RESUMEN
CEP-32215 is a new, potent, selective, and orally bioavailable inverse agonist of the histamine H3 receptor (H3R) with drug-like properties. High affinity in human (hH3R Ki = 2.0 ± 0.2 nM) and rat (rH3R Ki = 3.6 ± 0.7 nM) H3R radioligand binding assays was demonstrated. Potent functional antagonism (Kb = 0.3 ± 0.1 nM) and inverse agonism (EC50 = 0.6 ± 0.2 nM) were demonstrated in [(35)S]guanosine 5(')-O-(γ-thio)-triphosphate binding assays. Oral bioavailability and dose-related exposure was consistent among rat, dog, and monkey. After oral dosing, occupancy of H3R by CEP-32215 was estimated by the inhibition of ex vivo binding in rat cortical slices (ED50 = 0.1 mg/kg p.o.). Functional antagonism in brain was demonstrated by the inhibition of R-α-methylhistamine-induced drinking in the rat dipsogenia model (ED50 = 0.92 mg/kg). CEP-32215 significantly increased wake duration in the rat EEG model at 3-30 mg/kg p.o. Increased motor activity, sleep rebound or undesirable events (such as spike wave or seizure activity) was not observed following doses up to 100 mg/kg p.o., indicating an acceptable therapeutic index. CEP-32215 may have potential utility in the treatment of a variety of sleep disorders. This article is part of the Special Issue entitled 'Histamine Receptors'.
Asunto(s)
Agonismo Inverso de Drogas , Antagonistas de los Receptores Histamínicos H3/farmacología , Piperidinas/farmacología , Pirazinas/farmacología , Compuestos de Espiro/farmacología , Vigilia/efectos de los fármacos , Administración Oral , Animales , Disponibilidad Biológica , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Perros , Ingestión de Líquidos/efectos de los fármacos , Ingestión de Líquidos/fisiología , Evaluación Preclínica de Medicamentos , Agonistas de los Receptores Histamínicos/farmacología , Antagonistas de los Receptores Histamínicos H3/farmacocinética , Humanos , Macaca fascicularis , Masculino , Metilhistaminas/farmacología , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Piperidinas/farmacocinética , Pirazinas/farmacocinética , Ratas Sprague-Dawley , Receptores Histamínicos H3/metabolismo , Sueño/efectos de los fármacos , Sueño/fisiología , Compuestos de Espiro/farmacocinética , Vigilia/fisiologíaRESUMEN
In search of a next generation molecule to the novel wake-promoting agent modafinil, a series of aryl-heteroayl-derived wakefulness enhancing agents (in rats) was developed. From this work, compound 16 was separated into its enantiomers to profile them individually.
Asunto(s)
Compuestos de Bencidrilo/química , Estimulantes del Sistema Nervioso Central/química , Sulfóxidos/química , Tiofenos/química , Animales , Área Bajo la Curva , Compuestos de Bencidrilo/síntesis química , Compuestos de Bencidrilo/farmacocinética , Estimulantes del Sistema Nervioso Central/síntesis química , Estimulantes del Sistema Nervioso Central/farmacocinética , Inhibidores Enzimáticos del Citocromo P-450 , Sistema Enzimático del Citocromo P-450/metabolismo , Semivida , Modafinilo , Unión Proteica , Ratas , Estereoisomerismo , Relación Estructura-Actividad , Sulfóxidos/síntesis química , Sulfóxidos/farmacocinética , Simportadores/química , Simportadores/metabolismo , Tiofenos/síntesis química , Tiofenos/farmacocinética , Vigilia/efectos de los fármacosRESUMEN
Utilizing atypical wake-promoting agent modafinil (inactive in both rH(3) and hH(3) binding assays) as a launching pad, a series of sulfinyl- and sulfone-derived H(3) receptor inverse agonists were developed. Brain-permeable compound 27, a potent member of the series displayed excellent selectivity against related family members (H(1), H(2), and H(4) receptors).
