RESUMEN
The optimization of a novel series of non-nucleoside reverse transcriptase inhibitors (NNRTI) led to the identification of pyridone 36. In cell cultures, this new NNRTI shows a superior potency profile against a range of wild type and clinically relevant, resistant mutant HIV viruses. The overall favorable preclinical pharmacokinetic profile of 36 led to the prediction of a once daily low dose regimen in human. NNRTI 36, now known as MK-1439, is currently in clinical development for the treatment of HIV infection.
Asunto(s)
Fármacos Anti-VIH/farmacología , Descubrimiento de Drogas , Farmacorresistencia Viral/efectos de los fármacos , VIH-1/efectos de los fármacos , Piridonas/química , Piridonas/farmacología , Inhibidores de la Transcriptasa Inversa/síntesis química , Inhibidores de la Transcriptasa Inversa/farmacología , Triazoles/química , Triazoles/farmacología , Animales , Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/química , Células Cultivadas , Cristalografía por Rayos X , Perros , VIH-1/genética , Humanos , Concentración 50 Inhibidora , Estructura Molecular , Mutación , Ratas , Ratas Sprague-Dawley , Inhibidores de la Transcriptasa Inversa/químicaRESUMEN
An in vitro screening protocol was used to transform a systemically-distributed SCD inhibitor into a liver-targeted compound. Incorporation of a key nicotinic acid moiety enables molecular recognition by OATP transporters, as demonstrated by uptake studies in transfected cell lines, and likely serves as a critical component of the observed liver-targeted tissue distribution profile. Preclinical anti-diabetic oGTT efficacy is demonstrated with nicotinic acid-based, liver-targeting SCD inhibitor 10, and studies with a close-structural analog devoid of SCD1 activity, suggest this efficacy is a result of on-target activity.
Asunto(s)
Inhibidores Enzimáticos/química , Hipoglucemiantes/química , Hipoglucemiantes/farmacología , Ácidos Nicotínicos/química , Estearoil-CoA Desaturasa/antagonistas & inhibidores , Administración Oral , Animales , Línea Celular , Evaluación Preclínica de Medicamentos , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacocinética , Inhibidores Enzimáticos/farmacología , Humanos , Hipoglucemiantes/síntesis química , Hipoglucemiantes/farmacocinética , Hígado/efectos de los fármacos , Hígado/enzimología , Ratones , Ratones Endogámicos C57BL , Ácidos Nicotínicos/síntesis química , Ácidos Nicotínicos/farmacocinética , Ácidos Nicotínicos/farmacología , Ratas , Estearoil-CoA Desaturasa/metabolismo , Relación Estructura-Actividad , Distribución TisularRESUMEN
The trifluoroethylamine group found in cathepsin K inhibitors like odanacatib can be replaced by a difluoroethylamine group. This change increased the basicity of the nitrogen which positively impacted the log D. This translated into an improved oral bioavailability in pre-clinical species. Difluoroethylamine compounds exhibit a similar potency against cathepsin K and selectivity profile against other cathepsins when compared to trifluoroethylamine analogs.
Asunto(s)
Catepsina K/antagonistas & inhibidores , Etilaminas/química , Inhibidores de Proteasas/química , Administración Oral , Amidas/química , Animales , Compuestos de Bifenilo/química , Compuestos de Bifenilo/farmacología , Catepsina K/metabolismo , Perros , Etilaminas/síntesis química , Etilaminas/farmacocinética , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/farmacocinética , RatasRESUMEN
A weak, UDP-competitive antagonist of the pyrimidinergic receptor P2RY(14) with a naphthoic acid core was identified through high-throughput screening. Optimization provided compounds with improved potency but poor pharmacokinetics. Acylglucuronidation was determined to be the major route of metabolism. Increasing the electron-withdrawing nature of the substituents markedly reduced glucuronidation and improved the pharmacokinetic profile. Additional optimization led to the identification of compound 38 which is an 8 nM UDP-competitive antagonist of P2Y(14) with a good pharmacokinetic profile.
Asunto(s)
Ácidos Carboxílicos/síntesis química , Naftalenos/síntesis química , Antagonistas del Receptor Purinérgico P2/síntesis química , Receptores Purinérgicos P2 , Uridina Difosfato , Animales , Unión Competitiva , Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacocinética , Ácidos Carboxílicos/farmacología , Ratones , Estructura Molecular , Naftalenos/química , Naftalenos/farmacocinética , Naftalenos/farmacología , Pan troglodytes , Unión Proteica/efectos de los fármacos , Antagonistas del Receptor Purinérgico P2/química , Antagonistas del Receptor Purinérgico P2/farmacocinética , Antagonistas del Receptor Purinérgico P2/farmacología , Receptores Purinérgicos P2Y , Relación Estructura-ActividadRESUMEN
The SAR study of a series of 6-aryloxymethyl-8-aryl substituted quinolines is described. Optimization of the series led to the discovery of compound 26b, a highly potent (IC50=0.6 nM) and selective PDE4D inhibitor with a 75-fold selectivity over the A, B, and C subtypes and over 18,000-fold selectivity against other PDE family members. Rat pharmacokinetics and tissue distribution are also summarized.
