RESUMEN
The desymmetrization of a prochiral 6-oxaspiro[3.3]heptane-2-carboxylic acid derivative via biocatalytic ketoreductase-mediated reduction has provided access to both enantiomers in high ee. The axially chiral alcohol was converted to the corresponding ester alcohol, amino acid, and amino alcohol building blocks while high enantiopurity was maintained.
Asunto(s)
Ácidos Carboxílicos , Heptanos , Alcoholes , Biocatálisis , Ácidos Carboxílicos/química , EstereoisomerismoRESUMEN
In our efforts to identify novel small molecule inhibitors for the treatment of adrenoleukodystrophy (ALD), we conducted a high-throughput radiometric screen for inhibitors of elongation of very long chain fatty acid 1 (ELOVL1) enzyme. We developed a series of highly potent, central nervous system (CNS)-penetrant pyrimidine ether-based compounds with favorable pharmacokinetics culminating in compound 22. Compound 22 is a selective inhibitor of ELOVL1, reducing C26:0 VLCFA synthesis in ALD patient fibroblasts and lymphocytes in vitro. Compound 22 reduced C26:0 lysophosphatidyl choline (LPC), a subtype of VLCFA, in the blood of ATP binding cassette transporter D1 (ABCD1) KO mice, a murine model of ALD to near wild-type levels. Compound 22 is a low-molecular-weight, potent ELOVL1 inhibitor that may serve as a useful tool for exploring therapeutic approaches to the treatment of ALD.
Asunto(s)
Descubrimiento de Drogas , Inhibidores Enzimáticos/farmacología , Elongasas de Ácidos Grasos/antagonistas & inhibidores , Pirimidinas/farmacología , Administración Oral , Adrenoleucodistrofia/tratamiento farmacológico , Animales , Disponibilidad Biológica , Perros , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/farmacocinética , Éteres/química , Células HEK293 , Humanos , Macaca fascicularis , Ratones , Pirimidinas/administración & dosificación , Pirimidinas/farmacocinética , RatasRESUMEN
Accumulation of very long chain fatty acids (VLCFAs) due to defects in ATP binding cassette protein D1 (ABCD1) is thought to underlie the pathologies observed in adrenoleukodystrophy (ALD). Pursuing a substrate reduction approach based on the inhibition of elongation of very long chain fatty acid 1 enzyme (ELOVL1), we explored a series of thiazole amides that evolved into compound 27âa highly potent, central nervous system (CNS)-penetrant compound with favorable in vivo pharmacokinetics. Compound 27 selectively inhibits ELOVL1, reducing C26:0 VLCFA synthesis in ALD patient fibroblasts, lymphocytes, and microglia. In mouse models of ALD, compound 27 treatment reduced C26:0 VLCFA concentrations to near-wild-type levels in blood and up to 65% in the brain, a disease-relevant tissue. Preclinical safety findings in the skin, eye, and CNS precluded progression; the origin and relevance of these findings require further study. ELOVL1 inhibition is an effective approach for normalizing VLCFAs in models of ALD.
Asunto(s)
Descubrimiento de Drogas , Inhibidores Enzimáticos/farmacología , Elongasas de Ácidos Grasos/administración & dosificación , Pirazoles/farmacología , Adrenoleucodistrofia/tratamiento farmacológico , Adrenoleucodistrofia/patología , Amidas/química , Animales , Inhibidores Enzimáticos/farmacocinética , Inhibidores Enzimáticos/uso terapéutico , Humanos , Pirazoles/química , Pirazoles/farmacocinética , Pirazoles/uso terapéutico , Relación Estructura-ActividadRESUMEN
Phosphoinositide 3-kinase (PI3Kγ) is a drug target that has been implicated in the treatment of a range of diseases. We have developed a synthesis of a novel PI3Kγ inhibitor containing a 1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one scaffold. The key step in the synthesis involved a ruthenium-catalyzed [2 + 2 + 2] cyclotrimerization reaction between a diyne and an alkoxycarbonyl isocyanate, a previously unreported coupling partner in such a reaction.
RESUMEN
The lipid kinase phosphoinositide 3-kinase γ (PI3Kγ) has attracted attention as a potential target to treat a variety of autoimmune disorders, including multiple sclerosis, due to its role in immune modulation and microglial activation. By minimizing the number of hydrogen bond donors while targeting a previously uncovered selectivity pocket adjacent to the ATP binding site of PI3Kγ, we discovered a series of azaisoindolinones as selective, brain penetrant inhibitors of PI3Kγ. This ultimately led to the discovery of 16, an orally bioavailable compound that showed efficacy in murine experimental autoimmune encephalomyelitis (EAE), a preclinical model of multiple sclerosis.
