RESUMEN
Multidrug resistant Gram-negative bacterial infections are an increasing public health threat due to rapidly rising resistance toward ß-lactam antibiotics. The hydrolytic enzymes called ß-lactamases are responsible for a large proportion of the resistance phenotype. ß-Lactamase inhibitors (BLIs) can be administered in combination with ß-lactam antibiotics to negate the action of the ß-lactamases, thereby restoring activity of the ß-lactam. Newly developed BLIs offer some advantage over older BLIs in terms of enzymatic spectrum but are limited to the intravenous route of administration. Reported here is a novel, orally bioavailable diazabicyclooctane (DBO) ß-lactamase inhibitor. This new DBO, ETX1317, contains an endocyclic carbon-carbon double bond and a fluoroacetate activating group and exhibits broad spectrum activity against class A, C, and D serine ß-lactamases. The ester prodrug of ETX1317, ETX0282, is orally bioavailable and, in combination with cefpodoxime proxetil, is currently in development as an oral therapy for multidrug resistant and carbapenem-resistant Enterobacterales infections.
Asunto(s)
Antibacterianos/química , Compuestos de Azabiciclo/química , Inhibidores de beta-Lactamasas/química , beta-Lactamasas/química , Administración Oral , Animales , Antibacterianos/farmacocinética , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Compuestos de Azabiciclo/metabolismo , Compuestos de Azabiciclo/farmacología , Compuestos de Azabiciclo/uso terapéutico , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Semivida , Humanos , Ratones , Pruebas de Sensibilidad Microbiana , Proteínas de Unión a las Penicilinas/química , Proteínas de Unión a las Penicilinas/metabolismo , Profármacos/química , Profármacos/metabolismo , Unión Proteica , Ratas , Enfermedades de la Piel/tratamiento farmacológico , Enfermedades de la Piel/patología , Enfermedades de la Piel/veterinaria , Relación Estructura-Actividad , Inhibidores de beta-Lactamasas/metabolismo , Inhibidores de beta-Lactamasas/farmacología , Inhibidores de beta-Lactamasas/uso terapéutico , beta-Lactamasas/metabolismoRESUMEN
Bacterially expressed ß-lactamases are rapidly eroding the clinical utility of the important ß-lactam class of antibacterials, significantly impairing our ability to fight serious bacterial infections. This paper describes a study of oxaborole-derived ß-lactamase inhibitors in which crystal structures and computational modeling aided in the rational design of analogues with improved spectrum of activity against class A, C, and D enzymes. Crystal structures of two of these inhibitors covalently bound to two different serine ß-lactamases, class C Pseudomonas aeruginosa AmpC and class D OXA-10, are described herein. Improved physicochemical properties as well as increased activity against an array of ß-lactamases resulted in substantial restoration of susceptibility to ceftazidime in Escherichia coli and Klebsiella pneumoniae.
RESUMEN
We present a comprehensive study of C6-alkylidene containing oxapenems. We show that this class of ß-lactamase inhibitors possesses an unprecedented spectrum with activity against class A, C, and D enzymes. Surprisingly, this class of compounds displayed significant photolytic instability in addition to the known hydrolytic instability. Quantum mechanical calculations were used to develop models to predict the stability of new analogues.
RESUMEN
This article reviews 101 patent applications published in 2011 that disclosed small-molecule antibacterials and reported bacterial growth inhibition, in which the compounds were not similarly disclosed to be toxic to fungal or mammalian cells. The patent applications were analyzed according to their biological target and/or antibacterial class. Protein synthesis inhibitors included ligands of the 50S ribosome subunit (oxazolidinones, macrolides/ketolides and pleuromutilins), the 30S ribosome subunit (aminoglycosides and tetracyclines) and nonribosomal targets. DNA synthesis inhibitors included ligands of topoisomerase type II and type IV. Inhibitors directed at the bacterial cell envelope included those that act on cell envelope synthesis (LpxC inhibitors, penicillin-binding protein inhibitors and glycopeptides) as well as membrane disruptors (lantibiotics). Other antibacterial targets included cell division (FtsZ and WalR) and fatty acid biosynthesis (FabH/I). Compounds for which the targets are unknown or undisclosed are also covered, as are compounds aimed at overcoming resistance mechanisms (efflux inhibitors, ß-lactamase inhibitors).
