RESUMEN
[reaction: see text]. A novel variant of the atom-economical Passerini reaction between suitably protected argininal, dipeptide isonitrile, and proline components afforded adduct 13. Orthogonal N-deprotection of 13 led, via a smooth O- to N-acyl migration, to 14, which constitutes the N(10)-C(17) fragment of the cyclotheonamide family of serine protease inhibitors. Each reaction in this three-step protocol proceeds in good yield and under very mild conditions.
Asunto(s)
Péptidos Cíclicos/síntesis química , Inhibidores de Serina Proteinasa/síntesis química , Acilación , Animales , Antitrombinas/síntesis química , Fragmentos de Péptidos/síntesis química , Poríferos/químicaRESUMEN
Judicious combination of P-region sequences of highly potent anticoagulant proteins including NAP5, NAP6, Ecotin, and Antistasin with SAR from small molecule FXa inhibitors led to a series of chimeric inhibitors of formula 1a-j. We report herein the design, synthesis, and biological activity of this novel family of FXa inhibitors that express both high in vitro potency and superb selectivity against related serine proteases.
Asunto(s)
Antifibrinolíticos/síntesis química , Proteínas de Escherichia coli , Inhibidores del Factor Xa , Proteínas Periplasmáticas , Inhibidores de Serina Proteinasa/síntesis química , Antifibrinolíticos/química , Antifibrinolíticos/farmacología , Proteínas Bacterianas/química , Diseño de Fármacos , Proteínas del Helminto/química , Humanos , Hormonas de Invertebrados/química , Estructura Molecular , Proteínas Recombinantes de Fusión/antagonistas & inhibidores , Inhibidores de Serina Proteinasa/química , Inhibidores de Serina Proteinasa/farmacología , Relación Estructura-ActividadRESUMEN
[reaction: see text] The Passerini reaction of N-protected amino aldehydes, isonitriles, and TFA using pyridine-type bases proceeds under mild conditions and directly affords alpha-hydroxy-beta-amino amide derivatives in moderate to high yields. These adducts are readily hydrolyzed to alpha-hydroxy-beta-amino carboxylic acids. Application of these key intermediates to concise syntheses of P(1)-alpha-ketoamide protease inhibitors is illustrated.
Asunto(s)
Amidas/síntesis química , Leucina/análogos & derivados , Aminoácidos/química , Fluorenos/química , Cetoácidos/síntesis química , Leucina/síntesis química , Inhibidores de Proteasas/síntesis química , Relación Estructura-ActividadRESUMEN
[structure: see text] A new strategy for the synthesis of peptidyl and peptidomimetic P1-aldehydes 3 on HCAM solid support is described. The appropriate C-terminal aldehyde precursors were prepared and anchored to a resin support via a semicarbazone linkage (HCAM resin). After synthetic elaboration, acidic hydrolysis efficiently delivered C-terminal target aldehydes 3a-h in good overall yields and in excellent purity.
Asunto(s)
Aldehídos/síntesis química , Poliestirenos/química , Inhibidores de Proteasas/síntesis química , Aldehídos/farmacología , Técnicas Químicas Combinatorias , Estructura Molecular , Péptidos/síntesis química , Péptidos/farmacología , Inhibidores de Proteasas/farmacologíaRESUMEN
A novel series of rigid P3-guanylpiperidine peptide mimics 3-14 was designed as potential factor Xa and prothrombinase inhibitors. Incorporation into a P2-gly-P1-argininal motif led to highly potent and selective inhibitors. The synthesis and biological activities of these derivatives are reported herein.
