RESUMEN
Herein we report a scaffold-hopping approach to identify a new scaffold with a zinc binding headgroup. Structural information was used to give novel oxazolidinone-based LpxC inhibitors. In particular, the most potent compound, 23j, showed a low efflux ratio, nanomolar potencies against E. coli LpxC enzyme, and excellent antibacterial activity against E. coli and K. pneumoniae. Computational docking was used to predict the interaction between 23j and E. coli LpxC, suggesting that the interactions with C207 and C63 contribute to the strong activity. These results provide new insights into the design of next-generation LpxC inhibitors.
RESUMEN
We previously identified KCA-1490 [(-)-6-(7-methoxy-2-trifluoromethyl-pyrazolo[1,5-a]pyridin-4-yl)-5-methyl-4,5-dihydro-3-(2H)-pyridazinone], a dual PDE3/4 inhibitor. In the present study, we found highly potent selective PDE4 inhibitors derived from the structure of KCA-1490. Among them, N-(3,5-dichloropyridin-4-yl)-7-methoxy-2-(trifluoromethyl)pyrazolo[1,5-a]pyridine-4-carboxamide (2a) had good anti-inflammatory effects in an animal model.
Asunto(s)
Antiinflamatorios , Diseño de Fármacos , Inhibidores de Fosfodiesterasa 4 , Pirazoles/síntesis química , Piridinas , Animales , Antiinflamatorios/síntesis química , Antiinflamatorios/química , Antiinflamatorios/farmacología , Activación Enzimática/efectos de los fármacos , Concentración 50 Inhibidora , Modelos Animales , Estructura Molecular , Inhibidores de Fosfodiesterasa 4/síntesis química , Inhibidores de Fosfodiesterasa 4/química , Inhibidores de Fosfodiesterasa 4/farmacología , Pirazoles/química , Pirazoles/farmacología , Piridinas/síntesis química , Piridinas/química , Piridinas/farmacología , Ratas , Relación Estructura-ActividadRESUMEN
(-)-6-(7-Methoxy-2-(trifluoromethyl)pyrazolo[1,5-a]pyridin-4-yl)-5-methyl-4,5-dihydropyridazin-3(2H)-one (KCA-1490) exhibits moderate dual PDE3/4-inhibitory activity and promises as a combined bronchodilatory/anti-inflammatory agent. N-alkylation of the pyridazinone ring markedly enhances potency against PDE4 but suppresses PDE3 inhibition. Addition of a 6-aryl-4,5-dihydropyridazin-3(2H)-one extension to the N-alkyl group facilitates both enhancement of PDE4-inhibitory activity and restoration of potent PDE3 inhibition. Both dihydropyridazinone rings, in the core and extension, can be replaced by achiral 4,4-dimethylpyrazolone subunits and the core pyrazolopyridine by isosteric bicyclic heteroaromatics. In combination, these modifications afford potent dual PDE3/4 inhibitors that suppress histamine-induced bronchoconstriction in vivo and exhibit promising anti-inflammatory activity via intratracheal administration.
Asunto(s)
Antiinflamatorios/química , Broncodilatadores/química , Inhibidores de Fosfodiesterasa 3/química , Inhibidores de Fosfodiesterasa 4/química , Administración por Inhalación , Animales , Antiinflamatorios/síntesis química , Antiinflamatorios/farmacología , Líquido del Lavado Bronquioalveolar/citología , Broncodilatadores/síntesis química , Broncodilatadores/farmacología , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 3/química , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 3/metabolismo , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/química , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/metabolismo , Diseño de Fármacos , Leucocitos/efectos de los fármacos , Inhibidores de Fosfodiesterasa 3/síntesis química , Inhibidores de Fosfodiesterasa 3/farmacología , Inhibidores de Fosfodiesterasa 4/síntesis química , Inhibidores de Fosfodiesterasa 4/farmacología , Unión Proteica , Piridazinas/química , Piridinas/química , Ratas , Relación Estructura-ActividadRESUMEN
(-)-6-(7-Methoxy-2-trifluoromethylpyrazolo[1,5-a]pyridin-4-yl)-5-methyl-4,5-dihydro-3-(2H)-pyridazinone (KCA-1490) is a dual PDE3/4 inhibitor that exhibits potent combined bronchodilatory and anti-inflammatory activity. Here we show that a 4,4-dimethylpyrazolone subunit serves as an effective surrogate for the 5-methyl-4,5-dihydropyridazin-3(2H)-one ring of KCA-1490 whilst lacking a stereogenic centre. The 2- and 7-substituents in the pyrazolo[1,5-a]pyridine subunit markedly influence the PDE-inhibitory profile and can be adjusted to afford either potent PDE4-selective inhibitors or dual PDE3/4 inhibitors. A survey of bicyclic heteroaromatic replacements for the pyrazolo[1,5-a]pyridine allowed further refinement of the inhibitory profile and identified 3-(8-methoxy-2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl)-4,4-dimethyl-1H-pyrazol-5(4H)-one as an orally active, achiral KCA-1490 analog with well-balanced dual PDE3/4-inhibitory activity.
