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1.
J Med Chem ; 67(5): 3400-3418, 2024 Mar 14.
Artículo en Inglés | MEDLINE | ID: mdl-38387069

RESUMEN

The use of ß-lactam (BL) and ß-lactamase inhibitor combination to overcome BL antibiotic resistance has been validated through clinically approved drug products. However, unmet medical needs still exist for the treatment of infections caused by Gram-negative (GN) bacteria expressing metallo-ß-lactamases. Previously, we reported our effort to discover pan inhibitors of three main families in this class: IMP, VIM, and NDM. Herein, we describe our work to improve the GN coverage spectrum in combination with imipenem and relebactam. This was achieved through structure- and property-based optimization to tackle the GN cell penetration and efflux challenges. A significant discovery was made that inhibition of both VIM alleles, VIM-1 and VIM-2, is essential for broad GN coverage, especially against VIM-producing P. aeruginosa. In addition, pharmacokinetics and nonclinical safety profiles were investigated for select compounds. Key findings from this drug discovery campaign laid the foundation for further lead optimization toward identification of preclinical candidates.


Asunto(s)
Antibacterianos , Inhibidores de beta-Lactamasas , Humanos , Inhibidores de beta-Lactamasas/farmacología , Inhibidores de beta-Lactamasas/uso terapéutico , Inhibidores de beta-Lactamasas/química , Antibacterianos/química , Imipenem/farmacología , beta-Lactamasas , Bacterias Gramnegativas , Pruebas de Sensibilidad Microbiana
2.
J Med Chem ; 65(24): 16234-16251, 2022 12 22.
Artículo en Inglés | MEDLINE | ID: mdl-36475645

RESUMEN

With the emergence and rapid spreading of NDM-1 and existence of clinically relevant VIM-1 and IMP-1, discovery of pan inhibitors targeting metallo-beta-lactamases (MBLs) became critical in our battle against bacterial infection. Concurrent with our fragment and high-throughput screenings, we performed a knowledge-based search of known metallo-beta-lactamase inhibitors (MBLIs) to identify starting points for early engagement of medicinal chemistry. A class of compounds exemplified by 11, discovered earlier as B. fragilis metallo-beta-lactamase inhibitors, was selected for in silico virtual screening. From these efforts, compound 12 was identified with activity against NDM-1 only. Initial exploration on metal binding design followed by structure-guided optimization led to the discovery of a series of compounds represented by 23 with a pan MBL inhibition profile. In in vivo studies, compound 23 in combination with imipenem (IPM) robustly lowered the bacterial burden in a murine infection model and became the lead for the invention of MBLI clinical candidates.


Asunto(s)
Infecciones Bacterianas , Inhibidores de beta-Lactamasas , Animales , Ratones , Inhibidores de beta-Lactamasas/farmacología , Inhibidores de beta-Lactamasas/uso terapéutico , Inhibidores de beta-Lactamasas/química , Imipenem/farmacología , Imipenem/uso terapéutico , beta-Lactamasas/metabolismo , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Antibacterianos/química , Pruebas de Sensibilidad Microbiana
3.
J Am Chem Soc ; 131(46): 16720-34, 2009 Nov 25.
Artículo en Inglés | MEDLINE | ID: mdl-19886610

RESUMEN

We report the efficient N-arylation of acyclic secondary amides and related nucleophiles with aryl nonaflates, triflates, and chlorides. This method allows for easy variation of the aromatic component in tertiary aryl amides. A new biaryl phosphine with P-bound 3,5-(bis)trifluoromethylphenyl groups was found to be uniquely effective for this amidation. The critical aspects of the ligand were explored through synthetic, mechanistic, and computational studies. Systematic variation of the ligand revealed the importance of (1) a methoxy group on the aromatic carbon of the "top ring" ortho to the phosphorus and (2) two highly electron-withdrawing P-bound 3,5-(bis)trifluoromethylphenyl groups. Computational studies suggest the electron-deficient nature of the ligand is important in facilitating amide binding to the LPd(II)(Ph)(X) intermediate.


Asunto(s)
Amidas/química , Cloruros/química , Paladio/química , Catálisis , Simulación por Computador , Ligandos , Fosfinas/química , Sulfonamidas/química
4.
Org Lett ; 10(4): 681-4, 2008 Feb 21.
Artículo en Inglés | MEDLINE | ID: mdl-18205377

RESUMEN

The pyran-containing fragments 1 and 2 of AM3 have been synthesized from the common pyran intermediate 3. Careful orchestration of the alcohol protecting groups was necessary to facilitate deprotection of alcohol functionality in the presence of the chemically sensitive polyene chain.


Asunto(s)
Alquenos/síntesis química , Piranos/síntesis química , Alcoholes/química , Alquenos/química , Animales , Dinoflagelados/química , Estructura Molecular , Polienos/química , Piranos/química
5.
Org Lett ; 9(26): 5621-4, 2007 Dec 20.
Artículo en Inglés | MEDLINE | ID: mdl-18027963

RESUMEN

Treatment of unsaturated 1,5-diols 2 with TES-Cl (1.1 equiv), imidazole, and catalytic DMAP in 1:1 CH2Cl2-DMF at -78 degrees C effects selective silylation of the allylic alcohol with >95:5 chemoselectivity when the allylic and homoallylic alcohols are in similar steric environments.


Asunto(s)
Éteres/química
6.
Org Lett ; 18(6): 1394-7, 2016 Mar 18.
Artículo en Inglés | MEDLINE | ID: mdl-26950496

RESUMEN

The development of a convergent and highly stereoselective synthesis of an HCV NS3/4a protease inhibitor possessing a unique spirocyclic and macrocyclic architecture is described. A late-stage spirocyclization strategy both enabled rapid structure-activity relationship studies in the drug discovery phase and simultaneously served as the basis for the large scale drug candidate preparation for clinical use. Also reported is the discovery of a novel InCl3-catalyzed carbonyl reduction with household aluminum foil or zinc powder as the terminal reductant.


Asunto(s)
Antivirales/síntesis química , Antivirales/farmacología , Hepacivirus/efectos de los fármacos , Hepatitis C/tratamiento farmacológico , Compuestos Heterocíclicos de 4 o más Anillos/síntesis química , Compuestos Macrocíclicos/síntesis química , Compuestos Macrocíclicos/farmacología , Compuestos de Espiro/síntesis química , Compuestos de Espiro/farmacología , Proteínas no Estructurales Virales/antagonistas & inhibidores , Antivirales/química , Descubrimiento de Drogas , Compuestos Heterocíclicos de 4 o más Anillos/química , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Compuestos Macrocíclicos/química , Estructura Molecular , Compuestos de Espiro/química , Relación Estructura-Actividad
7.
Org Lett ; 7(24): 5509-12, 2005 Nov 24.
Artículo en Inglés | MEDLINE | ID: mdl-16288543

RESUMEN

[reaction: see text] A synthesis of the C(43)-C(67) fragment of amphidinol 3 (AM3) has been accomplished by a route that features the use of a double allylboration reaction for synthesis of 1,5-diol 4b, which serves as a precursor to dihydropyran 11.


Asunto(s)
Alcoholes/síntesis química , Alquenos/síntesis química , Compuestos de Boro/química , Piranos/síntesis química , Alquenos/química , Animales , Catálisis , Dinoflagelados/química , Estructura Molecular , Piranos/química , Estereoisomerismo
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