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1.
Bioorg Med Chem Lett ; 27(23): 5190-5196, 2017 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-29107541

RESUMEN

Analogues of bedaquiline where the phenyl B-unit was replaced with monocyclic heterocycles of widely differing lipophilicity (thiophenes, furans, pyridines) were synthesised and evaluated. While there was an expected broad positive correlation between lipophilicity and anti-TB activity, the 4-pyridyl derivatives appeared to have an additional contribution to antibacterial potency. The majority of the compounds were (desirably) more polar and had higher rates of clearance than bedaquiline, and showed acceptable oral bioavailability, but there was only limited (and unpredictable) improvement in their hERG liability.


Asunto(s)
Antituberculosos/síntesis química , Diarilquinolinas/química , Compuestos Heterocíclicos/química , Administración Oral , Animales , Antituberculosos/farmacocinética , Antituberculosos/farmacología , Diarilquinolinas/farmacocinética , Diarilquinolinas/farmacología , Canal de Potasio ERG1/antagonistas & inhibidores , Canal de Potasio ERG1/metabolismo , Semivida , Humanos , Concentración 50 Inhibidora , Pruebas de Sensibilidad Microbiana , Microsomas Hepáticos/metabolismo , Mycobacterium tuberculosis/efectos de los fármacos , Ratas , Relación Estructura-Actividad
2.
Bioorg Med Chem Lett ; 20(1): 294-8, 2010 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-19906529

RESUMEN

Pursuing our efforts in designing 5-pyrimidylhydroxamic acid anti-cancer agents, we have identified a new series of potent histone deacetylase (HDAC) inhibitors. These compounds exhibit enzymatic HDAC inhibiting properties with IC(50) values in the nanomolar range and inhibit tumor cell proliferation at similar levels. Good solubility, moderate bioavailability, and promising in vivo activity in xenograft model made this series of compounds interesting starting points to design new potent HDAC inhibitors.


Asunto(s)
Antineoplásicos/química , Inhibidores de Histona Desacetilasas/química , Histona Desacetilasas/química , Ácidos Hidroxámicos/química , Animales , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Línea Celular Tumoral , Proliferación Celular , Diseño de Fármacos , Inhibidores de Histona Desacetilasas/síntesis química , Inhibidores de Histona Desacetilasas/farmacología , Histona Desacetilasas/metabolismo , Ácidos Hidroxámicos/síntesis química , Ácidos Hidroxámicos/farmacología , Ratones , Ratones Desnudos , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de Xenoinjerto
3.
Eur J Mass Spectrom (Chichester) ; 25(3): 291-299, 2019 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-30518251

RESUMEN

Mycobacterium tuberculosis infection results in more than two million deaths per year and is the leading cause of mortality in people infected with HIV. A new structural class of antimycobacterials, the diarylquinolines, has been synthesized and is being highly effective against both M. tuberculosis and multidrug-resistant tuberculosis. As diarylquinolines are biologically active only under their ( R,S) stereoisomeric form, it is essential to differentiate the stereoisomers ( R,S) and ( R,R). To achieve this, tandem mass spectrometry and ion mobility spectrometry-mass spectrometry have been performed with 10 diarylquinoline diastereomers couples. In this study, we investigated cationization with alkali metal cations and several ion mobility drift gases in order to obtain diastereomer differentiations. We have shown that diastereomers of the diarylquinolines family can be differentiated separately by tandem mass spectrometry and in mixture by ion mobility spectrometry-mass spectrometry. However, although the structure of each diastereomer is close, several behaviors could be observed concerning the cationization and the ion mobility spectrometry separation. The ion mobility spectrometry isomer separation efficiency is not easily predictable; it was however observed for all diastereomeric couples with a significant improvement of separation using alkali adducts compared to protonated molecules. With the use of drift gas with higher polarizability only an improvement of separation was obtained in a few cases. Finally, a good correlation of the experimental collision cross section (relative to three-dimensional structure of ions) and the theoretical collision cross section has been shown.


Asunto(s)
Antituberculosos/química , Diarilquinolinas/química , Espectrometría de Movilidad Iónica/métodos , Antituberculosos/uso terapéutico , Diarilquinolinas/uso terapéutico , Humanos , Estructura Molecular , Estereoisomerismo , Tuberculosis/tratamiento farmacológico
4.
J Med Chem ; 51(4): 875-96, 2008 Feb 28.
Artículo en Inglés | MEDLINE | ID: mdl-18254606

RESUMEN

A preceding paper (Bonfanti et al. J. Med Chem. 2007, 50, 4572-4584) reported the optimization of the pharmacokinetic profile of substituted benzimidazoles by reducing their tissue retention. However, the modifications that were necessary to achieve this goal also led to a significant drop in anti-RSV activity. This paper describes a molecular modeling study followed by a lead optimization program that led to the recovery of the initial potent antiviral activity and the selection of TMC353121 as a clinical candidate.


