. As a result, RORγt has been identified as a potential target for the treatment of various immunological disorders such as psoriasis, psoriatic arthritis, and inflammatory bowel diseases. Structure and computer-assisted drug design led to the identification of a novel series of tricyclic RORγt inverse agonists with significantly improved in vitro activity in the reporter (Gal4) and human whole blood assays compared to our previous chemotype. Through careful structure activity relationship, several potent and selective RORγt inverse agonists have been identified. Pharmacokinetic studies allowed the identification of the lead molecule 32 with a low peak-to-trough ratio. This molecule showed excellent activity in an IL-2/IL-23-induced mouse pharmacodynamic study and demonstrated biologic-like efficacy in an IL-23-induced preclinical model of psoriasis.

2.
J Am Chem Soc ; 141(16): 6726-6739, 2019 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-30943023

RESUMO

Historically accessed through two-electron, anionic chemistry, ketones, alcohols, and amines are of foundational importance to the practice of organic synthesis. After placing this work in proper historical context, this Article reports the development, full scope, and a mechanistic picture for a strikingly different way of forging such functional groups. Thus, carboxylic acids, once converted to redox-active esters (RAEs), can be utilized as formally nucleophilic coupling partners with other carboxylic derivatives (to produce ketones), imines (to produce benzylic amines), or aldehydes (to produce alcohols). The reactions are uniformly mild, operationally simple, and, in the case of ketone synthesis, broad in scope (including several applications to the simplification of synthetic problems and to parallel synthesis). Finally, an extensive mechanistic study of the ketone synthesis is performed to trace the elementary steps of the catalytic cycle and provide the end-user with a clear and understandable rationale for the selectivity, role of additives, and underlying driving forces involved.

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.
Nature ; 540(7633): 458-461, 2016 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-27926736

RESUMO

CC chemokine receptor 2 (CCR2) is one of 19 members of the chemokine receptor subfamily of human class A G-protein-coupled receptors. CCR2 is expressed on monocytes, immature dendritic cells, and T-cell subpopulations, and mediates their migration towards endogenous CC chemokine ligands such as CCL2 (ref. 1). CCR2 and its ligands are implicated in numerous inflammatory and neurodegenerative diseases including atherosclerosis, multiple sclerosis, asthma, neuropathic pain, and diabetic nephropathy, as well as cancer. These disease associations have motivated numerous preclinical studies and clinical trials (see http://www.clinicaltrials.gov) in search of therapies that target the CCR2-chemokine axis. To aid drug discovery efforts, here we solve a structure of CCR2 in a ternary complex with an orthosteric (BMS-681 (ref. 6)) and allosteric (CCR2-RA-[R]) antagonist. BMS-681 inhibits chemokine binding by occupying the orthosteric pocket of the receptor in a previously unseen binding mode. CCR2-RA-[R] binds in a novel, highly druggable pocket that is the most intracellular allosteric site observed in class A G-protein-coupled receptors so far; this site spatially overlaps the G-protein-binding site in homologous receptors. CCR2-RA-[R] inhibits CCR2 non-competitively by blocking activation-associated conformational changes and formation of the G-protein-binding interface. The conformational signature of the conserved microswitch residues observed in double-antagonist-bound CCR2 resembles the most inactive G-protein-coupled receptor structures solved so far. Like other protein-protein interactions, receptor-chemokine complexes are considered challenging therapeutic targets for small molecules, and the present structure suggests diverse pocket epitopes that can be exploited to overcome obstacles in drug design.


Assuntos
Pirrolidinonas/química , Pirrolidinonas/farmacologia , Quinazolinas/química , Quinazolinas/farmacologia , Receptores CCR2/antagonistas & inibidores , Receptores CCR2/química , Sítio Alostérico/efeitos dos fármacos , Sítios de Ligação , Quimiocinas CC/metabolismo , Cristalografia por Raios X , Desenho de Drogas , Proteínas Heterotriméricas de Ligação ao GTP/metabolismo , Humanos , Ligantes , Modelos Moleculares
6.
J Med Chem ; 59(21): 9837-9854, 2016 11 10.
Artigo em Inglês | MEDLINE | ID: mdl-27726358

RESUMO

Fingolimod (1) is the first approved oral therapy for the treatment of relapsing remitting multiple sclerosis. While the phosphorylated metabolite of fingolimod was found to be a nonselective S1P receptor agonist, agonism specifically of S1P1 is responsible for the peripheral blood lymphopenia believed to be key to its efficacy. Identification of modulators that maintain activity on S1P1 while sparing activity on other S1P receptors could offer equivalent efficacy with reduced liabilities. We disclose in this paper a ligand-based drug design approach that led to the discovery of a series of potent tricyclic agonists of S1P1 with selectivity over S1P3 and were efficacious in a pharmacodynamic model of suppression of circulating lymphocytes. Compound 10 had the desired pharmacokinetic (PK) and pharmacodynamic (PD) profile and demonstrated maximal efficacy when administered orally in a rat adjuvant arthritis model.


