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1.
Bioorg Med Chem Lett ; 42: 128010, 2021 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-33811992

RESUMO

Myeloperoxidase (MPO), a critical enzyme in antimicrobial host-defense, has been implicated in chronic inflammatory diseases such as coronary artery disease. The design and evaluation of MPO inhibitors for the treatment of cardiovascular disease are reported herein. Starting with the MPO and triazolopyridine 3 crystal structure, novel inhibitors were designed incorporating a substituted pyrazole, which allowed for substituents to interact with hydrophobic and hydrophilic patches in the active site. SAR exploration of the substituted pyrazoles led to piperidine 17, which inhibited HOCl production from activated neutrophils with an IC50 value of 2.4 µM and had selectivity against thyroid peroxidase (TPO). Optimization of alkylation chemistry on the pyrazole nitrogen facilitated the preparation of many analogs, including macrocycles designed to bridge two hydrophobic regions of the active site. Multiple macrocyclization strategies were pursued to prepare analogs that optimally bound to the active site, leading to potent macrocyclic MPO inhibitors with TPO selectivity, such as compound 30.


Assuntos
Inibidores Enzimáticos/farmacologia , Compostos Macrocíclicos/farmacologia , Peroxidase/antagonistas & inibidores , Pirazóis/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Compostos Macrocíclicos/síntese química , Compostos Macrocíclicos/química , Estrutura Molecular , Peroxidase/metabolismo , Pirazóis/síntese química , Pirazóis/química , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química , Relação Estrutura-Atividade
2.
Bioorg Med Chem Lett ; 29(19): 126604, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31445854

RESUMO

This manuscript describes the discovery of a series of macrocyclic inhibitors of FXIa with oral bioavailability. Assisted by structure based drug design and ligand bound X-ray crystal structures, the group linking the P1 moiety to the macrocyclic core was modified with the goal of reducing H-bond donors to improve pharmacokinetic performance versus 9. This effort resulted in the discovery of several cyclic P1 linkers, exemplified by 10, that are constrained mimics of the bioactive conformation displayed by the acrylamide linker of 9. These cyclic P1 linkers demonstrated enhanced bioavailability and improved potency.


Assuntos
Desenho de Fármacos , Descoberta de Drogas , Fator XIa/antagonistas & inibidores , Compostos Macrocíclicos/administração & dosagem , Compostos Macrocíclicos/química , Inibidores de Serina Proteinase/administração & dosagem , Inibidores de Serina Proteinase/química , Administração Oral , Disponibilidade Biológica , Humanos , Ligantes , Compostos Macrocíclicos/farmacologia , Modelos Moleculares , Estrutura Molecular , Inibidores de Serina Proteinase/farmacologia , Relação Estrutura-Atividade
3.
J Med Chem ; 61(17): 7425-7447, 2018 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-29775297

RESUMO

With the introduction of thrombin and factor Xa inhibitors to the oral anticoagulant market, significant improvements in both efficacy and safety have been achieved. Early clinical and preclinical data suggest that inhibitors of factor XIa can provide a still safer alternative, with expanded efficacy for arterial indications. This Perspective provides an overview of target rationale and details of the discovery and development of inhibitors of factor XIa as next generation antithrombotic agents.


Assuntos
Anticoagulantes/química , Anticoagulantes/farmacologia , Fator XIa/antagonistas & inibidores , Anticorpos Monoclonais/química , Anticorpos Monoclonais/farmacologia , Aptâmeros de Nucleotídeos/química , Aptâmeros de Nucleotídeos/farmacologia , Domínio Catalítico , Ensaios Clínicos como Assunto , Fator XIa/química , Fator XIa/metabolismo , Humanos , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia
4.
Bioorg Med Chem Lett ; 25(7): 1635-42, 2015 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-25728130

RESUMO

Compound 2 was previously identified as a potent inhibitor of factor XIa lacking oral bioavailability. A structure-based approach was used to design analogs of 2 with novel P1 moieties with good selectivity profiles and oral bioavailability. Further optimization of the P1 group led to the identification of a 4-chlorophenyltetrazole P1 analog, which when combined with further modifications to the linker and P2' group provided compound 32 with FXIa Ki=6.7 nM and modest oral exposure in dogs.


