RESUMO
The use of machine learning methods for the prediction of reaction yield is an emerging area. We demonstrate the applicability of support vector regression (SVR) for predicting reaction yields, using combinatorial data. Molecular descriptors used in regression tasks related to chemical reactivity have often been based on time-consuming, computationally demanding quantum chemical calculations, usually density functional theory. Structure-based descriptors (molecular fingerprints and molecular graphs) are quicker and easier to calculate and are applicable to any molecule. In this study, SVR models built on structure-based descriptors were compared to models built on quantum chemical descriptors. The models were evaluated along the dimension of each reaction component in a set of Buchwald-Hartwig amination reactions. The structure-based SVR models outperformed the quantum chemical SVR models, along the dimension of each reaction component. The applicability of the models was assessed with respect to similarity to training. Prospective predictions of unseen Buchwald-Hartwig reactions are presented for synthetic assessment, to validate the generalizability of the models, with particular interest along the aryl halide dimension.
Assuntos
Aprendizado de Máquina , Estudos ProspectivosRESUMO
Reducing the required frequence of drug dosing can improve the adherence of patients to chronic treatments. Hence, drugs with longer in vivo half-lives are highly desirable. One of the most promising approaches to extend the in vivo half-life of drugs is conjugation to human serum albumin (HSA). In this work, we describe the use of AlbuBinder 1, a small-molecule noncovalent HSA binder, to extend the in vivo half-life and pharmacology of small-molecule BMP1/TLL inhibitors in humanized mice (HSA KI/KI). A series of conjugates of AlbuBinder 1 with BMP1/TLL inhibitors were prepared. In particular, conjugate c showed good solubility and a half-life extension of >20-fold versus the parent molecule in the HSA KI/KI mice, reaching half-lives of >48 h with maintained maximal inhibition of plasma BMP1/TLL. The same conjugate showed a half-life of only 3 h in the wild-type mice, suggesting that the half-life extension was principally due to specific interactions with HSA. It is envisioned that conjugation to AlbuBinder 1 should be applicable to a wide range of small molecule or peptide drugs with short half-lives. In this context, AlbuBinders represent a viable alternative to existing half-life extension technologies.
Assuntos
Metaloproteases/metabolismo , Inibidores de Proteases/farmacologia , Albumina Sérica Humana/metabolismo , Bibliotecas de Moléculas Pequenas/metabolismo , Animais , Proteína Morfogenética Óssea 1/metabolismo , Meia-Vida , Humanos , Camundongos , Estudo de Prova de Conceito , Inibidores de Proteases/farmacocinéticaRESUMO
Activation of MrgX2, an orphan G protein-coupled receptor expressed on mast cells, leads to degranulation and histamine release. Human MrgX2 binds promiscuously to structurally diverse peptides and small molecules that tend to have basic properties (basic secretagogues), resulting in acute histamine-like adverse drug reactions of injected therapeutic agents. We set out to identify MrgX2 orthologues from other mammalian species used in nonclinical stages of drug development. Previously, the only known orthologue of human MrgX2 was from mouse, encoded by Mrgprb2. MrgX2 genes of rat, dog (beagle), minipig, pig, and Rhesus and cynomolgus monkey were identified by bioinformatic approaches and verified by their ability to mediate calcium mobilization in transfected cells in response to the classical MrgX2 agonist, compound 48/80. The peptide GSK3212448 is an inhibitor of the PRC2 epigenetic regulator that caused profound anaphylactoid reactions upon intravenous infusion to rat. We showed GSK3212448 to be a potent MrgX2 agonist particularly at rat MrgX2. We screened sets of drug-like molecules and peptides to confirm the highly promiscuous nature of MrgX2. Approximately 20% of drug-like molecules activated MrgX2 (pEC50 ranging from 4.5 to 6), with the principle determinant being basicity. All peptides tested of net charge +3 or greater exhibited agonist activity, including the cell penetrating peptides polyarginine (acetyl-Arg9-amide) and TAT (49-60), a fragment of HIV-1 TAT protein. Finally, we showed that the glycopeptide antibiotic vancomycin, which is associated with clinical pseudo-allergic reactions known as red man syndrome, is an agonist of MrgX2.
