RESUMO
Previous reports from our laboratories described potent tripeptide thrombin inhibitors which incorporate heterocycle-substituted chlorophenyl groups in the P1 position. Using these as lead compounds for further optimization, we identified sites of metabolism and designed analogs with 4-fluoroproline in P2 and cyclopropane-containing side chains in P3 as an approach to reducing metabolism and improving their oral pharmacokinetic performance. The large (300-fold) difference in potency between analogs containing (4R)- and (4S)-4-fluoroproline was rationalized by analyzing inhibitor-enzyme interactions in crystal structures of related compounds and by molecular modeling which indicated that the more potent (4R)-4-fluoroproline isomer stabilizes a proline ring conformation that is preferred for binding to the enzyme. An optimal compound from this work, 41, exhibits high potency in a coagulation assay in human plasma (2xAPTT=190 nM), excellent selectivity versus the digestive enzyme trypsin (K(i)=3300 nM), and excellent oral bioavailability in dogs with moderate clearance (F=100%, CL=12 mL/min/kg).
Assuntos
Inibidores Enzimáticos/farmacologia , Prolina/análogos & derivados , Trombina/antagonistas & inibidores , Sítios de Ligação , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Técnicas In Vitro , Modelos Moleculares , Conformação Molecular , Prolina/química , Conformação Proteica , Estrutura Terciária de Proteína , Estereoisomerismo , Relação Estrutura-Atividade , Trombina/metabolismo , Tripsina/efeitos dos fármacos , Tripsina/metabolismoRESUMO
We describe a series of highly potent and efficacious thrombin inhibitors based on a 3-amino-4-sulfonylpyridinone acetamide template. The functionally dense sulfonyl group stabilizes the aminopyridinone, conformationally constrains the 4-substituent, and forms a hydrogen bond to the insertion loop tyrosine OH. We also describe a related series of fused bicyclic dihydrothiadiazinedioxide derivatives, of which one had improved pharmacokinetics in dogs after oral dosing.
Assuntos
Acetamidas/química , Acetamidas/farmacologia , Piridonas/química , Piridonas/farmacologia , Tiadiazinas/química , Tiadiazinas/farmacologia , Trombina/antagonistas & inibidores , Acetamidas/farmacocinética , Administração Oral , Animais , Modelos Animais de Doenças , Cães , Compostos Férricos/toxicidade , Humanos , Modelos Moleculares , Piridonas/farmacocinética , Ratos , Relação Estrutura-Atividade , Sulfonas/química , Sulfonas/farmacocinética , Sulfonas/farmacologia , Tiadiazinas/farmacocinética , Trombose/induzido quimicamente , Inibidores da Tripsina/química , Inibidores da Tripsina/farmacocinética , Inibidores da Tripsina/farmacologiaRESUMO
Starting from a 2-amino-6-methylpyridine P1 group and following a strategy of enlarging it whilst reducing its polarity, we have developed a series of potent, moderately basic azaindoles which are intrinsically much more selective for thrombin versus trypsin. Certain pyrazinone acetamide azaindole derivatives have pharmacokinetic parameters after oral administration to dogs, or efficacy in vitro, comparable to an optimized pyrazinone acetamide 2-amino-6-methylpyridine derivative.
Assuntos
Compostos Aza/química , Compostos Aza/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Indóis/química , Indóis/farmacologia , Trombina/antagonistas & inibidores , Administração Oral , Animais , Compostos Aza/farmacocinética , Cães , Inibidores Enzimáticos/farmacocinética , Humanos , Indóis/farmacocinética , Modelos Moleculares , Tempo de Tromboplastina Parcial , Piridinas/química , Piridinas/farmacologia , Relação Estrutura-Atividade , Especificidade por Substrato , Trombina/metabolismo , Tripsina/metabolismoRESUMO
Addition of the Reformatsky reagent derived from ethyl bromodifluoroacetate to alkyl- and aryl-substituted N-tert-butylsulfinimines furnishes beta-tert-butylsulfinamyl-beta-substituted alpha,alpha-difluoroproponiates in diastereomeric ratios ranging from 80:20 to 95:5. The diastereomers are easily separated and the enantiomerically pure, protected beta-amino esters are readily transformed to the corresponding acid, amide, and amine derivatives as useful synthons for medicinal chemistry targets.