Asunto(s)
Compuestos de Bencidrilo/química , Pirrolidinas/química , Receptores Histamínicos H3/química , Sulfonas/química , Administración Oral , Animales , Compuestos de Bencidrilo/agonistas , Compuestos de Bencidrilo/farmacocinética , Estimulantes del Sistema Nervioso Central/agonistas , Estimulantes del Sistema Nervioso Central/química , Estimulantes del Sistema Nervioso Central/farmacocinética , Agonismo Inverso de Drogas , Semivida , Cinética , Modafinilo , Unión Proteica , Pirrolidinas/agonistas , Pirrolidinas/farmacocinética , Ratas , Receptores Histamínicos H3/metabolismo , Relación Estructura-Actividad , Sulfonas/agonistas , Sulfonas/farmacocinética , Vigilia/efectos de los fármacosRESUMEN
In search of a next generation molecule to the novel wake promoting agent modafinil, a series of diphenyl ether derived wakefulness enhancing agents (in rat) was developed. From this work, racemic compound 16 was separated into its chiral enantiomers to profile them individually.
Asunto(s)
Compuestos de Bencidrilo/farmacología , Vigilia/efectos de los fármacos , Animales , Compuestos de Bencidrilo/química , Inhibidores Enzimáticos del Citocromo P-450 , Descubrimiento de Drogas , Humanos , Modafinilo , RatasRESUMEN
In searching for a next generation molecule to the novel wake promoting agent modafinil (compound 1), a series of fluorene-derived wakefulness enhancing agents were developed and evaluated in rat. Extensive pharmacokinetic studies of a potent member of the series (compound 15) revealed that the wake promotion activity of the analog was likely due to an active metabolite (compound 3).
Asunto(s)
Compuestos de Bencidrilo/química , Fluorenos/química , Fármacos Neuroprotectores/química , Sulfóxidos/química , Animales , Compuestos de Bencidrilo/síntesis química , Compuestos de Bencidrilo/farmacocinética , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Fluorenos/síntesis química , Fluorenos/farmacocinética , Inyecciones Intraperitoneales , Modafinilo , Fármacos Neuroprotectores/síntesis química , Fármacos Neuroprotectores/farmacocinética , Ratas , Sulfóxidos/síntesis química , Sulfóxidos/farmacocinéticaRESUMEN
Optimization of a series of aminomethyl ketone diamine H(3)R antagonists to reduce the brain exposure by lowering the pKa, led to molecules with improved pharmacokinetic properties. Compounds 9, 19, and 25 had high affinity for human H(3)R and demonstrated in vivo H(3)R functional activity in the rat dipsogenia model. Compound 9 displayed modest wake-promoting activity in the rat EEG/EMG model.
Asunto(s)
Agonismo Inverso de Drogas , Agonistas de los Receptores Histamínicos , Cetonas/química , Vigilia/efectos de los fármacos , 1-Propanol/química , 1-Propanol/farmacología , Animales , Agonistas de los Receptores Histamínicos/química , Agonistas de los Receptores Histamínicos/farmacología , Humanos , Cetonas/farmacología , Metilaminas/química , Metilaminas/farmacología , Fenoles/química , Fenoles/farmacología , Pirrolidinas/química , Pirrolidinas/farmacología , Ratas , Trastornos del Sueño del Ritmo Circadiano/tratamiento farmacológicoRESUMEN
Structure-activity relationship on a novel ketone class of H(3)R antagonists/inverse agonists is disclosed. Compound 4 showed excellent target potency, selectivity and brain penetration. Evaluation of antagonist 4 in the rat EEG/EMG model demonstrated robust wake activity thereby establishing preclinical proof of concept.
Asunto(s)
Agonistas de los Receptores Histamínicos/farmacología , Cetonas/química , Morfolinas/química , Receptores Histamínicos H3 , Vigilia/efectos de los fármacos , Animales , Electroencefalografía , Agonistas de los Receptores Histamínicos/química , Humanos , Cetonas/farmacología , Masculino , Estructura Molecular , Morfolinas/farmacología , Ratas , Relación Estructura-ActividadRESUMEN
In search of a next generation molecule to modafinil, a novel wake promoting agent, we previously disclosed bi-phenyl derived racemate compound (±)-2 as a new generation of wake-promoting agent. Here we describe the profiles of the individual enantiomers (-)-2 and (+)-2, respectively.
