RESUMEN
Antagonists of the TRPV4 receptor were identified using a focused screen, followed by a limited optimization program. The leading compounds obtained from this exercise, RN-1665 23 and RN-9893 26, showed moderate oral bioavailability when dosed to rats. The lead molecule, RN-9893 26, inhibited human, rat and murine variants of TRPV4, and showed excellent selectivity over related TRP receptors, such as TRPV1, TRPV3 and TRPM8. The overall profile for RN-9893 may permit its use as a proof-of-concept probe for in vivo applications.
Asunto(s)
Piperazinas/administración & dosificación , Piperazinas/farmacología , Canales Catiónicos TRPV/antagonistas & inhibidores , Administración Oral , Animales , Disponibilidad Biológica , Relación Dosis-Respuesta a Droga , Humanos , Ratones , Estructura Molecular , Piperazinas/síntesis química , Piperazinas/química , Ratas , Ratas Wistar , Relación Estructura-Actividad , Canales Catiónicos TRPV/metabolismoRESUMEN
The discovery and development of antimicrobial agents that do not give rise to resistance remains an ongoing challenge. Our efforts in this regard continue to reveal new potential therapeutic agents with differing physicochemical properties while retaining the effective N,N-dichloroamine pharmacophore as the key antimicrobial warhead. In this Letter, we disclose agents containing polyol units as a water solubilizing group. These sulfonyl-polyol agents show broad spectrum bactericidal and virucidal activity. These compounds show 1 h MBC's of 16-512 µg/mL against Escherichia coli and 4-256 µg/mL against Staphylococcus aureus at neutral pH, and 1-h IC50's of 4.5-32 µM against Adenovirus 5 and 0.7-3.0 µM against Herpes simplex virus 1. The lead compounds were tested in a tissue culture irritancy assay and showed only minimal irritation at the highest concentrations tested.
Asunto(s)
Aminas/química , Antiinfecciosos/química , Polímeros/química , Adenoviridae/metabolismo , Aminas/síntesis química , Aminas/farmacología , Animales , Antiinfecciosos/síntesis química , Antiinfecciosos/farmacología , Línea Celular Tumoral , Chlorocebus aethiops , Efecto Citopatogénico Viral/efectos de los fármacos , Escherichia coli/efectos de los fármacos , Herpesvirus Humano 1/metabolismo , Humanos , Concentración de Iones de Hidrógeno , Pruebas de Sensibilidad Microbiana , Staphylococcus aureus/efectos de los fármacos , Células VeroRESUMEN
5,6,7,8-Tetrahydroquinolines and 5,6,7,8-tetrahydronaphthyridines with appended trifluoromethyl groups are valuable chemotypes in medicinal chemistry due to the presence of a partially-saturated bicyclic ring and metabolically-stable CF(3) group. (1)H NMR studies were used to optimize the preparation of such compounds, using a three-step/one-pot procedure, to provide novel 2,6-disubstitued derivatives with a tertiary-substituent. Racemic 2,6-disubstituted tetrahydroquinolines were separated by chiral HPLC to provide single enantiomers.
Asunto(s)
Hidrocarburos Fluorados/química , Naftiridinas/síntesis química , Quinolinas/síntesis química , Estructura Molecular , Naftiridinas/química , Quinolinas/químicaRESUMEN
Structure stability/activity relationships (SXR) of a new class of N,N-dichloroamine compounds were explored to improve antimicrobial activity against Escherichia coli, Staphylococcus aureus, and Candida albicans while maintaining aqueous solution stability. This study identified a new class of solution-stable and topical antimicrobial agents. These agents are sulfone-stabilized and possess either a quaternary ammonium or sulfonate appendages as a water solubilizing group. Several unique challenges were confronted in the synthesis of these novel compounds which are highlighted in the discussion.
Asunto(s)
Antiinfecciosos/síntesis química , Cloraminas/síntesis química , Sulfonas/síntesis química , Agua/química , Antibacterianos/síntesis química , Antibacterianos/química , Antibacterianos/farmacología , Antiinfecciosos/farmacología , Cloraminas/química , Cloraminas/farmacología , Estabilidad de Medicamentos , Escherichia coli/efectos de los fármacos , Estructura Molecular , Staphylococcus aureus/efectos de los fármacos , Relación Estructura-Actividad , Sulfonas/química , Sulfonas/farmacologíaRESUMEN
Antimicrobial compounds with broad-spectrum activity and minimal potential for antibiotic resistance are urgently needed. Toward this end, we prepared and investigated a novel series of N-chloroheterocycles. Of the compounds examined, the N-chloroamine series were found superior over N-chloroamide series in regards to exhibiting high antimicrobial activity, low cytotoxicity, and long-term aqueous stability.
Asunto(s)
Antiinfecciosos/química , Antiinfecciosos/farmacología , Bacterias/efectos de los fármacos , Hongos/efectos de los fármacos , Compuestos Heterocíclicos/química , Compuestos Heterocíclicos/farmacología , Antiinfecciosos/síntesis química , Cloro/química , Compuestos Heterocíclicos/síntesis química , Pruebas de Sensibilidad Microbiana , Estructura MolecularRESUMEN
Antimicrobial resistance against many known therapeutics is on the rise. We examined derivatives of 3-chlorooxazolidin-2-one 1a (X=H) as antibacterial and antifungal agents. The key findings were that the activity and apparent in vitro cytotoxicity could be controlled by the substitution of charged solubilizers at the 4- and 5- positions. These changes both significantly increase the antifungal potency and decrease cytotoxicity. Particularly effective were trialkylammonium groups which led to 400- to 600-fold increases in the antifungal therapeutic index when compared to their unsubstituted counterparts.
Asunto(s)
Antiinfecciosos/farmacología , Bacterias/efectos de los fármacos , Cloro/química , Hongos/efectos de los fármacos , Oxazolidinonas/farmacología , Antiinfecciosos/síntesis química , Antiinfecciosos/química , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Oxazolidinonas/síntesis química , Oxazolidinonas/químicaRESUMEN
Introduction of oxetan-3-yl and azetidin-3-yl groups into heteroaromatic bases was achieved by using a radical addition method (Minisci reaction). To demonstrate utility, the process was used to introduce an oxetane or azetidine into heteroaromatic systems that have found important uses in the drug discovery industry, such as the marketed EGFR inhibitor gefitinib, a quinolinecarbonitrile Src tyrosine kinase inhibitor, and the antimalarial hydroquinine.
RESUMEN
The oxetan-3-yl and azetidin-3-yl substituents have previously been identified as privileged motifs within medicinal chemistry. An efficient approach to installing these two modules into aromatic systems, using a nickel-mediated alkyl-aryl Suzuki coupling, is presented.
Asunto(s)
Azetidinas/síntesis química , Derivados del Benceno/síntesis química , Éteres Cíclicos/síntesis químicaRESUMEN
The Rh(I) catalyzed intramolecular [4 + 2] cycloaddition of representative achiral and chiral enedienes has been shown to proceed with excellent levels of stereoselectivity and in high yield under mild reaction conditions. In contrast, the corresponding noncatalyzed cycloadditions for three substrates in the latter category require higher temperatures and exhibit low levels of stereocontrol.