Assuntos
Desenho de Drogas , Cloridrato de Fingolimode/farmacologia , Compostos Heterocíclicos com 3 Anéis/farmacologia , Receptores de Lisoesfingolipídeo/agonistas , Animais , Artrite Experimental/tratamento farmacológico , Artrite Experimental/imunologia , Cães , Relação Dose-Resposta a Droga , Cloridrato de Fingolimode/administração & dosagem , Cloridrato de Fingolimode/química , Adjuvante de Freund/administração & dosagem , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Compostos Heterocíclicos com 3 Anéis/química , Ligantes , Linfócitos/efeitos dos fármacos , Macaca fascicularis , Masculino , Camundongos , Estrutura Molecular , Mycobacterium/efeitos dos fármacos , Ratos , Ratos Endogâmicos Lew , Relação Estrutura-Atividade , Distribuição Tecidual
7.
ACS Med Chem Lett ; 6(4): 439-44, 2015 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-25893046

RESUMO

We describe the hybridization of our previously reported acyclic and cyclic CC chemokine receptor 2 (CCR2) antagonists to lead to a new series of dual antagonists of CCR2 and CCR5. Installation of a γ-lactam as the spacer group and a quinazoline as a benzamide mimetic improved oral bioavailability markedly. These efforts led to the identification of 13d, a potent and orally bioavailable dual antagonist suitable for use in both murine and monkey models of inflammation.

8.
Bioorg Med Chem Lett ; 24(7): 1843-5, 2014 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-24613378

RESUMO

We describe novel alkylsulfones as potent CCR2 antagonists with reduced hERG channel activity and improved pharmacokinetics over our previously described antagonists. Several of these new alkylsulfones have a profile that includes functional antagonism of CCR2, in vitro microsomal stability, and oral bioavailability. With this improved profile, we demonstrate that two of these antagonists, 2 and 12, are orally efficacious in an animal model of inflammatory recruitment.


Assuntos
Receptores CCR2/antagonistas & inibidores , Sulfonas/química , Animais , Cicloexanos , Relação Dose-Resposta a Droga , Humanos , Camundongos , Conformação Molecular , Relação Estrutura-Atividade
9.
Bioorg Med Chem Lett ; 22(19): 6181-4, 2012 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-22939233

RESUMO

We describe the design, synthesis, and evaluation of benzimidazoles as benzamide replacements within a series of trisubstituted cyclohexane CCR2 antagonists. 7-Trifluoromethylbenzimidazoles displayed potent binding and functional antagonism of CCR2 while being selective over CCR3. These benzimidazoles were also incorporated into lactam-containing antagonists, thus completely eliminating the customary bis-amide.


Assuntos
Benzimidazóis/farmacologia , Cicloexanos/química , Receptores CCR2/antagonistas & inibidores , Benzimidazóis/síntese química , Benzimidazóis/química , Relação Dose-Resposta a Droga , Desenho de Drogas , Humanos , Microssomos/efeitos dos fármacos , Estrutura Molecular , Relação Estrutura-Atividade
10.
Bioorg Med Chem Lett ; 22(9): 3311-6, 2012 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-22475558

RESUMO

We describe an isostere-driven approach to improve upon a previously-described series of capped dipeptide antagonists of CC Chemokine Receptor 2 (CCR2). Modification of the substitution around the isostere was combined with additional changes in a distal aromatic substituent to provide single-digit nanomolar antagonists of CCR2. These studies led to the identification of 18, a compound that was suitable for studies in murine models of CCR2 activity.


Assuntos
Amino Álcoois/química , Receptores CCR2/antagonistas & inibidores , Amino Álcoois/farmacologia , Animais , Disponibilidade Biológica , Camundongos
11.
Bioorg Med Chem Lett ; 22(3): 1384-7, 2012 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-22225639

RESUMO

We report the synthesis of 3-phenylsulfonylmethyl cyclohexylaminobenzamides (4) as CCR2 inhibitors for the potential treatment of inflammatory diseases. Several of the compounds display nanomolar binding affinity for CCR2. The in vitro structure-activity relationships of 4 are described, and are also reconciled with those from the related 2-phenylsulfonylmethyl series.