Assuntos
Anafilaxia/induzido quimicamente , Mastócitos/efeitos dos fármacos , Proteínas do Tecido Nervoso/agonistas , Fragmentos de Peptídeos/efeitos adversos , Receptores Acoplados a Proteínas G/agonistas , Receptores de Neuropeptídeos/agonistas , Vancomicina/efeitos adversos , Anafilaxia/imunologia , Animais , Degranulação Celular/efeitos dos fármacos , Degranulação Celular/imunologia , Linhagem Celular Tumoral , Peptídeos Penetradores de Células/administração & dosagem , Peptídeos Penetradores de Células/efeitos adversos , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos/efeitos adversos , Células HEK293 , Histona-Lisina N-Metiltransferase/antagonistas & inibidores , Humanos , Mastócitos/imunologia , Mastócitos/metabolismo , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/imunologia , Proteínas do Tecido Nervoso/metabolismo , Fragmentos de Peptídeos/administração & dosagem , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/imunologia , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Neuropeptídeos/genética , Receptores de Neuropeptídeos/imunologia , Receptores de Neuropeptídeos/metabolismo , Proteínas Recombinantes/genética , Proteínas Recombinantes/imunologia , Proteínas Recombinantes/metabolismo , Síndrome , Vancomicina/administração & dosagem , p-Metoxi-N-metilfenetilamina/farmacologiaRESUMO
A DNA-encoded macrocyclic peptide library was designed and synthesized with 2.4 × 1012 members composed of 4-20 natural and non-natural amino acids. Affinity-based selection was performed against two therapeutic targets, VHL and RSV N protein. On the basis of selection data, some peptides were selected for resynthesis without a DNA tag, and their activity was confirmed.
Assuntos
Biblioteca de Peptídeos , Peptídeos Cíclicos/química , Peptídeos Cíclicos/farmacologia , Proteínas Virais/metabolismo , Proteína Supressora de Tumor Von Hippel-Lindau/metabolismo , Aminoácidos/química , DNA/química , Avaliação Pré-Clínica de Medicamentos/métodos , Terapia de Alvo Molecular , Peptídeos Cíclicos/genética , Reação em Cadeia da Polimerase , Vírus Sinciciais Respiratórios , Proteínas Virais/antagonistas & inibidores , Proteínas Virais/química , Proteína Supressora de Tumor Von Hippel-Lindau/químicaRESUMO
A six-stage stereoselective synthesis of indanyl-7-(3'-pyridyl)-(3R,6R,7R)-2,5-diketopiperazines oxytocin antagonists from indene is described. SAR studies involving mono- and disubstitution in the 3'-pyridyl ring and variation of the 3-isobutyl group gave potent compounds (pK(i) > 9.0) with good aqueous solubility. Evaluation of the pharmacokinetic profile in the rat, dog, and cynomolgus monkey of those derivatives with low cynomolgus monkey and human intrinsic clearance gave 2',6'-dimethyl-3'-pyridyl R-sec-butyl morpholine amide Epelsiban (69), a highly potent oxytocin antagonist (pK(i) = 9.9) with >31000-fold selectivity over all three human vasopressin receptors hV1aR, hV2R, and hV1bR, with no significant P450 inhibition. Epelsiban has low levels of intrinsic clearance against the microsomes of four species, good bioavailability (55%) and comparable potency to atosiban in the rat, but is 100-fold more potent than the latter in vitro and was negative in the genotoxicity screens with a satisfactory oral safety profile in female rats.
Assuntos
Dicetopiperazinas/síntese química , Morfolinas/síntese química , Ocitocina/metabolismo , Receptores de Ocitocina/antagonistas & inibidores , Administração Oral , Animais , Disponibilidade Biológica , Inibidores das Enzimas do Citocromo P-450 , Dicetopiperazinas/administração & dosagem , Dicetopiperazinas/farmacocinética , Dicetopiperazinas/farmacologia , Cães , Feminino , Humanos , Técnicas In Vitro , Macaca fascicularis , Masculino , Microssomos Hepáticos/metabolismo , Morfolinas/administração & dosagem , Morfolinas/farmacocinética , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Solubilidade , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
The synthesis of various 6-substituted-4-hydroxy-2-pyridinones is reported. The functionalized keto-dioxinones were constructed via a diethylzinc mediated crossed Claisen condensation reaction and subsequent enamine formation, thermolysis, and cyclization-aromatization providing the pyridinone unit.