Asunto(s)
Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/metabolismo , Inhibidores de Fosfodiesterasa/química , Inhibidores de Fosfodiesterasa/farmacología , Quinolinas/química , Quinolinas/farmacología , Animales , Asma/tratamiento farmacológico , Humanos , Concentración 50 Inhibidora , Masculino , Inhibidores de Fosfodiesterasa/síntesis química , Inhibidores de Fosfodiesterasa/farmacocinética , Quinolinas/síntesis química , Quinolinas/farmacocinética , Ratas , Ratas Wistar , Relación Estructura-ActividadRESUMEN
A series of stearoyl-CoA desaturase 1 (SCD1) inhibitors were developed. Investigations of enzyme potency and metabolism led to the identification of the thiadiazole-pyridazine derivative MF-438 as a potent SCD1 inhibitor. MF-438 exhibits good pharmacokinetics and metabolic stability, thereby serving as a valuable tool for further understanding the role of SCD inhibition in biological and pharmacological models of diseases related to metabolic disorders.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Piridazinas/síntesis química , Estearoil-CoA Desaturasa/antagonistas & inhibidores , Tiadiazoles/síntesis química , Administración Oral , Animales , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacocinética , Ratones , Microsomas Hepáticos/metabolismo , Piridazinas/química , Piridazinas/farmacocinética , Ratas , Estearoil-CoA Desaturasa/metabolismo , Relación Estructura-Actividad , Tiadiazoles/química , Tiadiazoles/farmacocinéticaRESUMEN
Substituted 8-arylquinoline analogs bearing alkyl-linked side chain were identified as potent inhibitors of type 4 phophodiesterase. These compounds address the potential liabilities of the clinical candidate L-454560. The pharmacokinetic profile of the best analogs and the in vivo efficacy in an ovalbumin-induced bronchoconstriction assay in conscious guinea pigs are reported.
Asunto(s)
Antiinflamatorios/química , Inhibidores de Fosfodiesterasa 4 , Inhibidores de Fosfodiesterasa/química , Quinolinas/química , Animales , Antiinflamatorios/síntesis química , Antiinflamatorios/farmacocinética , Hidrocarburo de Aril Hidroxilasas/metabolismo , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/metabolismo , Citocromo P-450 CYP2C9 , Cobayas , Humanos , Leucocitos Mononucleares/metabolismo , Ovalbúmina/farmacología , Inhibidores de Fosfodiesterasa/síntesis química , Inhibidores de Fosfodiesterasa/farmacocinética , Quinolinas/síntesis química , Quinolinas/farmacocinética , Ratas , Saimiri , Relación Estructura-ActividadRESUMEN
Motivated by the recent report of a heteroleptic ruthenium bis-terpyridine complex [Ru(toltpy)(bipytpy)](PF6)2 (toltpy: 4'-(tolyl)-2,2':6',2''-terpyridine; bipytpy: 4'-(4-bromophenyl)-4,4''':4'',4''''-di-pyridinyl-2,2':6',2''-terpyridine) capable of driving the photo-evolution of hydrogen with a constant rate of activity for 12 days [M. Rupp et al., Inorg. Chem., 2019, 58, 9127-9134], we investigated the impact of an internal electron donor on the photoactivity of three new ruthenium bis-terpyridine photosensitizers. We used 4'-(N,N-dimethylaminophenyl)-4,4''-di-tert-butyl-2,2':6',2''-terpyridine (Dtpy) as the donor ligand. These complexes also bear peripheral coordination sites at various positions on the terpyridine backbone, allowing for photosensitizer-catalyst interactions. Their performances in photocatalysis under blue and green light (450 and 525 nm, respectively) were measured, in the presence of triethanolamine, using a cobaloxime catalyst [Co(dmgH)2(H2O)2](BF4)2. Complexes C1[Ru(Dtpy)(pytpy)](PF6)2 (pytpy: 4'-(pyridin-4-yl)-2,2':6',2''-terpyridine) and C3[Ru(Dtpy)(bipytpy)](PF6)2 appeared to have a photostability similar to that of [Ru(toltpy)(bipytpy)](PF6)2 but with lower activity rates, while C2[Ru(Dtpy)(pz2bpy)](PF6)2 (pz2bpy: 2,6-di(pyrazin-2-yl)-4,4'-bipyridine) showed a better peak activity, however, followed by a progressive decay. After 24 hours, complexes C1, C2 and C3 had reached TONs of 18, 35 and 52 under blue light and 14, 20 and 47 under green light, respectively, and were still found to be active. Their photophysical and electronic properties are discussed to rationalize the photocatalytic trends.
