RESUMEN
Extensive phase II metabolism of an advanced PKCε inhibitor resulted in sub-optimal pharmacokinetics in rat marked by elevated clearance. Synthesis of the O-glucuronide metabolite as a standard was followed by three distinct strategies to specifically temper phase II metabolic degradation of the parent molecule. In this study, it was determined that the introduction of proximal polarity to the primary alcohol generally curbed O-glucuronidation and improved PK and physical chemical properties while maintaining potency against the target. Utilization of a Jacobsen hydrolytic kinetic resolution to obtain optically enriched final compounds is also discussed.
Asunto(s)
Glucurónidos/farmacología , Proteína Quinasa C-epsilon/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Animales , Perros , Relación Dosis-Respuesta a Droga , Glucurónidos/química , Glucurónidos/metabolismo , Estructura Molecular , Proteína Quinasa C-epsilon/metabolismo , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/metabolismo , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
Efforts to substitute the cyclopropane ring in a series of aryl cyclopropylnitriles led to the discovery of an operationally simple one-pot method for Knoevenagel condensation and subsequent Corey-Chaykovsky cyclopropanation giving diastereomerically pure products as a racemic mixture of enantiomers. Method development and results for variably substituted aryl acetonitriles and aldehydes in the reaction are reported. A concise synthesis of (±)-bicifadine in two steps is provided to demonstrate the utility of the method.
Asunto(s)
Aldehídos/química , Ciclopropanos/química , Nitrilos/química , Estructura Molecular , EstereoisomerismoRESUMEN
Aza-peptide Michael acceptors are a novel class of inhibitors that are potent and specific for caspases-2, -3, -6, -7, -8, -9, and -10. The second-order rate constants are in the order of 10(6) M(-1) s(-1). The aza-peptide Michael acceptor inhibitor 18t (Cbz-Asp-Glu-Val-AAsp-trans-CH=CH-CON(CH(2)-1-Naphth)(2) is the most potent compound and it inhibits caspase-3 with a k(2) value of 5620000 M(-1) s(-1). The inhibitor 18t is 13700, 190, 6.4, 594, 37500, and 173-fold more selective for caspase-3 over caspases-2, -6, -7, -8, -9, and -10, respectively. Aza-peptide Michael acceptors designed with caspase specific sequences are selective and do not show any cross reactivity with clan CA cysteine proteases such as papain, cathepsin B, and calpains. High-resolution crystal structures of caspase-3 and caspase-8 in complex with aza-peptide Michael acceptor inhibitors demonstrate the nucleophilic attack on C2 and provide insight into the selectivity and potency of the inhibitors with respect to the P1' moiety.
Asunto(s)
Compuestos Aza/síntesis química , Inhibidores de Caspasas , Oligopéptidos/síntesis química , Compuestos Aza/química , Caspasa 10 , Caspasa 2 , Caspasa 3 , Caspasa 6 , Caspasa 7 , Caspasa 9 , Caspasas/química , Cristalografía por Rayos X , Cinética , Modelos Moleculares , Oligopéptidos/química , Relación Estructura-ActividadRESUMEN
Aza-peptide epoxides, a novel class of irreversible protease inhibitors, are specific for the clan CD cysteine proteases. Aza-peptide epoxides with an aza-Asp residue at P1 are excellent irreversible inhibitors of caspases-1, -3, -6, and -8 with second-order inhibition rates up to 1 910 000 M(-1) s(-1). In general, the order of reactivity of aza-peptide epoxides is S,S > R,R > trans > cis. Interestingly, some of the R,R epoxides while being less potent are actually more selective than the S,S epoxides. Our aza-peptide epoxides designed for caspases are stable, potent, and specific inhibitors, as they show little to no inhibition of other proteases such as the aspartyl proteases porcine pepsin, human cathepsin D, plasmepsin 2 from P. falciparum, HIV-1 protease, and the secreted aspartic proteinase 2 (SAP-2) from Candida albicans; the serine proteases granzyme B and alpha-chymotrypsin; and the cysteine proteases cathepsin B and papain (clan CA), and legumain (clan CD).
