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1.
Bioorg Med Chem Lett ; 25(4): 925-30, 2015 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-25592713

RESUMO

The structure-activity relationships (SAR) of six-membered ring replacements for the imidazole ring scaffold is described. This work led to the discovery of the potent and selective pyridine (S)-23 and pyridinone (±)-24 factor XIa inhibitors. SAR and X-ray crystal structure data highlight the key differences between imidazole and six-membered ring analogs.


Assuntos
Fator XIa/antagonistas & inibidores , Piridinas/farmacologia , Piridonas/farmacologia , Cristalografia por Raios X , Modelos Moleculares , Relação Estrutura-Atividade
2.
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
3.
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
4.
Bioorg Med Chem Lett ; 23(6): 1604-7, 2013 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-23416003

RESUMO

Bicyclic pyrazinone and pyrimidinone amides were designed and synthesized as potent TF-FVIIa inhibitors. SAR demonstrated that the S2 and S3 pockets of FVIIa prefer to bind small, lipophilic groups. An X-ray crystal structure of optimized compound 9b bound in the active site of FVIIa showed that the bicyclic scaffold provides 5 hydrogen bonding interactions in addition to projecting groups for interactions within the S1, S2 and S3 pockets. Compound 9b showed excellent FVIIa potency, good selectivity against FIXa, Xa, XIa and chymotrypsin, and good clotting activity.


Assuntos
Amidas/química , Amidinas/síntese química , Desenho de Fármacos , Fator VIIa/antagonistas & inibidores , Pirazinas/química , Pirazinas/síntese química , Pirimidinonas/química , Inibidores de Serina Proteinase/síntese química , Amidas/síntese química , Amidas/metabolismo , Amidinas/química , Amidinas/metabolismo , Sítios de Ligação , Compostos Bicíclicos com Pontes/química , Domínio Catalítico , Cristalografia por Raios X , Fator VIIa/metabolismo , Ligação Proteica , Pirazinas/metabolismo , Inibidores de Serina Proteinase/química , Inibidores de Serina Proteinase/metabolismo , Relação Estrutura-Atividade
5.
J Pharmacol Exp Ther ; 303(3): 1114-20, 2002 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-12438534

RESUMO

Platelet accretion into arterial thrombus in stenotic arterial vessels involves shear-induced platelet activation and adhesion. The Cone and Plate(let) Analyzer (CPA) is designed to simulate such conditions in vitro under a rotating high shear rate in whole blood. In the present study, we evaluated various experimental conditions (including aspirin, temperature, and calcium concentration) and investigated the effects of small molecules along with peptide glycoprotein IIb/IIIa antagonists on platelet adhesion using the CPA system. Concentration-dependent effect of glycoprotein IIb/IIIa antagonists on shear-induced platelet adhesion showed marked differences in potencies: IC50 = 34, 35, 91, 438, and 606 nM for DPC802 (a specific glycoprotein IIb/IIIa antagonist), roxifiban, sibrafiban, lotrafiban, and orbofiban (free acid forms), respectively, and IC50 values of 43, 430, and 5781 nM for abciximab, tirofiban, and eptifibatide, respectively. Parallel study was also conducted to evaluate the effect of glycoprotein IIb/IIIa inhibitors using optical aggregometry. The potency of fibans in blocking shear-induced platelet adhesion correlated well with their binding affinity to the resting and activated glycoprotein IIb/IIIa receptors, as well as their "off-rates". Nevertheless, none of these fibans was able to effectively block shear-induced platelet adhesion at targeted clinical dosing regimens except for abciximab. These data suggest that glycoprotein IIb/IIIa antagonists that show similar efficacy in the inhibition of platelet aggregation in a static in vitro assay may differ substantially in a shear-based system of platelet adhesion. The clinical significance of this phenomenon awaits further investigation.


Assuntos
Ativação Plaquetária/efeitos dos fármacos , Adesividade Plaquetária/efeitos dos fármacos , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/antagonistas & inibidores , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo , Abciximab , Alanina/metabolismo , Alanina/farmacologia , Amidinas/metabolismo , Amidinas/farmacologia , Análise de Variância , Anticorpos Monoclonais/farmacologia , Anticoagulantes/farmacologia , Aspirina/farmacologia , Agregação Celular/efeitos dos fármacos , Agregação Celular/fisiologia , Relação Dose-Resposta a Droga , Eptifibatida , Humanos , Fragmentos Fab das Imunoglobulinas/farmacologia , Isoxazóis/metabolismo , Isoxazóis/farmacologia , Peptídeos/farmacologia , Ativação Plaquetária/fisiologia , Adesividade Plaquetária/fisiologia , Pirrolidinas/metabolismo , Pirrolidinas/farmacologia , Reologia , Resistência ao Cisalhamento , Temperatura , Tirofibana , Tirosina/análogos & derivados , Tirosina/farmacologia
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