Assuntos
Etilenos/química , Cetonas/química , Oxiquinolina/química , Piridonas/síntese química , Ciclização , Hidroxilação , Estrutura Molecular , EstereoisomerismoRESUMO
The synthesis of biologically active o-aminoalkyl resorcylates and related dihydroxyisoindolinones from functionalized α-amino acids without the use of phenolic protection is described. The key aminoalkyl-diketo-dioxinone intermediates were prepared utilizing a crossed Claisen condensation reaction in the presence of diethylzinc. The aromatic unit was constructed via late stage cyclization and aromatization, and subsequent modification provided the novel resorcylates which showed activity against a selection of receptors and kinases, including 5-HT and CDK.
Assuntos
Aminoácidos/química , Aminoácidos/síntese química , Quinases Ciclina-Dependentes/química , Dioxinas/química , Dioxinas/síntese química , Isoindóis/química , Serotonina/química , Quinases Ciclina-Dependentes/antagonistas & inibidores , Ciclização , Humanos , Concentração Inibidora 50 , Estrutura Molecular , EstereoisomerismoRESUMO
Our anesthesia care team was called to care for a patient who was admitted to the emergency department with the esophageal-tracheal double-lumen airway device (Combitube, Tyco Healthcare, Nellcor, Pleasanton, California) in place, which needed to be exchanged for a definitive airway because the patient required an extended period of mechanical ventilation. Several techniques were attempted to exchange the esophageal-tracheal Combitube (ETC) without success. First, we attempted direct laryngoscopy with the ETC in place after deflation of the No. 1 proximal cuff and sweeping the ETC to the left. We were prepared to use bougie-assisted intubation but could not identify any airway anatomy. After removal of the ETC, we unsuccessfully attempted ventilation/intubation with a laryngeal mask airway (LMA Fastrach, LMA North America, San Diego, California). Our third attempt was insertion of another laryngeal mask airway (LMA Unique, LMA North America) with marginal ventilation, but we again experienced unsuccessful intubation using a fiberscope. The ETC was reinserted after each intubation attempt because mask ventilation was impossible. Before proceeding with cricothyrotomy, we repeated direct laryngoscopy but without the ETC in place. We identified the tip of the epiglottis, which allowed for bougie-assisted intubation. This obviated the need for emergency cricothyrotomy.
Assuntos
Intubação Intratraqueal/instrumentação , Laringoscopia/métodos , Respiração Artificial/instrumentação , Emergências/enfermagem , Tratamento de Emergência/métodos , Tratamento de Emergência/enfermagem , Epiglote/anatomia & histologia , Desenho de Equipamento , Falha de Equipamento , Hematoma Subdural/complicações , Hematoma Subdural/terapia , Humanos , Intubação Intratraqueal/métodos , Intubação Intratraqueal/enfermagem , Máscaras Laríngeas , Músculos Laríngeos/cirurgia , Laringoscopia/enfermagem , Masculino , Pessoa de Meia-Idade , Enfermeiros Anestesistas , Avaliação em Enfermagem/métodos , Obesidade Mórbida/complicações , Seringas , Inconsciência/complicações , Inconsciência/terapiaRESUMO
A case series of five patients is described demonstrating the utility of the intubating laryngeal mask airway in the prehospital setting, both as a primary airway rescue device and as a bridge to tracheal intubation. All patients were hypoxaemic, had sustained severe polytrauma and were trapped in their vehicles following road traffic collisions. A probability of survival study showed better-than-predicted outcomes for the group as a whole.