Assuntos
Amidas/síntese química , Aminobenzoatos/síntese química , Modelos Moleculares , Receptores CCR2/antagonistas & inibidores , Enxofre/química , Amidas/química , Amidas/farmacologia , Aminobenzoatos/química , Aminobenzoatos/farmacologia , Animais , Ciclização , Humanos , Concentração Inibidora 50 , Camundongos , Microssomos/enzimologia , Estrutura Molecular , Ligação Proteica/efeitos dos fármacos , Ratos , Estereoisomerismo , Relação Estrutura-Atividade , Especificidade por Substrato , Enxofre/farmacologia
12.
Bioorg Med Chem Lett ; 20(8): 2425-30, 2010 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-20346664

RESUMO

We describe the design, synthesis, and evaluation, of gamma-lactams as glycinamide replacements within a series of di- and trisubstituted cyclohexane CCR2 antagonists. The lactam-containing trisubstituted cyclohexanes proved to be more potent than the disubstituted analogs, as trisubstituted analog, lactam 13, displayed excellent activity (CCR2 binding IC(50)=1.0 nM and chemotaxis IC(50) = 0.5 nM) and improved metabolic stability over its parent glycinamide.


Assuntos
Cicloexanos/farmacologia , Glicina/análogos & derivados , Lactamas/química , Receptores CCR2/antagonistas & inibidores , Animais , Quimiotaxia/efeitos dos fármacos , Cicloexanos/química , Glicina/química , Camundongos
13.
J Org Chem ; 74(16): 6368-70, 2009 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-19588919

RESUMO

An efficient enantioselective synthesis of benzyl (1S,2R,4R)-4-(tert-butoxycarbonylamino)-2-(hydroxymethyl)cyclohexylcarbamate 2, an essential intermediate for a series of potent CCR2 antagonists, is described. The key step in the sequence is an iodolactamization to yield the highly functionalized (1R,2S,4S,5S)-tert-butyl 2-(benzyloxycarbonylamino)-4-iodo-7-oxo-6-azabicyclo[3.2.1]octane-6-carboxylate 11. An examination of the reaction mechanism within the 2-step iodolactamization sequence led to the discovery of a single-pot transformation of increased efficiency.


Assuntos
Carbamatos/química , Carbamatos/síntese química , Cicloexanos/química , Cicloexanos/síntese química , Lactamas/química , Anidridos Ftálicos/química , Estereoisomerismo , Especificidade por Substrato
14.
Bioorg Med Chem Lett ; 19(13): 3418-22, 2009 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-19481449

RESUMO

Potent sulfone-containing di- and trisubstituted cyclohexanes were synthesized and evaluated as CC chemokine receptor 2 (CCR2) antagonists. This led to the trisubstituted derivative 54, which exhibited excellent binding (CCR2 IC(50)=1.3nM) and functional antagonism (calcium flux IC(50)=0.5nM and chemotaxis IC(50)=0.2nM). The superiority of the trisubstituted scaffold was rationalized to be the result of a conformational rigidification, which provided insight into the bioactive conformation of this chemotype.


Assuntos
Cicloexanos/síntese química , Receptores CCR2/antagonistas & inibidores , Sulfonas/química , Cicloexanos/química , Cicloexanos/farmacologia , Conformação Molecular , Receptores CCR2/metabolismo , Sulfonas/síntese química
15.
Bioorg Med Chem Lett ; 19(3): 597-601, 2009 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-19131247

RESUMO

A series of trisubstituted cyclohexanes was designed, synthesized and evaluated as CC chemokine receptor 2 (CCR2) antagonists. This led to the identification of two distinct substitution patterns about the cyclohexane ring as potent and selective CCR2 antagonists. Compound 36 exhibited excellent binding (CCR2 IC(50)=2.4 nM) and functional antagonism (calcium flux IC(50)=2.0 nM and chemotaxis IC(50)=5.1 nM).


Assuntos
Química Farmacêutica/métodos , Receptores CCR2/antagonistas & inibidores , Receptores CCR2/química , Sítios de Ligação , Cálcio/química , Quimiocina CCL2/química , Quimiotaxia , Cicloexanos/química , Desenho de Drogas , Humanos , Concentração Inibidora 50 , Modelos Químicos , Estrutura Molecular , Ligação Proteica , Relação Estrutura-Atividade
16.
Bioorg Med Chem Lett ; 18(18): 5063-5, 2008 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-18722120

RESUMO

A series of cis-3,4-disubstituted piperidines was synthesized and evaluated as CC chemokine receptor 2 (CCR2) antagonists. Compound 24 emerged with an attractive profile, possessing excellent binding (CCR2 IC(50)=3.4 nM) and functional antagonism (calcium flux IC(50)=2.0 nM and chemotaxis IC(50)=5.4 nM). Studies to explore the binding of these piperidine analogs utilized a key CCR2 receptor mutant (E291A) with compound 14 and revealed a significant reliance on Glu291 for binding.