Asunto(s)
Compuestos de Bifenilo/síntesis química , Estimulantes del Sistema Nervioso Central/síntesis química , Vigilia/efectos de los fármacos , Animales , Área Bajo la Curva , Compuestos de Bifenilo/farmacocinética , Compuestos de Bifenilo/farmacología , Estimulantes del Sistema Nervioso Central/farmacocinética , Estimulantes del Sistema Nervioso Central/farmacología , Inhibidores Enzimáticos del Citocromo P-450 , Sistema Enzimático del Citocromo P-450/metabolismo , Electroencefalografía , Inyecciones Intraperitoneales , Actividad Motora/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Ácido Retinoico 4-Hidroxilasa , Sueño/efectos de los fármacos , Estereoisomerismo , Relación Estructura-Actividad , Vigilia/fisiologíaRESUMEN
Serotoninergic neurotransmission has been implicated in modulation of learning and memory. It has been demonstrated that 5-hydroxytryptamine(6) (5-HT(6)) receptor antagonists show beneficial effect on cognition in several animal models. Based on a pharmacophore model reported in the literature, we have designed and successfully identified a 7-benzenesulfonyl-1,2,3,4-tetrahydro-benzo[4,5]furo[2,3-c]pyridine (3a) scaffold as a novel class of 5-HT(6) receptor antagonists. Despite good activity against 5-HT(6) receptor, 3a exhibited poor liver microsome stability in mouse, rat and dog. It was demonstrated that the saturation of the double bond of the tetrahydropyridine ring of 3a enhanced metabolic stability. However the resulting compound, 4a (7-phenylsulfonyl-1,2,3,4,4a,9a-hexahydro-benzo[4,5]furo[2,3-c] pyridine-HCl salt) exhibited â¼30-fold loss in potency along with introduction of two chiral centers. In our optimization process for this series, we found that substituents at the 2 or 3 positions on the distal aryl group are important for enhancing activity against 5-HT(6). Separation of enantiomers and subsequent optimization and SAR with bis substituted phenyl sulfone provided potent 5-HT(6) antagonists with improved PK profiles in rat. A potent, selective 5-HT(6)R antagonist (15k) was identified from this study which showed good oral bioavailability (F=39%) in rat with brain penetration (B/P=2.76) and in vivo activity in a rat social recognition test.
Asunto(s)
Encéfalo/efectos de los fármacos , Compuestos Heterocíclicos con 3 Anillos/química , Compuestos Heterocíclicos con 3 Anillos/farmacología , Antagonistas de la Serotonina/química , Antagonistas de la Serotonina/farmacología , Sulfonas/química , Sulfonas/farmacología , Animales , Perros , Humanos , Concentración 50 Inhibidora , Ratones , Microsomas Hepáticos/efectos de los fármacos , Estructura Molecular , Ratas , Receptores de Serotonina , Antagonistas de la Serotonina/farmacocinética , EstereoisomerismoRESUMEN
In search of a next generation molecule to the novel wake promoting agent modafinil, a series of bi-phenyl derived wakefulness enhancing agents (in rat) was developed. From this work, compound 17 has been selected for additional studies.
