RESUMEN
Although the S3 pocket of the thrombin active site is lined with lipophilic amino acid residues, the accommodation of polarity within the lipophilic P3 moiety of small molecule inhibitors is possible provided that the polar functionality is capable of pointing away from the binding pocket outwards toward solvent while simultaneously allowing the lipophilic portion of the P3 ligand to interact with the S3 amino acid residues. Manipulation of this motif provided the means to effect optimization of functional potency, in vivo antithrombotic efficacy and oral bioavailability in a series of 3-aminopyrazinone thrombin inhibitors which contained non-charged groups at the P1 position.
Asunto(s)
Anticoagulantes/síntesis química , Trastornos de la Coagulación Sanguínea/tratamiento farmacológico , Diseño de Fármacos , Pirazinas/síntesis química , Trombina/antagonistas & inhibidores , Administración Oral , Animales , Anticoagulantes/química , Anticoagulantes/farmacología , Sitios de Unión , Disponibilidad Biológica , Perros , Estructura Molecular , Pirazinas/química , Pirazinas/farmacología , Ratas , Relación Estructura-ActividadRESUMEN
A novel 1,3,5-trisubstituted benzamide thrombin inhibitor template was designed via hybridization of a known aminopyridinoneacetamide and a known 1,3,5-trisubstituted phenyl ether. Optimization of this lead afforded a novel potent series of biaryl 1,3,5-trisubstituted benzenes with excellent functional anticoagulant potency.
Asunto(s)
Antitrombinas/síntesis química , Benceno/síntesis química , Diseño de Fármacos , Trombina/antagonistas & inhibidores , Antitrombinas/química , Antitrombinas/farmacología , Benceno/química , Benceno/farmacología , Humanos , Modelos Moleculares , Estructura Molecular , Relación Estructura-ActividadRESUMEN
Guided by X-ray crystallography of thrombin-inhibitor complexes and molecular modeling, alkylation of the N1 nitrogen of the imidazole P1 ligand of the pyridinoneacetamide thrombin inhibitor 1 with various acetamide moieties furnished inhibitors with significantly improved thrombin potency, trypsin selectivity, functional in vitro anticoagulant potency and in vivo antithrombotic efficacy. In the pyrazinoneacetamide series, oral bioavailability was also improved.
Asunto(s)
Anticoagulantes/farmacología , Antitrombinas/farmacología , Diseño de Fármacos , Imidazoles/síntesis química , Imidazoles/farmacología , Trombina/antagonistas & inhibidores , Administración Oral , Animales , Anticoagulantes/síntesis química , Anticoagulantes/química , Anticoagulantes/farmacocinética , Antitrombinas/síntesis química , Antitrombinas/química , Antitrombinas/farmacocinética , Disponibilidad Biológica , Cloruros , Cristalografía por Rayos X , Perros , Compuestos Férricos/farmacología , Imidazoles/química , Imidazoles/farmacocinética , Macaca mulatta , Modelos Moleculares , Estructura Molecular , Tiempo de Tromboplastina Parcial , Ratas , Relación Estructura-Actividad , Trombina/química , Trombina/metabolismo , Tripsina/metabolismoRESUMEN
Dipyrone is an analgesic and antipyretic drug that is sometimes encountered as an adulterant in illicit drug samples, particularly illicit fentanyl containing samples. It undergoes thermal decomposition to aminopyrine and 4-methylaminoantipyrine during analysis via gas chromatography (GC-FID) and gas chromatography-mass spectrometry (GC-MS). During analysis via high pressure liquid chromatography (HPLC) and high pressure liquid chromatography-mass spectrometry (HPLC-MS), it undergoes hydrolytic decomposition solely to 4-methylaminoantipyrine. Given that mass spectrometry is a widely used confirmatory analytical technique, these instabilities present challenges for the forensic chemist seeking to confirm the presence of dipyrone. Studies were conducted to determine rigorous confirmative protocols for the identification of dipyrone in multicomponent illicit drug samples.
Asunto(s)
Dipirona/análisis , Contaminación de Medicamentos , Drogas Ilícitas/química , Cromatografía Líquida de Alta Presión , Fentanilo/química , Toxicología Forense , Cromatografía de Gases y Espectrometría de Masas , Humanos , Espectrometría de Masa por Ionización de ElectrosprayRESUMEN
The number of analyses of synthetic cannabimimetic drugs of abuse by forensic laboratories in the United States grew rapidly from 2010 to 2012 and then declined somewhat in 2013. In 2010, according to the National Forensic Laboratory Information System (NFLIS), 3,287 reports by federal, state and local forensic laboratories were identified as containing synthetic cannabinoids. In 2011 and 2012, the numbers increased to 23,693 and 42,503, respectively. 27,119 reports were identified in 2013. Several commonly encountered structural sub-classes of these synthetic designer drugs, namely the naphthoylindoles, benzoylindoles, phenylacetylindoles, and cyclopropoylindoles contain a ketone functional group. The Duquenois-Levine color test for the presumptive identification of classical cannabinoids such as Δ(9)-tetrahydrocannabinol is negative for the synthetic cannabimimetics. The van Urk color test for the presumptive identification of indole containing drugs of abuse is also negative for these compounds. The use of 2,4-dinitrophenylhydrazine as an alternative color test reagent (targeting the keto moiety rather than the indole) for presumptive identification of these classes of drugs was investigated.
RESUMEN
Despite their relatively weak basicity, simple azoles, specifically imidazoles and aminothiazoles, can function as potent surrogates for the more basic amines (e.g., alkyl amines, amidines, guanidines, etc.) which are most often employed as the P1 ligand in the design of noncovalent small molecule inhibitors of thrombin.
Asunto(s)
Azoles/farmacología , Inhibidores Enzimáticos/farmacología , Trombina/antagonistas & inhibidores , Azoles/química , Diseño de Fármacos , Ligandos , Estructura Molecular , Relación Estructura-Actividad , Tripsina/efectos de los fármacosRESUMEN
In this manuscript we demonstrate that a modification principally directed toward the improvement of the aqueous solubility (i.e., introduction a P3 pyridine N-oxide) of the previous lead compound afforded a new series of potent orally bioavailable P1 N-benzylamide thrombin inhibitors. An expedited investigation of the P1 SAR with respect to oral bioavailability, plasma half-life, and human liver microsome stability revealed 5 as the best candidate for advanced evaluation.