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J Chromatogr A ; 1511: 101-106, 2017 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-28687240


Purification of many pharmaceutical compounds by supercritical fluid chromatography (SFC) has always been challenging because of degradation of compound during the isolation step in the presence of acidic or basic modifiers in the mobile phase. Stability of such acid or base-sensitive compounds could be improved by post-column addition of a solvent containing base or acid modifier as counter ion through a make-up pump respectively to neutralize the compound fraction without affecting the resolution. One such case study has been presented in this work where the stability of a base-sensitive compound was addressed by the addition of acidic co-solvent through the make-up pump. Details of this setup and the investigation of degradation of the in-house base-sensitive compound are discussed in this paper. In addition, poor retentivity and low recovery of many non-polar compounds in SFC eluting under low co-solvent percentage is another major concern. Even though the desired separation could be achieved with low percentage of co-solvent, it's difficult to get the proper recovery after purification due to precipitation of the sample and significant aerosol formation inside the cyclone. We have demonstrated the first-time use of a post-column make-up pump on SFC 350 system to introduce additional solvent prior to cyclone to avoid the precipitation, reduce the aerosol formation and thus improve the recovery of non-polar compounds eluting under less than 10% of co-solvent.

Cromatografia com Fluido Supercrítico/métodos , Dióxido de Carbono/química , Dioxolanos/análise , Furanos/análise , Ácidos Mandélicos/análise , Mianserina/análise , Preparações Farmacêuticas/análise , Solventes/química , Estereoisomerismo
J Med Chem ; 59(21): 9837-9854, 2016 11 10.
Artigo em Inglês | MEDLINE | ID: mdl-27726358


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.

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
J Med Chem ; 57(23): 9915-32, 2014 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-25405503


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.

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
Echocardiography ; 29(7): E169-72, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22404341


Isolated noncompaction of ventricular myocardium (INVM) is a genetic cardiomyopathy due to abnormal arrest in endomyocardial embryogenesis between fetal 5th and 8th week. Noncompaction of right ventricle alone is rare. Here we present one such case where a young man presented with progressive right heart failure and atrial fibrillation. Subsequent evaluation by echo and cardiac magnetic resonance imaging confirmed our diagnosis. The cardinal manifestations of INVM are heart failure, arrhythmia, and embolic events and our case presented with former two manifestations. Echocardiographic criteria for diagnosing INVM are discussed.

Fibrilação Atrial/diagnóstico por imagem , Insuficiência Cardíaca/diagnóstico por imagem , Miocárdio Ventricular não Compactado Isolado/diagnóstico por imagem , Adulto , Humanos , Masculino , Ultrassonografia