Asunto(s)
Compuestos de Bencidrilo/síntesis química , Compuestos de Bifenilo/síntesis química , Estimulantes del Sistema Nervioso Central/síntesis química , Vigilia/efectos de los fármacos , Animales , Área Bajo la Curva , Compuestos de Bencidrilo/farmacocinética , Compuestos de Bencidrilo/farmacología , Compuestos de Bifenilo/farmacocinética , Compuestos de Bifenilo/farmacología , Estimulantes del Sistema Nervioso Central/farmacocinética , Estimulantes del Sistema Nervioso Central/farmacología , Electroencefalografía , Inyecciones Intraperitoneales , Masculino , Modafinilo , Actividad Motora/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Sueño/efectos de los fármacos , Estereoisomerismo , Relación Estructura-Actividad , Vigilia/fisiologíaRESUMEN
CEP-26401 [irdabisant; 6-{4-[3-((R)-2-methyl-pyrrolidin-1-yl)-propoxy]-phenyl}-2H-pyridazin-3-one HCl] is a novel, potent histamine H3 receptor (H3R) antagonist/inverse agonist with drug-like properties. High affinity of CEP-26401 for H3R was demonstrated in radioligand binding displacement assays in rat brain membranes (K(i) = 2.7 ± 0.3 nM) and recombinant rat and human H3R-expressing systems (K(i) = 7.2 ± 0.4 and 2.0 ± 1.0 nM, respectively). CEP-26401 displayed potent antagonist and inverse agonist activities in [³5S]guanosine 5'-O-(γ-thio)triphosphate binding assays. After oral dosing of CEP-26401, occupancy of H3R was estimated by the inhibition of ex vivo binding in rat cortical slices (OCC50 = 0.1 ± 0.003 mg/kg), and antagonism of the H3R agonist R-α-methylhistamine- induced drinking response in the rat dipsogenia model was demonstrated in a similar dose range (ED50 = 0.06 mg/kg). CEP-26401 improved performance in the rat social recognition model of short-term memory at doses of 0.01 to 0.1 mg/kg p.o. and was wake-promoting at 3 to 30 mg/kg p.o. In DBA/2NCrl mice, CEP-26401 at 10 and 30 mg/kg i.p. increased prepulse inhibition (PPI), whereas the antipsychotic risperidone was effective at 0.3 and 1 mg/kg i.p. Coadministration of CEP-26401 and risperidone at subefficacious doses (3 and 0.1 mg/kg i.p., respectively) increased PPI. These results demonstrate potent behavioral effects of CEP-26401 in rodent models and suggest that this novel H3R antagonist may have therapeutic utility in the treatment of cognitive and attentional disorders. CEP-26401 may also have therapeutic utility in treating schizophrenia or as adjunctive therapy to approved antipsychotics.
Asunto(s)
Cognición/efectos de los fármacos , Antagonistas de los Receptores Histamínicos H3/farmacología , Nootrópicos , Piridazinas/farmacología , Pirrolidinas/farmacología , Vigilia/efectos de los fármacos , Animales , Autorradiografía , Conducta Animal/efectos de los fármacos , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , ADN Complementario/biosíntesis , ADN Complementario/genética , Relación Dosis-Respuesta a Droga , Ingestión de Líquidos/efectos de los fármacos , Electroencefalografía/efectos de los fármacos , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Masculino , Memoria a Corto Plazo/efectos de los fármacos , Ensayo de Unión Radioligante , Ratas , Ratas Long-Evans , Ratas Sprague-Dawley , Reconocimiento en Psicología/efectos de los fármacos , Reflejo de Sobresalto/efectos de los fármacos , Sueño/efectos de los fármacos , Conducta SocialRESUMEN
7-Arylsulfonyl substituted benzofuropiperidine was discovered as a novel scaffold for 5HT(6) receptor antagonists. Optimization by substitution at C-1 position led to identification of selective, orally bioavailable, brain penetrant antagonists with reduced hERG liability. An advanced analog tested in rat social recognition model showed significant activity suggesting potential utility in the enhancement of short-term memory.
Asunto(s)
Benzofuranos/química , Piperidinas/química , Receptores de Serotonina/química , Antagonistas de la Serotonina/farmacología , Animales , Encéfalo/embriología , Encéfalo/metabolismo , Canal de Potasio ERG1 , Canales de Potasio Éter-A-Go-Go/metabolismo , Humanos , Concentración 50 Inhibidora , Cinética , Memoria a Corto Plazo/efectos de los fármacos , Modelos Químicos , Ratas , Esquizofrenia/tratamiento farmacológico , Relación Estructura-ActividadRESUMEN
A substantial body of evidence supports the utility of antiangiogenesis inhibitors as a strategy to block or attenuate tumor-induced angiogenesis and inhibition of primary and metastatic tumor growth in a variety of solid and hematopoietic tumors. Given the requirement of tumors for different cytokine and growth factors at distinct stages of their growth and dissemination, optimal antiangiogenic therapy necessitates inhibition of multiple, complementary, and nonredundant angiogenic targets. 11-(2-Methylpropyl)-12,13-dihydro-2-methyl-8-(pyrimidin-2-ylamino)-4H-indazolo[5,4-a]pyrrolo[3,4-c]carbazol-4-one (11b, CEP-11981) is a potent orally active inhibitor of multiple targets (TIE-2, VEGF-R1, 2, and 3, and FGF-R1) having essential and nonredundant roles in tumor angiogenesis and vascular maintenance. Outlined in this article are the design strategy, synthesis, and biochemical and pharmacological profile for 11b, which completed Phase I clinical assessing safety and pharmacokinetics allowing for the initiation of proof of concept studies.