Asunto(s)
Compuestos Aza/síntesis química , Inhibidores de Caspasas , Compuestos Epoxi/síntesis química , Oligopéptidos/síntesis química , Compuestos Aza/química , Caspasa 1/química , Caspasa 3 , Caspasa 6 , Caspasa 8 , Caspasas/química , Cristalografía por Rayos X , Diseño de Fármacos , Estabilidad de Medicamentos , Compuestos Epoxi/química , Humanos , Hidrólisis , Estructura Molecular , Oligopéptidos/química , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Aza-peptide epoxides, a new class of irreversible protease inhibitors, are specific for the clan CD cysteine proteases. The inhibitors have second-order rate constants up to 10(5) M(-1) s(-1), with the most potent epoxides having the S,S stereochemistry. The aza-Asn derivatives are effective legumain inhibitors, while the aza-Asp epoxides were specific for caspases. The inhibitors have little or no inhibition with other proteases such as chymotrypsin, papain, or cathepsin B.
Asunto(s)
Compuestos Aza/síntesis química , Inhibidores de Cisteína Proteinasa/síntesis química , Compuestos Epoxi/síntesis química , Oligopéptidos/síntesis química , Compuestos Aza/química , Inhibidores de Caspasas , Catepsina B/antagonistas & inhibidores , Cristalografía por Rayos X , Cisteína Endopeptidasas , Inhibidores de Cisteína Proteinasa/química , Compuestos Epoxi/química , Cinética , Oligopéptidos/química , Papaína/antagonistas & inhibidores , Proteínas de Plantas/antagonistas & inhibidores , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Aza-peptide Michael acceptors are a new class of irreversible inhibitors that are highly potent and specific for clan CD cysteine proteases. The aza-Asp derivatives were specific for caspases, while aza-Asn derivatives were effective legumain inhibitors. Aza-Lys and aza-Orn derivatives were potent inhibitors of gingipain K and clostripain. Aza-peptide Michael acceptors showed no cross reactivity toward papain, cathepsin B, and calpain.
Asunto(s)
Compuestos Aza/síntesis química , Inhibidores de Caspasas , Inhibidores de Cisteína Proteinasa/síntesis química , Péptidos/síntesis química , Adhesinas Bacterianas , Compuestos Aza/química , Caspasas/química , Cisteína Endopeptidasas/química , Inhibidores de Cisteína Proteinasa/química , Cisteína-Endopeptidasas Gingipaínas , Hemaglutininas/química , Cinética , Péptidos/químicaRESUMEN
Caspase-3 is a prototypic executioner caspase that plays a central role in apoptosis. Aza-peptide epoxides are a novel class of irreversible inhibitors that are highly specific for clan CD cysteine proteases. The five crystal structures of caspase-3-aza-peptide epoxide inhibitor complexes reported here reveal the structural basis for the mechanism of inhibition and the specificities at the S1' and the S4 subsites. Unlike the clan CA cysteine proteases, the catalytic histidine in caspase-3 plays a critical role during protonation and subsequent ring opening of the epoxide moiety and facilitates the nucleophilic attack by the active site cysteine. The nucleophilic attack takes place on the C3 carbon atom of the epoxide and results in an irreversible alkylation of the active site cysteine residue. A favorable network of hydrogen bonds involving the oxyanion hole, catalytic histidine, and the atoms in the prime site of the inhibitor enhance the binding affinity and specificity of the aza-peptide epoxide inhibitors toward caspase-3. The studies also reveal that subtle movements of the N-terminal loop of the beta-subunit occur when the P4 Asp is replaced by a P4 Ile, whereas the N-terminal loop and the safety catch Asp179 are completely disordered when the P4 Asp is replaced by P4 Cbz group.