RESUMO
A 5-step enantioselective synthesis of the potent anti-HIV nucleoside islatravir is reported. The highly efficient route was enabled by a novel enantioselective alkynylation of an α,ß-unsaturated ketone, a unique ozonolysis-dealkylation cascade in water, and an enzymatic aldol-glycosylation cascade.
RESUMO
The synthesis of the potent anti-HIV investigational treatment islatravir is described. The key step in this synthesis is a highly enantioselective catalytic asymmetric alkynylation of a ketone. This reaction is a rare example of the asymmetric addition of an alkyne nucleophile to a ketone through ligand-accelerated catalysis that was performed on a greater than 100 g scale. By leveraging a multienzyme cascade, a highly diastereoselective aldol-glycosylation was used to complete the target in eight steps.
RESUMO
The synthesis and structure activity relationship development of a pyrimidine series of heterocyclic Factor IXa inhibitors is described. Increased selectivity over Factor Xa inhibition was achieved through SAR expansion of the P1 element. Select compounds were evaluated in vivo to assess their plasma levels in rat.
Assuntos
Descoberta de Drogas , Fator IXa/antagonistas & inibidores , Inibidores do Fator Xa/farmacologia , Pirimidinas/farmacologia , Relação Dose-Resposta a Droga , Fator IXa/metabolismo , Inibidores do Fator Xa/síntese química , Inibidores do Fator Xa/química , Humanos , Estrutura Molecular , Pirimidinas/síntese química , Pirimidinas/química , Relação Estrutura-AtividadeRESUMO
A stereoselective nine-step synthesis of the potent HIV nucleoside reverse transcriptase translocation inhibitor (NRTTI) islatravir (EfdA, MK-8591) from 2-deoxyribose is described. Key findings include a diastereodivergent addition of an acetylide nucleophile to an enolizable ketone, a chemoselective ozonolysis of a terminal olefin and a biocatalytic glycosylation cascade that uses a unique strategy of byproduct precipitation to drive an otherwise-reversible transformation forward.
Assuntos
Desoxiadenosinas/síntese química , Desoxirribose/química , Alcinos/química , Inibidores da Transcriptase Reversa/síntese química , Silanos/química , EstereoisomerismoRESUMO
The ß-lactam core is a key structure responsible for inducing both IgE-mediated acute-onset hypersensitivity and T-cell-mediated delayed-onset hypersensitivity with penicillins in humans. There is essentially no clinically significant immunologic cross-reactivity noted between the ß-lactam cores of penicillins and cephalosporins based on challenge studies in humans. The side-chains appear to be more important in inducing IgE-mediated acute-onset hypersensitivity and T-cell delayed-onset hypersensitivity with cephalosporins in humans. Despite these clinical findings, the U. S. Food and Drug Administration (FDA) still requires the level of ß-lactam-related antibiotic residues to be controlled at very low levels in manufacturing facilities. Ceftolozane is Merck & Co., Inc., Kenilworth, NJ, USA's (MSD's) 5th generation broad spectrum cephalosporin antibiotic against gram-negative bacteria. In searching for the optimal decontamination method of ceftolozane, most methods were found to be very slow in opening the ß-lactam ring in ceftolozane. Moreover, most of the previously reported decontamination methods applied analytical methods that only monitored the disappearance of the parent molecule as the endpoint of degradation. In this way, many of the ß-lactam-containing degradation products could be overlooked. In order to develop an efficient decontamination solution for ceftolozane, a sensitive ultra high performance liquid chromatography-high resolution-electrospray ionization-tandem mass spectrometry (UHPLC-HRMS/MS) method was first developed to ensure the detection of the ß-lactam ring in all degradation products. Through online UHPLC-UV-HRMS monitoring, 2.5â¯N KOH in 50% aqueous MeOH or 50% aqueous EtOH was identified as the best condition to fully degrade the ß-lactam ring in ceftolozane. This decontamination could be done within 15â¯min, even at 100â¯mg/mL concentration, and thus enable a quick turnaround time for equipment cleaning in the ß-lactam manufacturing facility. This method was also successfully applied to 12 other commercially available ß-lactam antibiotics.