Assuntos
Ácido Glutâmico/metabolismo , Piperidinas/síntese química , Piperidinas/farmacologia , Receptores CCR2/antagonistas & inibidores , Técnicas de Química Combinatória , Ácido Glutâmico/química , Concentração Inibidora 50 , Estrutura Molecular , Piperidinas/química , Receptores CCR2/genética , Estereoisomerismo , Relação Estrutura-Atividade
17.
J Med Chem ; 51(4): 721-4, 2008 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-18232650

RESUMO

We describe the design, synthesis, and evaluation of novel disubstituted cyclohexanes as potent CCR2 antagonists. Exploratory SAR studies led to the cis-disubstituted derivative 22, which displayed excellent binding affinity for CCR2 (binding IC50 = 5.1 nM) and potent functional antagonism (calcium flux IC50 = 18 nM and chemotaxis IC 50 = 1 nM). Site-directed mutagenesis studies with 22 suggest the compound is binding near the key receptor residue Glu291, however, 22 is not reliant on Glu291 for its binding affinity.


Assuntos
Cicloexanos/síntese química , Receptores CCR2/antagonistas & inibidores , Ligação Competitiva , Cálcio/metabolismo , Quimiocina CCL2/metabolismo , Quimiotaxia de Leucócito/efeitos dos fármacos , Cicloexanos/química , Cicloexanos/farmacologia , Humanos , Técnicas In Vitro , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Modelos Moleculares , Mutagênese Sítio-Dirigida , Ensaio Radioligante , Receptores CCR2/genética , Estereoisomerismo , Relação Estrutura-Atividade
18.
Bioorg Med Chem Lett ; 17(19): 5455-61, 2007 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-17720492

RESUMO

A new series of CCR2 antagonists has been discovered that incorporates intramolecular hydrogen bonding as a strategy for rigidifying the scaffold. The structure-activity relationship was established through initial systematic modification of substitution pattern and chain length, followed by independent optimization of three different substituents (benzylamine, carboxamide, and benzamide). Several of the acyclic compounds display 10-30 nM binding affinity for CCR2. Moreover, these antagonists are able to block both MCP-1-induced Ca(2+) flux and monocyte chemotaxis, and are selective for binding to CCR2 over CCR1 and CCR3.


Assuntos
Dipeptídeos/síntese química , Dipeptídeos/farmacologia , Receptores CCR2/antagonistas & inibidores , Cálcio/metabolismo , Quimiocina CCL2/antagonistas & inibidores , Quimiocina CCL2/farmacologia , Quimiotaxia de Leucócito/efeitos dos fármacos , Ligações de Hidrogênio , Indicadores e Reagentes , Conformação Molecular , Monócitos/efeitos dos fármacos , Relação Estrutura-Atividade
19.
Org Lett ; 9(9): 1711-4, 2007 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-17385875

RESUMO

[reaction: see text] New methods for the palladium-catalyzed cyanation of aryl and heteroaryl chlorides have been developed, featuring sterically demanding, electron-rich phosphines. Highly challenging electron-rich aryl chlorides, in addition to electron-neutral and electron-deficient substrates, as well as nitrogen- and sulfur-containing heteroaryl chlorides can all undergo efficient cyanation under relatively mild conditions using readily available materials. In terms of substrate scope and temperature, these methods compare very favorably with the state-of-the-art cyanations of aryl chlorides.


Assuntos
Cloretos/química , Cianetos/química , Paládio/química , Compostos de Anilina/química , Catálise , Cloretos/síntese química , Ligantes , Estrutura Molecular
20.
Bioorg Med Chem Lett ; 16(4): 1028-31, 2006 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-16289878

RESUMO

Novel sultam hydroxamates with potent MMP activity were transformed into potent TACE inhibitors, lacking MMP activity. To accomplish this we relied on structural differences between the MMP and TACE S1' pockets and the known advantageous fit of a 2-methyl-4-quinolinylmethoxyphenyl group into this region. From this approach, compound 7d was identified as a potent TACE inhibitor (IC50 = 3.7 nM) that lacked MMP-1, -2, -9, and -13 activity.


Assuntos
Proteínas ADAM/antagonistas & inibidores , Inibidores Enzimáticos , Ácidos Hidroxâmicos , Metaloproteases/antagonistas & inibidores , Sulfonamidas , Proteína ADAM17 , Desenho de Drogas , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Ácidos Hidroxâmicos/síntese química , Ácidos Hidroxâmicos/química , Ácidos Hidroxâmicos/farmacologia , Estrutura Molecular , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química , Sulfonamidas/farmacologia
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