Assuntos
Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Fator XIa/antagonistas & inibidores , Indazóis/farmacologia , Administração Oral , Animais , Disponibilidade Biológica , Cães , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/química , Fator XIa/efeitos dos fármacos , Humanos , Indazóis/administração & dosagem , Indazóis/química , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade
5.
J Med Chem ; 57(23): 9915-32, 2014 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-25405503

RESUMO

Novel inhibitors of FXIa containing an (S)-2-phenyl-1-(4-phenyl-1H-imidazol-2-yl)ethanamine core have been optimized to provide compound 16b, a potent, reversible inhibitor of FXIa (Ki = 0.3 nM) having in vivo antithrombotic efficacy in the rabbit AV-shunt thrombosis model (ID50 = 0.6 mg/kg + 1 mg kg(-1) h(-1)). Initial analog selection was informed by molecular modeling using compounds 11a and 11h overlaid onto the X-ray crystal structure of tetrahydroquinoline 3 complexed to FXIa. Further optimization was achieved by specific modifications derived from careful analysis of the X-ray crystal structure of the FXIa/11h complex. Compound 16b was well tolerated and enabled extensive pharmacologic evaluation of the FXIa mechanism up to the ID90 for thrombus inhibition.


Assuntos
Fibrinolíticos/síntese química , Imidazóis/síntese química , Indazóis/síntese química , Animais , Cristalografia por Raios X , Fibrinolíticos/farmacocinética , Fibrinolíticos/farmacologia , Humanos , Imidazóis/farmacocinética , Imidazóis/farmacologia , Indazóis/farmacocinética , Indazóis/farmacologia , Modelos Moleculares , Tempo de Tromboplastina Parcial , Coelhos , Trombose/prevenção & controle
6.
J Med Chem ; 57(3): 955-69, 2014 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-24405333

RESUMO

Antithrombotic agents that are inhibitors of factor XIa (FXIa) have the potential to demonstrate robust efficacy with a low bleeding risk profile. Herein, we describe a series of tetrahydroquinoline (THQ) derivatives as FXIa inhibitors. Compound 1 was identified as a potent and selective tool compound for proof of concept studies. It exhibited excellent antithrombotic efficacy in rabbit thrombosis models and did not prolong bleeding times. This demonstrates proof of concept for the FXIa mechanism in animal models with a reversible, small molecule inhibitor.


Assuntos
Inibidores do Fator Xa , Fibrinolíticos/síntese química , Quinolinas/síntese química , Animais , Tempo de Sangramento , Cristalografia por Raios X , Fibrinolíticos/química , Fibrinolíticos/farmacologia , Humanos , Conformação Molecular , Simulação de Acoplamento Molecular , Quinolinas/química , Quinolinas/farmacologia , Coelhos , Estereoisomerismo , Relação Estrutura-Atividade
8.
Bioorg Med Chem Lett ; 18(7): 2428-33, 2008 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-18329876

RESUMO

As part of an effort to identify novel backups for previously reported pyrazole-based coagulation Factor Xa inhibitors, the pyrazole 5-carboxamide moiety was replaced by 3-(sulfonylamino)-2-piperidone. This led to the identification of a structurally diverse chemotype that was further optimized to incorporate neutral or weakly basic aryl and heteroaryl P1 groups while maintaining good potency versus Factor Xa. Substitution at the sulfonamide nitrogen provided further improvements in potency and as did introduction of alternate P4 moieties.