Asunto(s)
Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Inhibidores de las Quinasa Fosfoinosítidos-3 , Adenosina Trifosfato/metabolismo , Administración Oral , Animales , Sitios de Unión , Disponibilidad Biológica , Cristalografía por Rayos X , Diseño de Fármacos , Evaluación Preclínica de Medicamentos/métodos , Inhibidores Enzimáticos/administración & dosificación , Humanos , Enlace de Hidrógeno , Isoenzimas/antagonistas & inhibidores , Ratones Endogámicos C57BL , Esclerosis Múltiple/tratamiento farmacológico , Fosfatidilinositol 3-Quinasas/química , Fosfatidilinositol 3-Quinasas/metabolismo , Ftalimidas/química , Relación Estructura-ActividadRESUMEN
Benzimidazole 1 is the lead compound resulting from an antibacterial program targeting dual inhibitors of bacterial DNA gyrase and topoisomerase IV. With the goal of improving key drug-like properties, namely, the solubility and the formulability of 1, an effort to identify prodrugs was undertaken. This has led to the discovery of a phosphate ester prodrug 2. This prodrug is rapidly cleaved to the parent drug molecule upon both oral and intravenous administration. The prodrug achieved equivalent exposure of 1 compared to dosing the parent in multiple species. The prodrug 2 has improved aqueous solubility, simplifying both intravenous and oral formulation.
RESUMEN
Compound 3 is a potent aminobenzimidazole urea with broad-spectrum Gram-positive antibacterial activity resulting from dual inhibition of bacterial gyrase (GyrB) and topoisomerase IV (ParE), and it demonstrates efficacy in rodent models of bacterial infection. Preclinical in vitro and in vivo studies showed that compound 3 covalently labels liver proteins, presumably via formation of a reactive metabolite, and hence presented a potential safety liability. The urea moiety in compound 3 was identified as being potentially responsible for reactive metabolite formation, but its replacement resulted in loss of antibacterial activity and/or oral exposure due to poor physicochemical parameters. To identify second-generation aminobenzimidazole ureas devoid of reactive metabolite formation potential, we implemented a metabolic shift strategy, which focused on shifting metabolism away from the urea moiety by introducing metabolic soft spots elsewhere in the molecule. Aminobenzimidazole urea 34, identified through this strategy, exhibits similar antibacterial activity as that of 3 and did not label liver proteins in vivo, indicating reduced/no potential for reactive metabolite formation.
Asunto(s)
Antibacterianos/síntesis química , Bencimidazoles/síntesis química , Inhibidores Enzimáticos/síntesis química , Animales , Antibacterianos/metabolismo , Bencimidazoles/metabolismo , Girasa de ADN/metabolismo , Topoisomerasa de ADN IV/antagonistas & inhibidores , Diseño de Fármacos , Inhibidores Enzimáticos/metabolismo , Humanos , Pruebas de Sensibilidad Microbiana , Microsomas Hepáticos/metabolismo , Relación Estructura-Actividad , Inhibidores de Topoisomerasa II/metabolismo , Urea/análogos & derivados , Urea/síntesis química , Urea/metabolismoRESUMEN
A series of 4-amino-pyrido[2,3-d]pyrimidin-5(8H)-ones were designed and synthesized as a novel class of inhibitors of NAD(+)-dependent DNA ligase that possess potency against Gram-positive bacteria.
Asunto(s)
Antibacterianos/síntesis química , Proteínas Bacterianas/antagonistas & inhibidores , ADN Ligasas/antagonistas & inhibidores , Diseño de Fármacos , Inhibidores Enzimáticos/síntesis química , Pirimidinonas/química , Antibacterianos/química , Antibacterianos/farmacología , Proteínas Bacterianas/metabolismo , Sitios de Unión , Dominio Catalítico , Simulación por Computador , Cristalografía por Rayos X , ADN Ligasa (ATP) , ADN Ligasas/metabolismo , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , NAD/metabolismo , Relación Estructura-ActividadRESUMEN
To facilitate a drug discovery project, we needed to develop a robust asymmetric synthesis of (2S,5S)-5-substituted-azepane-2-carboxylate derivatives. Two key requirements for the synthesis were flexibility for elaboration at C5 and suitability for large scale preparation. To this end we have successfully developed a scalable asymmetric synthesis of these derivatives that starts with known hydroxy-ketone 8. The key step features an oxidative cleavage of aza-bicyclo[3.2.2]nonene 14, which simultaneously generates the C2 and C5 substituents in a stereoselective manner.