Asunto(s)
Inhibidores del Factor Xa , Guanina/farmacología , Péptidos/química , Piperidinas/farmacología , Inhibidores de Serina Proteinasa/farmacología , Cationes , Guanina/análogos & derivados , Guanina/química , Guanina/farmacocinética , Imitación Molecular , Piperidinas/química , Piperidinas/farmacocinética , Inhibidores de Serina Proteinasa/química , Inhibidores de Serina Proteinasa/farmacocinéticaRESUMEN
Rigid benzolactam P3-P2 dipeptide mimics were designed and prepared as potential inhibitors of blood coagulation factor Xa. Methoxy substitution of the tetrahydrobenzazepinone scaffold led to potent and selective inhibitors. The synthesis and biological activities of these derivatives are reported herein.
Asunto(s)
Inhibidores del Factor Xa , Lactamas/farmacología , Inhibidores de Serina Proteinasa/farmacología , Diseño de Fármacos , Lactamas/síntesis química , Lactamas/química , Inhibidores de Serina Proteinasa/síntesis química , Inhibidores de Serina Proteinasa/químicaRESUMEN
Application of the Sharpless AD protocol to a series of alpha-(E)-benzylidene-delta-lactam precursors followed by selective deoxygenation provided efficient synthetic routes to the chiral quaternary alpha-hydroxy-gammalactam derivatives 4 and 5. These functionalized intermediates and the diol precursors 3 are regarded as novel types of D-Phe-Pro dipeptide surrogates that are useful as enzyme active site probes.
Asunto(s)
Dipéptidos/síntesis química , Lactamas/química , Dipéptidos/química , Estructura Cuaternaria de ProteínaRESUMEN
A novel scaffold for P4-P2 dipeptide mimics containing a rigid pyridone spacer was designed based on a virtual library strategy. Several selected nonpeptidic 4-aralkyl or 4-alkylpyridones incorporating a P1-argininal sequence were prepared. The modeling studies, synthesis and biological activities of these unique pyridone derivatives are reported herein.
Asunto(s)
Arginina/química , Piridonas/síntesis química , Trombina/antagonistas & inhibidores , Trombina/química , Factor Xa/farmacología , Fibrinolisina/farmacología , Concentración 50 Inhibidora , Cinética , Modelos Químicos , Tripsina/farmacologíaRESUMEN
A series of novel FXa inhibitors 2a-m and 3a-f was discovered that feature heterocyclic carboxamides tethered to a d-diaminobutyric acid sidechain. These neutral amide derivatives serve as novel P3 d-arginine mimics. Pyrazine carboxamide scaffolds afforded the most potent FXa inhibitors (e.g., 2b IC50 = 4.6 nM). The synthesis and biological activity of two focused libraries are reported.
Asunto(s)
Amidas/química , Arginina/química , Inhibidores del Factor Xa , Compuestos Heterocíclicos/química , Inhibidores de Serina Proteinasa/síntesis química , Inhibidores de Serina Proteinasa/farmacología , Relación Estructura-ActividadRESUMEN
The crystal structures of three highly potent and selective low-molecular weight rigid peptidyl aldehyde inhibitors complexed with thrombin have been determined and refined to R values 0.152-0. 170 at 1.8-2.1 A resolution. Since the selectivity of two of the inhibitors was >1600 with respect to trypsin, the structures of trypsin-inhibited complexes of these inhibitors were also determined (R = 0.142-0.157 at 1.9-2.1 A resolution). The selectivity appears to reside in the inability of a benzenesulfonamide group to bind at the equivalent of the D-enantiomorphic S3 site of thrombin, which may be related to the lack of a 60-insertion loop in trypsin. All the inhibitors have a novel lactam moiety at the P3 position, while the two with greatest trypsin selectivity have a guanidinopiperidyl group at the P1 position that binds in the S1 specificity site. Differences in the binding constants of these inhibitors are correlated with their interactions with thrombin and trypsin. The kinetics of inhibition vary from slow to fast with thrombin and are fast in all cases with trypsin. The kinetics are examined in terms of the slow formation of a stable transition-state complex in a two-step mechanism. The structures of both thrombin and trypsin complexes show similar well-defined transition states in the S1 site and at the electrophilic carbon atom and Ser195OG. The trypsin structures, however, suggest that the first step in a two-step kinetic mechanism may involve formation of a weak transition-state complex, rather than binding dominated by the P2-P4 positions.