Asunto(s)
Antibacterianos/química , Antibacterianos/uso terapéutico , Patentes como Asunto , Animales , Humanos , Macrólidos/química , Macrólidos/uso terapéutico , Inhibidores de la Síntesis del Ácido Nucleico/química , Inhibidores de la Síntesis del Ácido Nucleico/uso terapéutico , Oxazolidinonas/química , Oxazolidinonas/uso terapéutico , Patentes como Asunto/legislación & jurisprudencia , beta-Lactamasas/química , beta-Lactamasas/uso terapéuticoRESUMEN
This review summarizes patent applications from 2010 for small molecules for which there is a claim of antibacterial activity. The primary criterion for inclusion in this analysis was reporting of cellular antibacterial activity data (MICs) for at least one compound. Patent applications are reviewed according to their biological target and antibacterial class. Protein synthesis inhibitors disclosed in this period include inhibitors of the 50S ribosome subunit (oxazolidinones, macrolides/ketolides and pleuromutilins), 30S ribosome subunit (aminoglycosides and tetracyclines) and nonribosomal targets (PDF inhibitors). DNA synthesis inhibitors include inhibitors of GyrA/ParC and GyrB/ParE. Cell envelope disruptors disclosed in 2010 cover both inhibitors of cell-envelope synthesis (LpxC inhibitors, ß-lactams and glycopeptides), as well as membrane disruptors (lipopeptides and polymyxins). Other antibacterial classes covered in this review include rifamycins and antibacterial peptides. Patent applications for compounds aimed at overcoming resistance mechanisms (efflux inhibitors and ß-lactamase inhibitors) are also described.
Asunto(s)
Antibacterianos , Animales , Antibacterianos/farmacología , Farmacorresistencia Bacteriana , Humanos , Inhibidores de la Síntesis del Ácido Nucleico/farmacología , Patentes como Asunto , Inhibidores de la Síntesis de la Proteína/farmacologíaRESUMEN
INTRODUCTION: The mammalian target of rapamycin (mTOR) is a protein kinase and a key component of the PI3K/Akt/mTOR signaling pathway, and is deregulated in half of all human cancers. Rapamycin and its analogs (rapalogs) are allosteric inhibitors of one functional mTOR complex, mTORC1, and are clinically proven therapeutic agents for the treatment of certain cancers. However, rapalogs mainly partially inhibit mTORC1, while ATP competitive inhibitors suppress both mTORC1 and mTORC2, and therefore may offer advantages in the clinic. Recently, small-molecule inhibitors have entered clinical trials that are mTOR-selective or dual mTOR/PI3K inhibitors. AREAS COVERED: This review focuses on ATP-competitive mTOR inhibitors that have appeared in the patent literature in 2010. Many inhibitors with new structural motifs have been discovered as well as inhibitors that are related to previously disclosed structures. This review endeavors to put into perspective the diverse structural elements that make up these compounds. Patent applications are covered that include either selective mTOR inhibitors or dual mTOR/PI3K inhibitors. EXPERT OPINION: The PI3K/mTOR signaling pathway is an exciting target for the development of pharmaceuticals to treat cancer and other diseases, due to the unique combination of a clinically and commercially validated pathway approach (i.e., rapalogs), combined with a biological rationale for further increased efficacy (i.e., ATP-competitive inhibitors). With the number of candidate drugs currently in development or at earlier stages of the drug discovery pipeline, we are bound to see small-molecule inhibitors reach pivotal trials, and hopefully the market, in the near future.
Asunto(s)
Adenosina Trifosfato/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3 , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Animales , Antineoplásicos/farmacología , Unión Competitiva , Sistemas de Liberación de Medicamentos , Diseño de Fármacos , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/fisiopatología , Patentes como AsuntoRESUMEN
mTOR is a serine-threonine kinase that plays a key role in the regulation of cellular growth. The mTOR pathway consists of two distinct complexes: mTOR/Raptor (mTORC1) and mTOR/Rictor (mTORC2). In response to changes in the levels of insulin, nutrients and energy supply, signaling through these complexes affects a variety of processes, including protein translation and cell proliferation. The efficacy of derivatives of the natural product rapamycin (sirolimus), which functions as an allosteric inhibitor of mTORC1, has validated mTOR inhibition as an anticancer treatment. More recently, extensive efforts have been focused on the discovery of ATP-competitive inhibitors of mTOR that would inhibit both mTORC1 and mTORC2 and may provide additional clinical benefit. This review provides a summary of recent research efforts in this field, focusing on mTOR inhibitors that are selective for mTOR over the related lipid kinase PI3K.