Asunto(s)
Compuestos Bicíclicos Heterocíclicos con Puentes/química , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 3/metabolismo , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/metabolismo , Diseño de Fármacos , Inhibidores de Fosfodiesterasa/síntesis química , Inhibidores de Fosfodiesterasa/farmacología , Pirazolonas/química , Piridazinas/farmacología , Piridinas/farmacología , Relación Dosis-Respuesta a Droga , Modelos Moleculares , Estructura Molecular , Inhibidores de Fosfodiesterasa/química , Piridazinas/síntesis química , Piridazinas/química , Piridinas/síntesis química , Piridinas/química , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
(-)-6-(7-Methoxy-2-trifluoromethylpyrazolo[1,5-a]pyridin-4-yl)-5-methyl-4,5-dihydro-3-(2H)-pyridazinone (KCA-1490) is a dual PDE3/4 inhibitor that exhibits potent combined bronchodilatory and anti-inflammatory activity. A survey of potential bicyclic heteroaromatic replacement subunits for the pyrazolo[1,5-a]pyridine core of KCA-1490 has identified the 4-methoxy-2-(trifluoromethyl)benzo[d]thiazol-7-yl and 8-methoxy-2-(trifluoromethyl)quinolin-5-yl analogues as dual PDE3/4-inhibitory compounds that potently suppress histamine-induced bronchoconstriction and exhibit anti-inflammatory activity in vivo.
Asunto(s)
Inhibidores de Fosfodiesterasa 3/química , Inhibidores de Fosfodiesterasa 3/farmacología , Inhibidores de Fosfodiesterasa 4/química , Inhibidores de Fosfodiesterasa 4/farmacología , Antiinflamatorios/síntesis química , Antiinflamatorios/química , Antiinflamatorios/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/síntesis química , Compuestos Bicíclicos Heterocíclicos con Puentes/química , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Broncoconstricción/efectos de los fármacos , Broncodilatadores/síntesis química , Broncodilatadores/química , Broncodilatadores/farmacología , Diseño de Fármacos , Humanos , Modelos Moleculares , Inhibidores de Fosfodiesterasa 3/síntesis química , Inhibidores de Fosfodiesterasa 4/síntesis química , Piridinas/síntesis química , Piridinas/química , Piridinas/farmacología , Relación Estructura-ActividadRESUMEN
A structural survey of pyrazolopyridine-pyridazinone phosphodiesterase (PDE) inhibitors was made with a view to optimization of their dual PDE3/4-inhibitory activity for respiratory disease applications. These studies identified (-)-6-(7-methoxy-2-trifluoromethylpyrazolo[1,5-a]pyridine-4-yl)-5-methyl-4,5-dihydro-3-(2H)-pyridazinone (KCA-1490, compound 2ac) as a compound with potent combined bronchodilatory and anti-inflammatory activity and an improved therapeutic window over roflumilast.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Broncodilatadores/farmacología , Diseño de Fármacos , Inhibidores de Fosfodiesterasa 3/farmacología , Inhibidores de Fosfodiesterasa 4/farmacología , Pirazoles/farmacología , Piridinas/farmacología , Animales , Antiinflamatorios no Esteroideos/síntesis química , Antiinflamatorios no Esteroideos/química , Broncodilatadores/síntesis química , Broncodilatadores/química , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 3/metabolismo , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/metabolismo , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Cobayas , Estructura Molecular , Inhibidores de Fosfodiesterasa 3/síntesis química , Inhibidores de Fosfodiesterasa 3/química , Inhibidores de Fosfodiesterasa 4/síntesis química , Inhibidores de Fosfodiesterasa 4/química , Pirazoles/síntesis química , Pirazoles/química , Piridinas/síntesis química , Piridinas/química , Ratas , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Ibudilast [1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one] is a nonselective phosphodiesterase inhibitor used clinically to treat asthma. Efforts to selectively develop the PDE3- and PDE4-inhibitory activity of ibudilast led to replacement of the isopropyl ketone by a pyridazinone heterocycle. Structure-activity relationship exploration in the resulting 6-(pyrazolo[1,5-a]pyridin-3-yl)pyridazin-3(2H)-ones revealed that the pyridazinone lactam functionality is a critical determinant for PDE3-inhibitory activity, with the nitrogen preferably unsubstituted. PDE4 inhibition is strongly promoted by introduction of a hydrophobic substituent at the pyridazinone N(2) centre and a methoxy group at C-7' in the pyrazolopyridine. Migration of the pyridazinone ring connection from the pyrazolopyridine 3'-centre to C-4' strongly enhances PDE4 inhibition. These studies establish a basis for development of potent PDE4-selective and dual PDE3/4-selective inhibitors derived from ibudilast.
Asunto(s)
Inhibidores de Fosfodiesterasa/química , Pirazoles/química , Piridazinas/química , Piridinas/química , Teprotido , Sitios de Unión , Activación Enzimática/efectos de los fármacos , Modelos Moleculares , Estructura Molecular , Inhibidores de Fosfodiesterasa/farmacología , Pirazoles/farmacología , Piridazinas/farmacología , Piridinas/farmacología , Relación Estructura-Actividad , Especificidad por Sustrato , Teprotido/síntesis química , Teprotido/química , Teprotido/farmacologíaRESUMEN
The novel 1-(2-fluorovinyl)-4-quinolone-3-carboxylic acid derivatives Z-15a-c, E-15a-c, Z-16a-c, and E-16a-c, conformationally restricted analogues of fleroxacin (5), were synthesized, and their in vitro antibacterial activity was evaluated. A dehydrosulfenylation of a 2-fluoro-2-[(4-methoxyphenyl)sulfinyl]ethyl group was employed as a key step for the construction of a 2-fluorovinyl group at the N-1 position. It appeared evident that the Z-isomers Z-15a-c and Z-16a-c exhibited 2- to 32-fold more potent in vitro antibacterial activity than the corresponding E-isomers E-15a-c and E-16a-c. Furthermore, since Z-15b showed in vitro antibacterial activity and DNA gyrase inhibition comparable to that of 5, it was hypothesized that the conformation of Z-15b would be equivalent to the active conformer of 5. The results revealed that the antibacterial Z-1-(2-fluorovinyl)quinolone derivatives carry the novel N-1 substituent of the fluoroquinolones.
Asunto(s)
Antibacterianos/síntesis química , Ácidos Carboxílicos/síntesis química , Fleroxacino/análogos & derivados , Fleroxacino/síntesis química , Antibacterianos/química , Antibacterianos/farmacología , Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacología , Fleroxacino/química , Fleroxacino/farmacología , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Modelos Moleculares , Conformación Molecular , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Novel 1-trifluoromethyl-4-quinolone derivatives (8a,b) were synthesized, and the antibacterial activity of each was evaluated. An oxidative desulfurization-fluorination reaction was employed to introduce a trifluoromethyl group at the N-1 position as a key step. Among the derivatives, 8a was found to exhibit antibacterial activity comparable to that of norfloxacin (1) against Staphylococcus aureus Smith, Streptococcus pneumoniae IID1210, and Escherichia coli NIHJ JC-2.