Asunto(s)
Guanidinas/química , Piperidinas/química , Inhibidores de Serina Proteinasa/química , Trombina/antagonistas & inhibidores , Trombina/química , Inhibidores de Tripsina/química , Tripsina/química , Aldehídos/metabolismo , Animales , Sitios de Unión , Bovinos , Glicina/metabolismo , Guanidinas/metabolismo , Guanidinas/farmacología , Humanos , Cinética , Sustancias Macromoleculares , Modelos Moleculares , Conformación Molecular , Piperidinas/metabolismo , Piperidinas/farmacología , Inhibidores de Serina Proteinasa/metabolismo , Inhibidores de Serina Proteinasa/farmacología , Especificidad por Sustrato , Trombina/metabolismo , Tripsina/metabolismo , Inhibidores de Tripsina/metabolismo , Inhibidores de Tripsina/farmacologíaRESUMEN
Crystal structure and evolving SAR considerations of potent, selective benzylsulfonamide lactam thrombin inhibitors and related serine protease inhibitors have led to the design of novel thrombin inhibitors 1a-g, featuring hydrophobic, basic, P4-alkylaminolactam scaffolds that serve as novel types of P3-P4 dipeptide mimics. The design, synthesis, and biological activity of these targets is presented.
Asunto(s)
Antitrombinas/química , Lactonas/química , Antitrombinas/farmacología , Relación Estructura-ActividadRESUMEN
A series of lactam derivatives 1b-g featuring P4-o-alkoxycarbonylbenzylsulfonamide residues along with the potential P4-homosaccharin prodrug candidate 1h was prepared in order to probe the thrombin S3 specificity pocket. The synthesis and alkoxide-catalyzed ring opening of the novel homosaccharin intermediate 7 followed by subsequent elaboration delivered the targets 1b-h which were potent and selective thrombin inhibitors. The design, synthesis, and biological activity of these targets will be presented.
Asunto(s)
Antitrombinas/química , Óxidos/química , Sacarina/química , Sulfonamidas/química , Antitrombinas/síntesis química , Antitrombinas/farmacología , Catálisis , Diseño de Fármacos , Estructura Molecular , Sacarina/síntesis química , Sacarina/farmacologíaRESUMEN
Potent serine protease inhibitor 1a featuring a hybrid P3-P4 quaternary lactam dipeptide surrogate was prepared based upon SAR and molecular modeling investigations and in order to further probe the S2/S3 thrombin and FXa subsites. An efficient and concise synthetic route to the key aminolactam intermediate 4 was developed. The design, synthesis, and biological activity of this target and its P3-P4 diastereomer 1b is presented.
Asunto(s)
Dipéptidos , Guanidinas/química , Lactamas , Piperidinas/química , Inhibidores de Serina Proteinasa/síntesis química , Trombina/antagonistas & inhibidores , Cromatografía Líquida de Alta Presión , Dipéptidos/química , Guanidinas/metabolismo , Humanos , Técnicas In Vitro , Lactamas/química , Espectroscopía de Resonancia Magnética , Modelos Químicos , Modelos Moleculares , Estructura Molecular , Piperidinas/metabolismo , Inhibidores de Serina Proteinasa/química , Relación Estructura-ActividadRESUMEN
Form A of the Attitude Toward Disabled Persons (ATDP-A) scale was used to discover whether physiotherapy students distinguish between personal and professional attitudes toward people with disabilities. Forty fourth-year students successively completed two copies of the ATDP-A scale, one with their personal views and one with their professional views. A two-tailed t-test for correlated samples showed that the mean professional score was significantly greater (p < 0.05) than the mean personal score. Results are discussed in terms of inconsistencies in the research literature as well as implications for physiotherapy training programmes.