Asunto(s)
Adenosina Trifosfato/farmacología , Péptidos y Proteínas de Señalización Intracelular , Proteínas Serina-Treonina Quinasas , Transducción de Señal/efectos de los fármacos , Animales , Humanos , Inmunosupresores , Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Péptidos y Proteínas de Señalización Intracelular/efectos de los fármacos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/efectos de los fármacos , Proteínas Serina-Treonina Quinasas/metabolismo , Purinas/química , Purinas/farmacología , Pirazoles/química , Pirazoles/farmacología , Piridinas/química , Piridinas/farmacología , Pirimidinas/química , Pirimidinas/farmacología , Sirolimus/farmacología , Serina-Treonina Quinasas TORRESUMEN
Incorporation of bridged morpholines in monocyclic triazine PI3K/mTOR inhibitors gave compounds with increased mTOR selectivity relative to the corresponding morpholine analogs. Compounds with ureidophenyl groups gave highly potent and selective mTOR inhibitors. Potency and selectivity was demonstrated both in vitro and in vivo through biomarker suppression studies. Select compounds exhibited potent inhibition of tumor growth in nude mouse xenograft assays upon PO and IV administration.
Asunto(s)
Adenosina Trifosfato/química , Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Morfolinas/química , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Triazinas/química , Triazinas/farmacología , Animales , Descubrimiento de Drogas , Concentración 50 Inhibidora , Ratones , Ratones Desnudos , Serina-Treonina Quinasas TORRESUMEN
Isosteric replacement of one of the 3,5-ethylene-bridged morpholines in 2-arylureidophenyl-4,6-di(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)triazines led to significant improvements in human microsomal stability. 3-R-Me-morpholine and tetrahydropyran were identified as preferred isosteres for the bridged morpholine. Combination of tetrahydropyran substitution with an N-Me-piperazinophenylureido group led to 27, that selectively suppressed mTOR biomarkers in vivo and possessed excellent efficacy in a murine xenograft model.
Asunto(s)
Microsomas/efectos de los fármacos , Triazinas/farmacología , Animales , Humanos , Concentración 50 Inhibidora , Ratones , Microsomas/metabolismo , Trasplante Heterólogo , Triazinas/químicaRESUMEN
Potent inhibitors of the mammalian target of rapamycin (mTOR) which contain the triazine scaffold and the (R)-3-methyl morpholine moiety have been identified. Such compounds also demonstrated good selectivity over the related lipid kinase PI3Kalpha. Incorporation of additional functionality at the 4-position of the arylureidophenyl ring resulted in compounds with enhanced cellular activity.
Asunto(s)
Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Morfolinas/química , Inhibidores de las Quinasa Fosfoinosítidos-3 , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Triazinas/farmacología , Fosfatidilinositol 3-Quinasas/metabolismo , Serina-Treonina Quinasas TOR , Triazinas/químicaRESUMEN
A series of pyrazolopyrimidine mammalian Target Of Rapamycin (mTOR) inhibitors with various substituents at the 1-position have been prepared, resulting in compounds with excellent potency, selectivity and microsomal stability. Combination of a 1-cyclohexyl ketal group with a 2,6-ethylene bridged morpholine in the 4-position and a ureidophenyl group in the 6-positon resulted in compound 8a, that selectively suppressed key mTOR biomarkers in vivo for at least 8h following iv administration and showed excellent oral activity in a xenograft tumor model.
Asunto(s)
Adenosina Trifosfato/metabolismo , Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Péptidos y Proteínas de Señalización Intracelular/química , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/química , Pirazoles/química , Piridinas/química , Adenosina Trifosfato/química , Administración Oral , Animales , Unión Competitiva , Estabilidad de Medicamentos , Humanos , Concentración 50 Inhibidora , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Ratones , Microsomas/enzimología , Estructura Molecular , Proteínas Serina-Treonina Quinasas/metabolismo , Pirazoles/síntesis química , Piridinas/síntesis química , Relación Estructura-Actividad , Serina-Treonina Quinasas TOR , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The morpholine hinge-region binding group on a series of pyrazolopyrimidine and thienopyrimidine mammalian target of rapamycin (mTOR) inhibitors was replaced with 3,6-dihydro-2H-pyran (DHP), giving compounds of equivalent potency and selectivity versus PI3K. These results establish the DHP group as a hinge-region binding motif for the preparation of highly potent and selective mTOR inhibitors.