Asunto(s)
Antivirales/síntesis química , Bencimidazoles/síntesis química , Morfolinas/síntesis química , Piridinas/síntesis química , Virus Sincitiales Respiratorios/efectos de los fármacos , Proteínas Virales de Fusión/genética , Internalización del Virus/efectos de los fármacos , Animales , Antivirales/química , Antivirales/farmacología , Bencimidazoles/farmacocinética , Bencimidazoles/farmacología , Sitios de Unión , Farmacorresistencia Viral , Masculino , Modelos Moleculares , Morfolinas/farmacocinética , Morfolinas/farmacología , Mutación , Unión Proteica , Piridinas/farmacocinética , Piridinas/farmacología , Ratas , Ratas Sprague-Dawley , Virus Sincitiales Respiratorios/fisiología , Sigmodontinae , Relación Estructura-Actividad
5.
Org Lett ; 20(19): 6003-6006, 2018 10 05.
Artículo en Inglés | MEDLINE | ID: mdl-30252482

RESUMEN

The development of a general, mild, and functional-group-tolerant direct functionalization of N-heteroarenes by C-H functionalization with N-protected amines, including azetidines under Minisci-mediated photoredox conditions, is reported. A broad scope of substituted azetidines, including spirocyclic derivatives, and heterocycles were explored. This reaction enables the production of sp3-rich complex druglike structures in one step from unactivated feedstock amines and heterocycles.

6.
J Med Chem ; 50(19): 4572-84, 2007 Sep 20.
Artículo en Inglés | MEDLINE | ID: mdl-17722899

RESUMEN

We previously reported the discovery of substituted benzimidazole fusion inhibitors with nanomolar activity against respiratory syncytial virus (Andries, K.; et al. Antiviral Res. 2003, 60, 209-219). A lead compound of the series was selected for preclinical evaluation. This drug candidate, JNJ-2408068 (formerly R170591, 1), showed long tissue retention times in several species (rat, dog, and monkey), creating cause for concern. We herein describe the optimization program to develop compounds with improved properties in terms of tissue retention. We have identified the aminoethyl-piperidine moiety as being responsible for the long tissue retention time of 1. We have investigated the replacement or the modification of this group, and we suggest that the pKa of this part of the molecules influences both the antiviral activity and the pharmacokinetic profile. We were able to identify new respiratory syncytial virus inhibitors with shorter half-lives in lung tissue.


Asunto(s)
Antivirales/síntesis química , Bencimidazoles/síntesis química , Piperidinas/síntesis química , Piridinas/síntesis química , Virus Sincitiales Respiratorios/efectos de los fármacos , Proteínas Virales de Fusión/antagonistas & inhibidores , Animales , Antivirales/farmacocinética , Antivirales/farmacología , Bencimidazoles/farmacocinética , Bencimidazoles/farmacología , Células HeLa , Humanos , Riñón/metabolismo , Hígado/metabolismo , Pulmón/metabolismo , Masculino , Piperidinas/farmacocinética , Piperidinas/farmacología , Piridinas/farmacocinética , Piridinas/farmacología , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Distribución Tisular
7.
Eur J Med Chem ; 42(5): 567-79, 2007 May.
Artículo en Inglés | MEDLINE | ID: mdl-17223230

RESUMEN

Novel diarylpyrimidines (DAPY), which represent next generation of non-nucleoside reverse transcriptase inhibitors (NNRTIs), were synthesized and their activities against human immunodeficiency virus type I (HIV-1) assessed. Modulations at positions 2 and 6 of the left phenyl ring generated interesting derivatives of TMC278 displaying high potency against wild-type and mutant viruses compared to nevirapine and efavirenz. The pharmacokinetic profile of the best newly synthesized DAPY was evaluated and compared with TMC278 now in phase II clinical trials.


Asunto(s)
VIH-1/efectos de los fármacos , Nitrilos/síntesis química , Nitrilos/farmacología , Pirimidinas/química , Inhibidores de la Transcriptasa Inversa/síntesis química , Inhibidores de la Transcriptasa Inversa/farmacología , Animales , Cromatografía Líquida de Alta Presión , Perros , Femenino , Espectroscopía de Resonancia Magnética , Masculino , Espectrometría de Masas , Pirimidinas/síntesis química , Pirimidinas/farmacología , Ratas , Ratas Wistar , Rilpivirina , Espectrofotometría Ultravioleta
9.
J Med Chem ; 52(23): 7473-87, 2009 Dec 10.
Artículo en Inglés | MEDLINE | ID: mdl-19645483

RESUMEN

A series of C-5 methyl substituted 4-arylthio- and 4-aryloxy-3-iodopyridin-2(1H)-ones has been synthesized as new pyridinone analogues for their evaluation as anti-HIV inhibitors. The optimization at the 5-position was developed through an efficient use of the key intermediates 5-ethoxycarbonyl- and 5-cyano-pyridin-2(1H)-ones (14 and 15). Biological studies revealed that several compounds show potent HIV-1 reverse transcriptase inhibitory properties, for example, compounds 93 and 99 are active at 0.6-50 nM against wild type HIV-1 and a panel of major simple/double HIV mutant strains.


Asunto(s)
Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/farmacología , VIH/efectos de los fármacos , Yodopiridonas/síntesis química , Yodopiridonas/farmacología , Fármacos Anti-VIH/química , Línea Celular , VIH/enzimología , VIH/genética , Transcriptasa Inversa del VIH/antagonistas & inhibidores , Transcriptasa Inversa del VIH/genética , Humanos , Concentración 50 Inhibidora , Yodopiridonas/química , Mutación , Bibliotecas de Moléculas Pequeñas/síntesis química , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacología
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