Assuntos
Anticoagulantes/farmacologia , Inibidores do Fator Xa , Lactamas/farmacologia , Piperidonas/farmacologia , Sulfonamidas/farmacologia , Anticoagulantes/síntese química , Sítios de Ligação , Testes de Coagulação Sanguínea , Lactamas/síntese química , Ligantes , Modelos Químicos , Piperidonas/síntese química , Relação Estrutura-Atividade , Sulfonamidas/síntese química
9.
Bioorg Med Chem Lett ; 17(5): 1432-7, 2007 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-17174550

RESUMO

The synthesis, SAR, pharmacokinetic profile, and modeling studies of both monocyclic and fused pyrazoles containing substituted N-arylpiperidinyl P4 moieties that are potent and selective factor Xa inhibitors will be discussed. Fused pyrazole analog 16a, with a 2'-methylsulfonylphenyl piperidine P4 group, was shown to be the best compound in this series (FXa Ki = 0.35 nM) based on potency, selectivity, and pharmacokinetic profile.


Assuntos
Inibidores do Fator Xa , Piperidinas/síntese química , Piperidinas/farmacocinética , Pirazóis/síntese química , Pirazóis/farmacocinética , Animais , Cães , Modelos Moleculares , Piperidinas/administração & dosagem , Ligação Proteica , Pirazóis/administração & dosagem , Relação Estrutura-Atividade
10.
Bioorg Med Chem Lett ; 14(21): 5263-7, 2004 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-15454208

RESUMO

Modifications to the P4 moiety and pyrazole C3 substituent of factor Xa inhibitor SN-429 provided several new compounds, which are 5-10nM inhibitors of factor IXa. An X-ray crystal structure of one example complexed to factor IXa shows that these compounds adopt a similar binding mode to that previously observed with pyrazole inhibitors in the factor Xa active site both with regard to how the inhibitor binds and the position of Tyr99.


Assuntos
Benzimidazóis/síntese química , Fator IXa/antagonistas & inibidores , Fator IXa/química , Inibidores do Fator Xa , Fator Xa/química , Pirazóis/síntese química , Benzimidazóis/química , Sítios de Ligação , Cristalografia por Raios X , Humanos , Modelos Moleculares , Estrutura Molecular , Pirazóis/química , Relação Estrutura-Atividade
11.
Curr Opin Drug Discov Devel ; 7(4): 460-9, 2004 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-15338955

RESUMO

Factor Xa (fXa) is a key enzyme in the coagulation cascade and an essential component of the prothrombinase complex, which activates prothrombin to thrombin, leading to fibrin clot formation. In the search for a more effective and safer orally active anticoagulant, fXa has emerged as a major target for potential therapeutic applications in the treatment and prevention of thrombosis. This review focuses on recent advances in the chemistry of drug design and lead optimization of orally bioavailable fXa inhibitors. Many of these orally active fXa inhibitors are currently in clinical trials and are anticipated to change the landscape of thrombosis therapy.


Assuntos
Administração Oral , Antitrombina III/uso terapêutico , Animais , Antitrombina III/química , Antitrombina III/classificação , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Sistemas de Liberação de Medicamentos/métodos , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos/métodos , Humanos , Estrutura Molecular , Tromboembolia/tratamento farmacológico
12.
Bioorg Med Chem Lett ; 14(2): 383-7, 2004 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-14698164

RESUMO

Analogues of isoxazoline alpha(v)beta(3) antagonist 1 designed to further restrict the four carbon alkyl tether were prepared by incorporating two spirocyclic scaffolds, 1-oxa-2-azaspiro[4,5]dec-2-ene and 1-oxa-2,7-diazaspiro[4,4]non-2-ene. Additional optimization provided potent antagonists of both alpha(v)beta(3) and alpha(5)beta(1) which are selective over GPIIb/IIIa.


Assuntos
Imidazóis/síntese química , Integrinas/antagonistas & inibidores , Sítios de Ligação/fisiologia , Avaliação Pré-Clínica de Medicamentos/métodos , Humanos , Imidazóis/metabolismo , Integrinas/metabolismo , Estereoisomerismo
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