Asunto(s)
Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Morfolinas/química , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Piranos/química , Pirazoles/química , Piridinas/química , Pirimidinas/química , Adenosina Trifosfato/química , Adenosina Trifosfato/metabolismo , Animales , Sitios de Unión , Unión Competitiva , Simulación por Computador , Descubrimiento de Drogas , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Ratones , Microsomas/metabolismo , Modelos Moleculares , Proteínas Serina-Treonina Quinasas/metabolismo , Pirazoles/síntesis química , Pirazoles/farmacología , Piridinas/síntesis química , Piridinas/farmacología , Pirimidinas/síntesis química , Pirimidinas/farmacología , Serina-Treonina Quinasas TORRESUMEN
2-Aryl-4-morpholinothieno[3,2-d]pyrimidines are known PI3K inhibitors. This class of compounds also potently inhibited the homologous enzyme mTOR. Replacement of the morpholine group in these compounds with an 8-oxa-3-azabicyclo[3.2.1]octane group led to mTOR inhibitors with selectivity over PI3K. Optimization of the 2-aryl substituent led to the discovery of 2-(4-ureidophenyl)-thienopyrimidines as highly potent (IC(50) <1nM) mTOR inhibitors with excellent selectivity (up to >1000-fold) over PI3K and good potency in a cellular proliferation assay (IC(50) <50nM).
Asunto(s)
Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Inhibidores de las Quinasa Fosfoinosítidos-3 , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Pirimidinas/química , Tropanos/química , Línea Celular Tumoral , Descubrimiento de Drogas , Humanos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Morfolinas/química , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Pirimidinas/síntesis química , Pirimidinas/farmacología , Relación Estructura-Actividad , Serina-Treonina Quinasas TORRESUMEN
Design and synthesis of a series of 4-morpholino-6-aryl-1H-pyrazolo[3,4-d]pyrimidines as potent and selective inhibitors of the mammalian target of rapamycin (mTOR) are described. Optimization of the 6-aryl substituent led to the discovery of inhibitors carrying 6-ureidophenyl groups, the first reported active site inhibitors of mTOR with subnanomolar inhibitory concentrations. The data presented in this paper show that 6-arylureidophenyl substituents led to potent mixed inhibitors of mTOR and phosphatidylinositol 3-kinase alpha (PI3K-alpha), whereas 6-alkylureidophenyl appendages gave highly selective mTOR inhibitors. Combination of 6-alkylureidophenyl groups with 1-carbamoylpiperidine substitution resulted in compounds with subnanomolar IC(50) against mTOR and greater than 1000-fold selectivity over PI3K-alpha. In addition, structure based drug design resulted in the preparation of several 6-arylureidophenyl-1H-pyrazolo[3,4-d]pyrimidines, substituted in the 4-position of the arylureido moiety with water solubilizing groups. These compounds combined potent mTOR inhibition (IC(50) < 1 nM) with unprecedented activity in cellular proliferation assays (IC(50) < 1 nM).
Asunto(s)
Adenosina Trifosfato/química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Quinasas/química , Pirimidinas/farmacología , Adenosina Trifosfato/metabolismo , Unión Competitiva , Procesos de Crecimiento Celular/efectos de los fármacos , Línea Celular Tumoral , Humanos , Masculino , Modelos Moleculares , Morfolinas/síntesis química , Morfolinas/química , Morfolinas/farmacología , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/patología , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Proteínas Quinasas/metabolismo , Pirazoles/síntesis química , Pirazoles/química , Pirazoles/farmacología , Pirimidinas/síntesis química , Pirimidinas/química , Relación Estructura-Actividad , Serina-Treonina Quinasas TORRESUMEN
A series of highly potent and selective pyrazolopyrimidine mTOR inhibitors which contain water-solubilizing groups attached to the 6-arylureidophenyl moiety have been prepared. Such derivatives displayed superior potency to those in which these appendages were attached to alternative sites. In comparison to unfunctionalized arylureido compounds, these analogs demonstrated enhanced cellular potency and significantly improved stability towards human microsomes, resulting in an mTOR inhibitor with impressive efficacy in a xenograft model with an intermittent dosing regimen.
Asunto(s)
Antineoplásicos/química , Péptidos y Proteínas de Señalización Intracelular/efectos de los fármacos , Microsomas Hepáticos/enzimología , Inhibidores de las Quinasa Fosfoinosítidos-3 , Inhibidores de Proteínas Quinasas/química , Proteínas Serina-Treonina Quinasas/efectos de los fármacos , Pirazoles/química , Pirimidinas/química , Animales , Antineoplásicos/síntesis química , Antineoplásicos/farmacocinética , Línea Celular Tumoral , Descubrimiento de Drogas , Estabilidad de Medicamentos , Humanos , Ratones , Ratones Desnudos , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacocinética , Pirazoles/síntesis química , Pirazoles/farmacocinética , Pirimidinas/síntesis química , Pirimidinas/farmacocinética , Solubilidad , Serina-Treonina Quinasas TOR , Agua/química , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Dramatic improvements in mTOR-targeting selectivity were achieved by replacing morpholine in pyrazolopyrimidine inhibitors with bridged morpholines. Analogues with subnanomolar mTOR IC(50) values and up to 26000-fold selectivity versus PI3Kalpha were prepared. Chiral morpholines gave inhibitors whose enantiomers had different selectivity and potency profiles. Molecular modeling suggests that a single amino acid difference between PI3K and mTOR (Phe961Leu) accounts for the profound selectivity seen by creating a deeper pocket in mTOR that can accommodate bridged morpholines.