RESUMO
Structure and property based drug design was exploited in the synthesis of sulfonamidopyrrolidin-2-one-based factor Xa (fXa) inhibitors, incorporating basic biaryl P4 groups, producing highly potent inhibitors with significant anticoagulant activities and encouraging oral pharmacokinetic profiles.
Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes/química , Inibidores do Fator Xa , Pirrolidinonas/química , Inibidores de Serina Proteinase/química , Animais , Anticoagulantes/química , Anticoagulantes/farmacocinética , Anticoagulantes/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/farmacocinética , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Interações Hidrofóbicas e Hidrofílicas , Masculino , Modelos Moleculares , Pirrolidinonas/farmacocinética , Pirrolidinonas/farmacologia , Ratos , Ratos Sprague-Dawley , Inibidores de Serina Proteinase/farmacocinética , Inibidores de Serina Proteinase/farmacologia , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Optimisation of a series of oxazole diketopiperazines has led to the discovery of a very potent and selective oxytocin antagonist GSK221149A. GSK221149A has been shown to inhibit oxytocin-induced uterine contractions in the anaesthetised rat.
Assuntos
Ocitocina/antagonistas & inibidores , Piperazinas/química , Piperazinas/farmacologia , Animais , Feminino , Humanos , Cinética , Ocitocina/metabolismo , Piperazinas/farmacocinética , Ratos , Ratos Sprague-Dawley , Receptores de Ocitocina/metabolismo , Relação Estrutura-Atividade , Contração Uterina/efeitos dos fármacosRESUMO
Structure and property based drug design was exploited in the synthesis of sulfonamidopyrrolidin-2-one-based factor Xa (fXa) inhibitors, incorporating biaryl P4 groups, producing highly potent inhibitors with encouraging oral pharmacokinetic profiles and significant but sub-optimal anticoagulant activities.
Assuntos
Inibidores do Fator Xa , Pirrolidinonas/química , Pirrolidinonas/farmacologia , Inibidores de Serina Proteinase/química , Inibidores de Serina Proteinase/farmacologia , Animais , Anticoagulantes/química , Anticoagulantes/farmacocinética , Anticoagulantes/farmacologia , Desenho de Fármacos , Masculino , Modelos Moleculares , Pirrolidinonas/farmacocinética , Ratos , Ratos Sprague-Dawley , Inibidores de Serina Proteinase/farmacocinética , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/farmacocinética , Sulfonamidas/farmacologiaAssuntos
Obstrução das Vias Respiratórias/terapia , Serviços Médicos de Emergência/métodos , Intubação Intratraqueal/instrumentação , Fatores Etários , Criança , Pré-Escolar , Emergências , Desenho de Equipamento , Fidelidade a Diretrizes , Humanos , Lactente , Recém-Nascido , Intubação Intratraqueal/métodos , Guias de Prática Clínica como AssuntoRESUMO
Structure-based drug design was exploited in the synthesis of 3-(6-chloronaphth-2-ylsulfonyl)aminopyrrolidin-2-one-based factor Xa (fXa) inhibitors, incorporating an alanylamide P4 group with acyclic tertiary amide termini. Optimized hydrophobic contacts of one amide substituent in P4 were complemented by hydrophobicity-modulating features in the second, producing potent fXa inhibitors including examples with excellent anticoagulant properties.
Assuntos
Alanina/química , Amidas/química , Antitrombina III/síntese química , Antitrombina III/farmacologia , Desenho de Fármacos , Pirróis/química , Anticoagulantes/síntese química , Anticoagulantes/química , Anticoagulantes/metabolismo , Anticoagulantes/farmacologia , Antitrombina III/química , Antitrombina III/metabolismo , Sítios de Ligação , Cristalografia por Raios X , Fator Xa/química , Fator Xa/metabolismo , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
A series of novel, non-basic 3-(6-chloronaphth-2-ylsulfonyl)aminopyrrolidin-2-one-based factor Xa (fXa) inhibitors, incorporating an alanylamide P4 group, was designed and synthesised. Within this series, the N-2-(morpholin-4-yl)-2-oxoethyl derivative 24 was shown to be a potent, selective fXa inhibitor with good anticoagulant activity. Moreover, 24 possessed highly encouraging rat and dog pharmacokinetic profiles with excellent oral bioavailabilities in both species.