RESUMEN
The structure-activity relationship of a novel series of 8-biarylquinolines acting as type 4 phosphodiesterase (PDE4) inhibitors is described herein. Prototypical compounds from this series are potent and non-selective inhibitors of the four distinct PDE4 (IC(50)<10 nM) isozymes (A-D). In a human whole blood in vitro assay, they inhibit (IC(50)<0.5 microM) the LPS-induced release of the cytokine TNF-alpha. Optimized inhibitors were evaluated in vivo for efficacy in an ovalbumin-induced bronchoconstriction model in conscious guinea pigs. Their propensity to produce an emetic response was evaluated by performing pharmacokinetic studies in squirrel monkeys. This work has led to the identification of several compounds with excellent in vitro and in vivo profiles, including a good therapeutic window of efficacy over emesis.
Asunto(s)
Compuestos de Bifenilo/química , Compuestos de Bifenilo/farmacología , Inhibidores de Fosfodiesterasa 4 , Inhibidores de Fosfodiesterasa/química , Inhibidores de Fosfodiesterasa/farmacología , Quinolinas/química , Quinolinas/farmacología , Animales , Disponibilidad Biológica , Compuestos de Bifenilo/síntesis química , Compuestos de Bifenilo/farmacocinética , Diseño de Fármacos , Cobayas , Humanos , Inhibidores de Fosfodiesterasa/síntesis química , Inhibidores de Fosfodiesterasa/farmacocinética , Piridinas/síntesis química , Piridinas/química , Piridinas/farmacocinética , Piridinas/farmacología , Quinolinas/síntesis química , Quinolinas/farmacocinética , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
A new series of EP(4) antagonists based on a quinoline acylsulfonamide scaffold have been identified as part of our on-going efforts to develop treatments for chronic inflammation. These compounds show subnanomolar intrinsic binding potency towards the EP(4) receptor, and excellent selectivity towards other prostanoid receptors. Acceptable pharmacokinetic profiles have also been demonstrated across a series of preclinical species.
Asunto(s)
Artritis Experimental/tratamiento farmacológico , Quinolinas/química , Quinolinas/farmacología , Receptores de Prostaglandina E/antagonistas & inhibidores , Receptores de Prostaglandina E/metabolismo , Sulfonamidas/química , Sulfonamidas/farmacología , Animales , Artritis Experimental/inducido químicamente , Perros , Cobayas , Humanos , Macaca mulatta , Estructura Molecular , Quinolinas/farmacocinética , Ratas , Subtipo EP4 de Receptores de Prostaglandina E , Relación Estructura-Actividad , Sulfonamidas/farmacocinéticaRESUMEN
Potent inhibitors of the human PDE IV enzyme are described. Substituted 8-arylquinoline analogs bearing nitrogen-linked side chain were identified as potent inhibitors based on the SAR described herein. The pharmacokinetic profile of the best analog and the in vivo efficacy in an ovalbumin-induced bronchoconstriction assay in conscious guinea pigs are reported.
Asunto(s)
Nitrógeno/química , Inhibidores de Fosfodiesterasa/química , Inhibidores de Fosfodiesterasa/farmacología , Quinolinas/química , Quinolinas/farmacología , Animales , Disponibilidad Biológica , Semivida , Inhibidores de Fosfodiesterasa/farmacocinética , Quinolinas/farmacocinética , Ratas , SaimiriRESUMEN
Based on our previous study with trifluoroethylamine as a P2-P3 amide isostere of cathepsin K inhibitor, further optimization led to identification of compound 22 (L-873724) as a potent and selective non-basic cathepsin K inhibitor. This compound showed excellent pharmacokinetics and efficacy in an ovariectomized (OVX) rhesus monkey model. The volumes of distribution close to unity were consistent with this compound not being lysosomotropic, which is a characteristic of basic cathepsin K inhibitors.
Asunto(s)
Catepsinas/antagonistas & inhibidores , Inhibidores de Cisteína Proteinasa/farmacología , Animales , Catepsina K , Cristalografía por Rayos X , Inhibidores de Cisteína Proteinasa/química , Inhibidores de Cisteína Proteinasa/farmacocinética , Femenino , Macaca mulatta , Modelos Moleculares , OvariectomíaRESUMEN
The discovery and SAR of a new series of substituted 8-arylquinoline PDE4 inhibitors are herein described. This work has led to the identification of several compounds with excellent in vitro and in vivo profiles, including a good therapeutic window of emesis to efficacy in several animal models. Typical optimized compounds from this series are potent inhibitors of PDE4 (IC(50)<1nM) and also of LPS-induced TNF-alpha release in human whole blood (IC(50)<0.5microM). The same compounds are potent inhibitors of ovalbumin-induced bronchoconstriction in conscious guinea pigs (EC(50)<0.1mg/kg ip) but require a dose of about 10mg/kg po in the squirrel monkey to produce an emetic response. From this series of compounds, 23a (L-454,560) was identified as an optimized compound.