Assuntos
Antibacterianos/análise , Cefalosporinas/análise , Descontaminação/métodos , Composição de Medicamentos/instrumentação , Contaminação de Equipamentos/prevenção & controle , Antibacterianos/química , Antibacterianos/toxicidade , Cefalosporinas/química , Cefalosporinas/toxicidade , Cromatografia Líquida de Alta Pressão/métodos , Composição de Medicamentos/métodos , Composição de Medicamentos/normas , Etanol/química , Hidróxidos/química , Metanol/química , Compostos de Potássio/química , Solventes/química , Espectrometria de Massas por Ionização por Electrospray/métodos , Espectrometria de Massas em Tandem/métodosRESUMO
A weak Brønsted acid-catalyzed asymmetric guanidine aza-conjugate addition reaction has been developed. C2-symmetric, dual hydrogen-bond donating bistriflamides are shown to be highly effective in activating α,ß-unsaturated esters toward the intramolecular addition of a pendant guanidinyl nucleophile. Preliminary mechanistic investigation, including density functional theory calculations and kinetics studies, support a conjugate addition pathway as more favorable energetically than an alternative electrocyclization pathway. This methodology has been successfully applied to the synthesis of the 3,4-dihydroquinazoline-containing antiviral, Letermovir, and a series of analogues.
Assuntos
Acetatos/síntese química , Antivirais/síntese química , Teoria Quântica , Quinazolinas/química , Acetatos/química , Acetatos/farmacologia , Antivirais/química , Antivirais/farmacologia , Catálise , Ciclização , Ligação de Hidrogênio , Estrutura Molecular , Quinazolinas/síntese química , Quinazolinas/farmacologiaRESUMO
A novel series of spiroimidazolone-based antagonists of the human glucagon receptor (hGCGR) has been developed. Our efforts have led to compound 1, N-((2H-tetrazol-5-yl)methyl)-4-((R)-1-((5r,8R)-8-(tert-butyl)-3-(3,5-dichlorophenyl)-2-oxo-1,4-diazaspiro[4.5]dec-3-en-1-yl)-4,4-dimethylpentyl)benzamide (SCH 900822), a potent hGCGR antagonist with exceptional selectivity over the human glucagon-like peptide-1 receptor. Oral administration of 1 lowered 24 h nonfasting glucose levels in imprinting control region mice on a high fat diet with diet-induced obesity following single oral doses of 3 and 10 mg/kg. Furthermore, compound 1, when dosed orally, was found to decrease fasting blood glucose at 30 mg/kg in a streptozotocin-treated, diet-induced obesity mouse pharmacodynamic assay and blunt exogenous glucagon-stimulated glucose excursion in prediabetic mice.
Assuntos
Benzamidas/síntese química , Benzamidas/farmacologia , Receptores de Glucagon/antagonistas & inibidores , Compostos de Espiro/síntese química , Compostos de Espiro/farmacologia , Animais , Glicemia/metabolismo , Cicloexanonas/química , Cicloexanonas/farmacologia , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Dieta Hiperlipídica , Descoberta de Drogas , Glucagon/farmacologia , Camundongos , Camundongos Endogâmicos ICR , Obesidade/tratamento farmacológico , Estado Pré-Diabético/tratamento farmacológico , Estado Pré-Diabético/metabolismo , Relação Estrutura-AtividadeRESUMO
A divergent and regioselective synthesis of either 3-substituted benzisoxazoles or 2-substituted benzoxazoles from readily accessible ortho-hydroxyaryl N-H ketimines is described. The reaction proceeds in two distinct pathways through a common N-Cl imine intermediate: (a) N-O bond formation to form benzisoxazole under anhydrous conditions and (b) NaOCl mediated Beckmann-type rearrangement to form benzoxazole, respectively. The reaction path also depends on the electronic nature of the aromatic ring, with the electron-rich aromatic rings favoring the rearrangement and the electron-deficient rings favoring the N-O bond formation. A Beckmann-type rearrangement mechanism via net [1,2]-aryl migration for the formation of 2-substituted benzoxazole is proposed.