Assuntos
Antitrombina III/farmacologia , Fibrinolíticos/farmacologia , Pirrolidinonas/farmacologia , Trombina/efeitos dos fármacos , Administração Oral , Animais , Antitrombina III/síntese química , Disponibilidade Biológica , Fibrinolíticos/síntese química , Masculino , Pirrolidinonas/síntese química , Ratos , Ratos WistarRESUMO
Emergency and unexpected difficult airway management can rapidly deteriorate into a critical airway event such as "cannot ventilate, cannot intubate" (CVCI). A critical airway event (i.e., inadequate mask ventilation, failed intubation, and CVCI) can be resolved by rescue ventilation, thus avoiding potential neurological disability or death. Recommended options include use of the larygeal mask airway, the esophageal-tracheal Combitube (ETC; Tyco-Healthcare-Nellcor, Pleasanton, Calif), transtracheal jet ventilation, or a surgical airway. This article reviews proper use of the ETC in combination with the self-inflating bulb (SIB) and/or portable carbon dioxide detector to resolve critical airway situations. The combined use of these 3 devices provides on ideal integrated system for airway control and ventilation. In addition, critical airway events and rescue ventilation options; ETC design, technical aspects, training, insertion, and ventilation; determining ETC location (i.e., esophagus vs trachea); and monitoring ETC lung ventilation are reviewed. The SIB primarily assesses ETC location within the esophagus or the trachea; the carbon dioxide detector also permits monitoring lung ventilation. Use of the ETC in prehospital, emergency medicine, and anesthesia settings, including ETC advantages, contraindications, and reported complications will be reviewed in Part 2. How to safely exchange the ETC for a definitive airway also will be reviewed.
Assuntos
Intubação Intratraqueal , Respiração Artificial , Competência Clínica/normas , Desenho de Equipamento , Falha de Equipamento , Humanos , Capacitação em Serviço/métodos , Intubação Gastrointestinal/instrumentação , Intubação Gastrointestinal/métodos , Intubação Intratraqueal/efeitos adversos , Intubação Intratraqueal/instrumentação , Intubação Intratraqueal/métodos , Máscaras Laríngeas , Manequins , Monitorização Fisiológica/instrumentação , Monitorização Fisiológica/métodos , Respiração Artificial/efeitos adversos , Respiração Artificial/instrumentação , Respiração Artificial/métodos , Falha de TratamentoRESUMO
Emergency and unexpected difficult airway management can rapidly deteriorate into a critical airway event (e.g., inadequate mask ventilation, failed tracheal intubation, or cannot ventilate-cannot intubate). Recommended options to resolve a critical airway event include the laryngeal mask airway, the esophageal tracheal Combitube (ETC; Tyco-Healthcare-Nellcor, Pleasanton, Calif), transtracheal jet ventilation, or a surgical airway to avoid potential neurological disability or death. Part 1, which was published in the February 2004 AANA Journal, reviewed use of the ETC in combination with the self-inflating bulb and/or portable carbon dioxide detector as an effective rescue airway system. Important aspects of rescue ventilation, ETC training methods, how to use the ETC, and determining ETC location also were reviewed. Part 2 reviews ETC advantages, contraindications, and reported complications in prehospital, emergency medicine, and anesthesia settings. Safe methods to exchange the ETC for a definitive airway also are described. Major ETC advantages include the following: (1) easy to learn, (2) can be inserted rapidly, (3) effectively secures the airway, (4) provides adequate lung ventilation, (5) minimizes aspiration risks, (6) facilitates application of high ventilatory pressures, and (7) can be exchanged safely for a definitive airway without compromising airway control or protection.