Asunto(s)
Ácidos Carboxílicos/química , Ácidos Carboxílicos/síntesis química , Compuestos Bicíclicos Heterocíclicos con Puentes/química , Descubrimiento de Drogas , Cetonas/químicaRESUMEN
The synthesis and evaluation of novel azetidine lincosamides 1 are described. Eleven new (3-trans-alkyl)azetidine-2-carboxylic acids were synthesized via alkylation of N-TBS-4-oxo-azetidine-2-carboxylic acid and subsequent elaboration then coupled to 7-chloro-1-methylthio-lincosamine. The resulting lincosamides differ from the drug clindamycin in both the size of the ring and the position/structure of the alkyl side-chain. SAR within the series was explored with attention to alkyl variants in positions 1 and 3 of the azetidine ring.
Asunto(s)
Antibacterianos/síntesis química , Antibacterianos/farmacología , Azetidinas/química , Macrólidos/síntesis química , Macrólidos/farmacología , Antibacterianos/química , Lincosamidas , Macrólidos/química , Viabilidad Microbiana/efectos de los fármacos , Estructura Molecular , Biosíntesis de Proteínas/efectos de los fármacos , Biosíntesis de Proteínas/genética , Relación Estructura-Actividad , Transcripción Genética/efectos de los fármacos , Transcripción Genética/genéticaRESUMEN
An enantioselective synthetic route to the enediyne antibiotic N1999A2 (1) is described, proceeding in 21 steps (0.4% yield, 77% average yield per step) from (R)-(+)-glycidol. The route involves the convergent assembly of three components: a (1-iodovinyl) stannane (2), a 1,5-hexadiyne-3,4-diol derivative (3), and a substituted naphthoic acid (4). Important transformations in the synthetic sequence include the palladium-catalyzed coupling of 2 and 3, an intramolecular oxidative cyclization of a terminal bisacetylene, and a transannular anionic (bi)cyclization of a cyclic bromoenetriyne. The careful selection and manipulation of protective groups throughout the sequence proved to be critical to the development of the synthetic route, where all late-stage intermediates were unstable and could not be concentrated. In the final step of the sequence, three protective groups were removed in a single operation, providing synthetic N1999A2 (1) in 76% yield. Conditions were found that, for the first time, led to the precipitation of 1 as a solid.
Asunto(s)
Enediinos/síntesis química , Compuestos Epoxi/síntesis química , Naftalenos/síntesis química , Enediinos/química , Compuestos Epoxi/química , Humanos , Naftalenos/química , EstereoisomerismoRESUMEN
Deoxynegamycin (1b) is a protein synthesis inhibitor with activity against Gram-negative (GN) bacteria. A series of conformationally restricted analogs were synthesized to probe its bioactive conformation. Indeed, some of the constrained analogs were found to be equal or better than deoxynegamycin in protein synthesis assay (1b, IC(50)=8.2 microM; 44, IC(50)=6.6 microM; 35e(2), IC(50)=1 microM). However, deoxynegamycin had the best in vitro whole cell antibacterial activity (Escherichia coli, MIC=4-16 microg/mL; Klebsiella pneumoniae, MIC=8 microg/mL) suggesting that other factors such as permeation may also be contributing to the overall whole cell activity. A new finding is that deoxynegamycin is efficacious in an E. coli murine septicemia model (ED(50)=4.8 mg/kg), providing further evidence of the favorable in vivo properties of this class of molecules.
Asunto(s)
Aminoácidos Diaminos/química , Aminoácidos Diaminos/farmacología , Animales , Escherichia coli/efectos de los fármacos , Escherichia coli/crecimiento & desarrollo , Klebsiella pneumoniae/efectos de los fármacos , Klebsiella pneumoniae/crecimiento & desarrollo , Ratones , Pruebas de Sensibilidad Microbiana/estadística & datos numéricos , Conformación MolecularRESUMEN
Negamycin 1 is a bactericidal antibiotic with activity against Gram-negative bacteria, and served as a template in an antibiotic discovery program. An orthogonally protected beta-amino acid derivative 3a was synthesized and used in parallel synthesis of negamycin derivatives on solid support. This advanced intermediate was also used for N- and C-terminal modifications using solution-phase methodologies. The N-terminal modifications have resulted in the identification of active analogues, whereas the C-terminal modifications resulted in complete loss of antibacterial activity. The N-methyl negamycin analogue, 19a, inhibits protein synthesis (IC(50)=2.3 microM), has antibacterial activity (Escherichia coli, MIC=16 microgram/mL), and is efficacious in an E. coli murine septicemia model (ED(50)=16.3mg/kg).