Asunto(s)
Morfolinas/farmacología , Proteínas Quinasas/química , Modelos Moleculares , Morfolinas/síntesis química , Morfolinas/química , Fosfatidilinositol 3-Quinasas/química , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3 , Proteínas Quinasas/metabolismo , Pirazoles/síntesis química , Pirazoles/química , Pirazoles/farmacología , Pirimidinas/síntesis química , Pirimidinas/química , Pirimidinas/farmacología , Relación Estructura-Actividad , Serina-Treonina Quinasas TORRESUMEN
The mammalian target of rapamycin (mTOR) is a central regulator of cell growth, metabolism, and angiogenesis and an emerging target in cancer research. High throughput screening (HTS) of our compound collection led to the identification of 3-(4-morpholin-4-yl-1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)phenol (5a), a modestly potent and nonselective inhibitor of mTOR and phosphoinositide 3-kinase (PI3K). Optimization of compound 5a, employing an mTOR homology model based on an X-ray crystal structure of closely related PI3Kgamma led to the discovery of 6-(1H-indol-5-yl)-4-morpholin-4-yl-1-[1-(pyridin-3-ylmethyl)piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidine (5u), a potent and selective mTOR inhibitor (mTOR IC(50) = 9 nM; PI3Kalpha IC(50) = 1962 nM). Compound 5u selectively inhibited cellular biomarker of mTORC1 (P-S6K, P-4EBP1) and mTORC2 (P-AKT S473) over the biomarker of PI3K/PDK1 (P-AKT T308) and did not inhibit PI3K-related kinases (PIKKs) in cellular assays. These pyrazolopyrimidines represent an exciting new series of mTOR-selective inhibitors with potential for development for cancer therapy.
Asunto(s)
Descubrimiento de Drogas , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Quinasas/metabolismo , Pirimidinas/farmacología , Unión Competitiva , Línea Celular Tumoral , Humanos , Concentración 50 Inhibidora , Modelos Moleculares , Conformación Molecular , Peso Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/metabolismo , Proteínas Quinasas/química , Pirimidinas/síntesis química , Pirimidinas/química , Pirimidinas/metabolismo , Transducción de Señal/efectos de los fármacos , Especificidad por Sustrato , Serina-Treonina Quinasas TORRESUMEN
The mammalian target of rapamycin (mTOR), a central regulator of growth, survival, and metabolism, is a validated target for cancer therapy. Rapamycin and its analogues, allosteric inhibitors of mTOR, only partially inhibit one mTOR protein complex. ATP-competitive, global inhibitors of mTOR that have the potential for enhanced anticancer efficacy are described. Structural features leading to potency and selectivity were identified and refined leading to compounds with in vivo efficacy in tumor xenograft models.
Asunto(s)
Adenosina Trifosfato/fisiología , Antineoplásicos/síntesis química , Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Pirazoles/síntesis química , Pirimidinas/síntesis química , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Sitios de Unión , Carbamatos/síntesis química , Carbamatos/química , Carbamatos/farmacología , Línea Celular Tumoral , Fosfatidilinositol 3-Quinasa Clase Ib , Cristalografía por Rayos X , Diseño de Fármacos , Péptidos y Proteínas de Señalización Intracelular/química , Isoenzimas/química , Ratones , Ratones Desnudos , Microsomas/metabolismo , Modelos Moleculares , Fosfatidilinositol 3-Quinasas/química , Proteínas Serina-Treonina Quinasas/química , Pirazoles/química , Pirazoles/farmacología , Pirimidinas/química , Pirimidinas/farmacología , Relación Estructura-Actividad , Serina-Treonina Quinasas TOR , Urea/análogos & derivados , Urea/síntesis química , Urea/química , Urea/farmacología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Conjugation of the phenol derived from rivastigmine with amphetamines gave access to novel carbamate cholinesterase inhibitors. All compounds possessed increased affinity and selectivity for AChE compared to rivastigmine and were orally bioavailable. Compound 4a, incorporating d-amphetamine, caused significant inhibition of cholinesterase in vivo at doses that were well tolerated. Release of amphetamine from 4a was demonstrated following in vitro and in vivo inhibition of cholinesterase. Compound 4a was also effective in alleviating scopolamine induced amnesia in a rat passive avoidance model.