Assuntos
Intubação Gastrointestinal/instrumentação , Intubação Intratraqueal/instrumentação , Contraindicações , Serviços Médicos de Emergência/métodos , Desenho de Equipamento , Falha de Equipamento , Humanos , Intubação Gastrointestinal/efeitos adversos , Intubação Gastrointestinal/métodos , Intubação Intratraqueal/efeitos adversos , Intubação Intratraqueal/métodos , Seleção de Pacientes , Respiração Artificial/instrumentação , Respiração Artificial/métodos , Resultado do TratamentoRESUMO
Advanced airway practitioners in anesthesiology, emergency medicine, and prehospital care can suddenly and unexpectedly face difficult airway situations that can surface without warning during mask ventilation or tracheal intubation. Although tracheal intubation remains the "gold standard" in airway management, it is not always achievable, and, when it proves impossible, appropriate alternative interventions must be used rapidly to avoid serious morbidity or mortality. The SLAM Emergency Airway Flowchart (SEAF) is intended to prevent the 3 reported primary causes of adverse respiratory events (ie, inadequate ventilation, undetected esophageal intubation, and difficult intubation). The 5 pathways of the SEAF include primary ventilation, rapid-sequence intubation, difficult intubation, rescue ventilation, and cricothyrotomy. It is intended for use with adult patients by advanced airway practitioners competent in direct laryngoscopy, tracheal intubation, administration of airway drugs, rescue ventilation, and cricothyrotomy. The SEAF has limitations (eg, suitable only for use with adult patients, cannot be used by certain categories of rescue personnel, and depends heavily on assessment of Spo2). A unique benefit is provision of simple alternative techniques that can be used when another technique fails.
Assuntos
Algoritmos , Árvores de Decisões , Intubação Intratraqueal/métodos , Avaliação em Enfermagem/métodos , Respiração Artificial/métodos , Ressuscitação/métodos , Gasometria , Emergências , Falha de Equipamento , Medicina Baseada em Evidências , Escala de Coma de Glasgow , Humanos , Intubação Intratraqueal/efeitos adversos , Intubação Intratraqueal/enfermagem , Máscaras Laríngeas , Laringoscopia , Enfermeiros Anestesistas/educação , Enfermeiros Anestesistas/organização & administração , Seleção de Pacientes , Respiração Artificial/efeitos adversos , Respiração Artificial/enfermagem , Ressuscitação/efeitos adversos , Ressuscitação/enfermagemRESUMO
Mechanism-based inhibitors of HCMV protease, which are stable to human plasma (> or = 20 h) and have single-figure potency in the microM range against HCMV protease, have been developed based on the dansylproline alpha-methyl pyrrolidine-5,5-trans-lactam nucleus.
Assuntos
Antivirais/química , Antivirais/farmacologia , Citomegalovirus/enzimologia , Lactamas/farmacologia , Prolina/análogos & derivados , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Pirrolidinas/química , Pirrolidinas/farmacologia , Compostos de Dansil/química , Estabilidade de Medicamentos , Meia-Vida , Humanos , Concentração Inibidora 50 , Lactamas/sangue , Lactamas/química , Prolina/química , Inibidores de Proteases/sangue , Pirrolidinas/sangue , Espectrometria de Massas por Ionização por ElectrosprayRESUMO
The stereospecific synthesis of a series of alpha-methylpyrrolidine-5,5-trans-lactam inhibitors of human cytomegalovirus (HCMV) protease is described. Examination of the SAR in this series has defined the size and chirality of the alpha-substituent, optimized the acyl substituent on the lactam nitrogen, and defined the steric constraint of this functionality. The SAR of the functionality on the pyrrolidine nitrogen of the trans-lactam has been investigated, and this has led to the discovery of potent serine protease inhibitors that are highly selective for the viral enzyme over the mammalian enzymes elastase, thrombin, and acetylcholine esterase. The mechanism of action of our lead compounds has been established by mass spectrometry, and enzymatic degradation of HCMV deltaAla protease acylated with these inhibitors showed that Ser 132 is the active site nucleophile. The crystal structure of HCMV protease was obtained and used to model the conformationally restricted, chiral (S)-proline-alpha-methyl-5,5-trans-lactams into the active site groove of the enzyme, enabling us to direct and rationalize the SAR in this series. The activity against HCMV deltaAla protease is the greatest with inhibitors based on the dansyl-(S)-proline alpha-methyl-5,5-trans-lactam template, which have low nanomolar activity against the viral enzyme.