RESUMEN
The rational design, syntheses and evaluation of potent sulfonamidopyrrolidin-2-one-based factor Xa inhibitors incorporating aminoindane and phenylpyrrolidine P4 motifs are described. These series delivered highly potent anticoagulant compounds with excellent oral pharmacokinetic profiles; however, significant time dependant P450 inhibition was an issue for the aminoindane series, but this was not observed with the phenylpyrrolidine motif, which produced candidate quality molecules with potential for once-daily oral dosing in humans.
Asunto(s)
Inhibidores del Factor Xa , Pirrolidinas/química , Pirrolidinas/farmacología , Inhibidores de Serina Proteinasa/química , Inhibidores de Serina Proteinasa/farmacología , Diseño de Fármacos , Modelos Moleculares , Relación Estructura-ActividadRESUMEN
The discovery and evaluation of potent and long-acting oral sulfonamidopyrrolidin-2-one factor Xa inhibitors with tetrahydroisoquinoline and benzazepine P4 motifs are described. Unexpected selectivity issues versus tissue plasminogen activator in the former series were addressed in the later, delivering a robust candidate for progression towards clinical studies.
Asunto(s)
Benzazepinas/síntesis química , Inhibidores del Factor Xa , Inhibidores de Serina Proteinasa/química , Tetrahidroisoquinolinas/química , Administración Oral , Animales , Benzazepinas/administración & dosificación , Benzazepinas/farmacología , Cristalografía por Rayos X , Evaluación Preclínica de Medicamentos , Estructura Molecular , Ratas , Inhibidores de Serina Proteinasa/administración & dosificación , Tetrahidroisoquinolinas/administración & dosificación , Tetrahidroisoquinolinas/farmacologíaRESUMEN
Structure and property based drug design was exploited in the synthesis of sulfonamidopyrrolidin-2-one-based factor Xa inhibitors, incorporating neutral and basic monoaryl P4 groups, ultimately producing potent inhibitors with effective levels of anticoagulant activity and extended oral pharmacokinetic profiles. However, time dependant inhibition of Cytochrome P450 3A4 was a particular issue with this series.
Asunto(s)
Anticoagulantes/química , Factor X/antagonistas & inhibidores , Pirrolidinonas/química , Anticoagulantes/síntesis química , Anticoagulantes/farmacología , Sitios de Unión , Simulación por Computador , Cristalografía por Rayos X , Diseño de Fármacos , Factor X/metabolismo , Pirrolidinonas/síntesis química , Pirrolidinonas/farmacología , Relación Estructura-ActividadRESUMEN
N,N'-diarylsquaramides were prepared and evaluated as antagonists of CXCR2. The compounds were found to be potent and selective antagonists of CXCR2. Significant differences in SAR was observed relative to the previously described N,N'-diarylurea series. As was the case in the N,N'-diarylurea series, placing sulfonamide substituent adjacent to the acidic phenol significantly reduced the clearance in rat pharmacokinetic studies.
Asunto(s)
Ciclobutanos/síntesis química , Ciclobutanos/farmacología , Ciclobutanos/farmacocinética , Receptores de Interleucina-8B/antagonistas & inhibidores , Urea/análogos & derivados , Urea/síntesis química , Urea/farmacología , Urea/farmacocinética , Animales , Células CHO , Fenómenos Químicos , Química Física , Cricetinae , Cricetulus , Indicadores y Reactivos , Espectrometría de Masas , Fenoles/química , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Sulfonamidas/químicaRESUMEN
The effect of P-glycoprotein (Pgp) and/or CYP3A on the disposition of xenobiotics has been extensively investigated and is often of interest during drug discovery lead optimization. We have previously described a monkey pharmacokinetic screen to rapidly estimate absorption and first-pass extraction. In the present work, this monkey screen has been expanded to include an assessment of Pgp/CYP3A effects on absorption and first-pass extraction, using ketoconazole as a prototypic dual Pgp/CYP3A inhibitor. To generate a ketoconazole dosing regimen, the pharmacokinetics of ketoconazole were first determined in the monkey and were found to be consistent with that previously described in the rat, dog, and human. Dose-ranging experiments demonstrated that a single 10-mg/kg intraduodenal ketoconazole dose would provide an appropriate exposure; this dose was used throughout subsequent interaction experiments. Next, erythromycin and propranolol were explored as positive and negative control substrates for Pgp/CYP3A interactions, respectively. As anticipated, ketoconazole produced no change in the absorption or first-pass extraction of propranolol but resulted in a substantial increase in absorption and decrease in first-pass extraction of erythromycin. Finally, this ketoconazole-based monkey screen was deployed in a drug discovery setting, and examples of such use are presented. These experiments have allowed a more complete characterization of ketoconazole as a prototypic dual Pgp/CYP3A inhibitor and its use as a tool in a preclinical setting and further demonstrate the use of the monkey to investigate the role of Pgp/CYP3A in limiting the oral bioavailability of new drug candidates.