Asunto(s)
Inhibidores de la Angiogénesis/síntesis química , Carbazoles/síntesis química , Indazoles/síntesis química , Receptor TIE-2/antagonistas & inhibidores , Receptores de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Administración Oral , Inhibidores de la Angiogénesis/farmacocinética , Inhibidores de la Angiogénesis/farmacología , Animales , Disponibilidad Biológica , Carbazoles/farmacocinética , Carbazoles/farmacología , Humanos , Indazoles/farmacocinética , Indazoles/farmacología , Macaca fascicularis , Masculino , Ratones , Ratones Desnudos , Modelos Moleculares , Neovascularización Fisiológica/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/antagonistas & inhibidores , Receptor TIE-2/química , Proteínas Recombinantes/antagonistas & inhibidores , Proteínas Recombinantes/química , Relación Estructura-Actividad , Receptor 1 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Receptor 2 de Factores de Crecimiento Endotelial Vascular/química , Receptor 3 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
H(3)R structure-activity relationships on a novel class of pyridazin-3-one H(3)R antagonists/inverse agonists are disclosed. Modifications of the pyridazinone core, central phenyl ring and linker led to the identification of molecules with excellent target potency, selectivity and pharmacokinetic properties. Compounds 13 and 21 displayed potent functional H(3)R antagonism in vivo in the rat dipsogenia model and demonstrated robust wake activity in the rat EEG/EMG model.
Asunto(s)
Ingestión de Líquidos/efectos de los fármacos , Agonistas de los Receptores Histamínicos/farmacología , Piridazinas/farmacología , Vigilia/efectos de los fármacos , Animales , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Agonistas de los Receptores Histamínicos/síntesis química , Agonistas de los Receptores Histamínicos/química , Humanos , Masculino , Estructura Molecular , Piridazinas/síntesis química , Piridazinas/química , Ratas , Receptores Histamínicos H3/metabolismo , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Optimization of a novel series of pyridazin-3-one histamine H(3) receptor (H(3)R) antagonists/inverse agonists identified 6-{4-[3-(R)-2-methylpyrrolidin-1-yl)propoxy]phenyl}-2H-pyridazin-3-one (8a, CEP-26401; irdabisant) as a lead candidate for potential use in the treatment of attentional and cognitive disorders. 8a had high affinity for both human (K(i) = 2.0 nM) and rat (K(i) = 7.2 nM) H(3)Rs with greater than 1000-fold selectivity over the hH(1)R, hH(2)R, and hH(4)R histamine receptor subtypes and against an in vitro panel of 418 G-protein-coupled receptors, ion channels, transporters, and enzymes. 8a demonstrated ideal pharmaceutical properties for a CNS drug in regard to water solubility, permeability and lipophilicity and had low binding to human plasma proteins. It weakly inhibited recombinant cytochrome P450 isoforms and human ether-a-go-go-related gene. 8a metabolism was minimal in rat, mouse, dog, and human liver microsomes, and it had good interspecies pharmacokinetic properties. 8a dose-dependently inhibited H(3)R agonist-induced dipsogenia in the rat (ED(50) = 0.06 mg/kg po). On the basis of its pharmacological, pharmaceutical, and safety profiles, 8a was selected for preclinical development. The clinical portions of the single and multiple ascending dose studies assessing safety and pharmacokinetics have been completed allowing for the initiation of a phase IIa for proof of concept.
Asunto(s)
Antagonistas de los Receptores Histamínicos/síntesis química , Piridazinas/síntesis química , Pirrolidinas/síntesis química , Receptores Histamínicos H3/metabolismo , Animales , Disponibilidad Biológica , Encéfalo/metabolismo , Cristalografía por Rayos X , Perros , Agonismo Inverso de Drogas , Antagonistas de los Receptores Histamínicos/farmacología , Antagonistas de los Receptores Histamínicos/toxicidad , Humanos , Técnicas In Vitro , Macaca fascicularis , Masculino , Ratones , Microsomas Hepáticos/metabolismo , Permeabilidad , Piridazinas/farmacología , Piridazinas/toxicidad , Pirrolidinas/farmacología , Pirrolidinas/toxicidad , Ratas , Ratas Sprague-Dawley , Solubilidad , Estereoisomerismo , Relación Estructura-Actividad , Distribución TisularRESUMEN
Fused dihydroindazolopyrrolocarbazole oximes have been identified as low nanomolar, potent dual TIE-2 and VEGF-R2 receptor tyrosine kinase inhibitors with excellent cellular potency. Development of the structure-activity relationships (SAR) led to identification of compounds 35 and 40 as potent, selective dual TIE-2/VEGF-R2 inhibitors with favorable pharmacokinetic properties. Compound 35 was orally active in tumor models with no observed toxicity.
Asunto(s)
Diseño de Fármacos , Melanoma Experimental/tratamiento farmacológico , Oximas/síntesis química , Oximas/farmacología , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Receptor TIE-2/antagonistas & inhibidores , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Administración Oral , Inhibidores de la Angiogénesis/síntesis química , Inhibidores de la Angiogénesis/farmacocinética , Inhibidores de la Angiogénesis/farmacología , Animales , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Endotelio Vascular/citología , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/metabolismo , Hemangiosarcoma/irrigación sanguínea , Hemangiosarcoma/tratamiento farmacológico , Hemangiosarcoma/enzimología , Humanos , Melanoma Experimental/sangre , Melanoma Experimental/irrigación sanguínea , Melanoma Experimental/enzimología , Estructura Molecular , Neovascularización Patológica , Oximas/farmacocinética , Inhibidores de Proteínas Quinasas/farmacocinética , Ratas , Receptor TIE-2/metabolismo , Relación Estructura-Actividad , Venas Umbilicales , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismoRESUMEN
KDR kinase inhibition is considered to play an important role in regulating angiogenesis, which is vital for the survival and proliferation of tumor cells. Recently we disclosed a structure-based kinase inhibitor design strategy which led to the identification of a new class of VEGFR-2/KDR kinase inhibitors bearing heterocyclic substituted pyrazolones as the core template. Instability in a rat S9 preparation and poor iv PK profiles for most of these inhibitors necessitated exploration of new pyrazolones to identify new analogs with improved metabolic stability. Optimization of the heterocyclic moiety led to the identification of the thiadiazole series of pyrazolones (D) as potent VEGFR-2/KDR kinase inhibitors. SAR modifications, kinase selectivity profiling, and structural elements for improved PK properties were explored. Oral bioavailability up to 29% was achieved in the rat. Modeling results based on the Glide XP docking approach supported our postulation regarding the interaction of the lactam segment of the pyrazolones with the hinge region of the KDR kinase.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Pirazolonas/síntesis química , Pirazolonas/farmacología , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Animales , Autorradiografía , Disponibilidad Biológica , Western Blotting , Diseño de Fármacos , Inhibidores Enzimáticos/farmacocinética , Humanos , Técnicas In Vitro , Modelos Moleculares , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/farmacología , Pirazolonas/farmacocinética , Ratas , Proteínas Recombinantes , Espectrometría de Fluorescencia , Relación Estructura-ActividadRESUMEN
Structural analysis of the essential binding elements of the oxindole-based kinase inhibitor (1) led to the identification of a novel class of heterocyclic-substituted pyrazolones. Knoevenagel condensation of a variety of activated methylene nucleophiles with indole or pyrrole carboxaldehydes provided a focused library of molecules, each containing elements of kinase pharmacophore probe. Initial screening for VEGFR-2 kinase inhibition eliminated several of the probes. Identification of an active pyrazolone motif and further optimization resulted in several highly potent VEGFR-2 inhibitors with cellular efficacy, anti-angiogenic activity ex vivo in rat aortic ring explant cultures, and oral anti-tumor efficacy in nude mice.