RESUMEN
The diastereoselective synthesis and biological activity of piperidine-3,4-diol and piperidine-3-ol-derived pyrrolotriazine inhibitors of anaplastic lymphoma kinase (ALK) are described. Although piperidine-3,4-diol and piperidine-3-ol derivatives showed comparable in vitro ALK activity, the latter subset of inhibitors demonstrated improved physiochemical and pharmacokinetic properties. Furthermore, the stereochemistry of the C3 and C4 centers had a marked impact on the in vivo inhibition of ALK autophosphorylation. Thus, trans-4-aryl-piperidine-3-ols (22) were more potent than the cis diastereomers (20).
Asunto(s)
Antineoplásicos/química , Antineoplásicos/uso terapéutico , Linfoma Anaplásico de Células Grandes/tratamiento farmacológico , Pirroles/química , Pirroles/uso terapéutico , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Triazinas/química , Triazinas/uso terapéutico , Quinasa de Linfoma Anaplásico , Animales , Antineoplásicos/farmacocinética , Línea Celular Tumoral , Cristalografía por Rayos X , Humanos , Linfoma Anaplásico de Células Grandes/enzimología , Ratones SCID , Modelos Moleculares , Piperidinas/química , Piperidinas/farmacocinética , Piperidinas/uso terapéutico , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirroles/farmacocinética , Ratas Sprague-Dawley , Proteínas Tirosina Quinasas Receptoras/metabolismo , Triazinas/farmacocinéticaRESUMEN
A series of fused cyclopropyl-4,5-dihydropyridazin-3-one (3,4-diaza-bicyclo[4.1.0]hept-4-en-2-one) phenoxypiperidine analogs was designed and synthesized, leading to the identification of (1R,6S)-5-[4-(1-cyclobutyl-piperidin-4-yloxy)-phenyl]-3,4-diaza-bicyclo[4.1.0]hept-4-en-2-one (R,S-4a) as a second-generation pyridazin-3-one H3R antagonist. Compound R,S-4a was a potent H3R functional antagonist in vivo in the rat dipsogenia model, demonstrated potent wake activity in the rat EEG/EMG model, and enhanced short-term memory in the rat social recognition memory model at doses as low as 0.03-0.3 mg/kg po.
Asunto(s)
Nootrópicos/química , Piperidinas/química , Piridazinas/química , Receptores Histamínicos H3/química , Animales , Trastornos del Conocimiento/tratamiento farmacológico , Modelos Animales de Enfermedad , Perros , Evaluación Preclínica de Medicamentos , Agonismo Inverso de Drogas , Semivida , Haplorrinos , Memoria a Corto Plazo/efectos de los fármacos , Nootrópicos/farmacocinética , Nootrópicos/farmacología , Nootrópicos/uso terapéutico , Piperidinas/farmacocinética , Piperidinas/farmacología , Piperidinas/uso terapéutico , Piridazinas/farmacocinética , Piridazinas/farmacología , Piridazinas/uso terapéutico , Ratas , Receptores Histamínicos H3/metabolismo , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
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
A novel class of 1'-cyclobutyl-6-(4-piperidyloxy)spiro[benzopyran-2,4'-piperidine] derivatives with low nanomolar affinity for the human and rat histamine-3 receptors (H(3)Rs) are described. The spirobenzopyran piperidine ether analogs demonstrated excellent H(3)R affinity and selectivity against histamine receptor subtypes (H(1)R, H(2)R, and H(4)R), were stable in liver microsomes, and had selectivity against CYP P450 enzymes. Compounds 10, 13, 15, and 16 demonstrated high H(3)R affinity, in vitro liver microsomal stability, selectivity against CYP isoforms, moreover, these ether analogs exhibited acceptable iv pharmacokinetic (PK) properties but had poor oral exposure in rat.
Asunto(s)
Benzopiranos/síntesis química , Antagonistas de los Receptores Histamínicos/síntesis química , Piperidinas/síntesis química , Receptores Histamínicos H3/metabolismo , Compuestos de Espiro/síntesis química , Administración Oral , Animales , Benzopiranos/farmacocinética , Benzopiranos/farmacología , Sistema Enzimático del Citocromo P-450/metabolismo , Antagonistas de los Receptores Histamínicos/farmacocinética , Antagonistas de los Receptores Histamínicos/farmacología , Humanos , Inyecciones Intravenosas , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Piperidinas/farmacocinética , Piperidinas/farmacología , Ratas , Compuestos de Espiro/farmacocinética , Compuestos de Espiro/farmacología , Relación Estructura-ActividadRESUMEN
A novel class of benzocinnolinones analogs of irdabisant were designed and synthesized as histamine H3R antagonists/inverse agonists. Modifications to the pyridazinone portion of the core and linker led to the identification of molecules with excellent target potency and selectivity with improved rat pharmacokinetic properties and reduced potential hERG liabilities.
Asunto(s)
Compuestos Heterocíclicos con 3 Anillos/síntesis química , Agonistas de los Receptores Histamínicos/síntesis química , Antagonistas de los Receptores Histamínicos H3/síntesis química , Nootrópicos/síntesis química , Piridazinas/síntesis química , Pirrolidinas/síntesis química , Receptores Histamínicos H3/química , Animales , Células CHO , Membrana Celular/efectos de los fármacos , Membrana Celular/metabolismo , Cricetinae , Relación Dosis-Respuesta a Droga , Agonismo Inverso de Drogas , Compuestos Heterocíclicos con 3 Anillos/farmacología , Agonistas de los Receptores Histamínicos/farmacología , Antagonistas de los Receptores Histamínicos H3/farmacología , Estructura Molecular , Nootrópicos/farmacología , Piridazinas/farmacología , Pirrolidinas/farmacología , Ratas , Receptores Histamínicos H3/metabolismo , Relación Estructura-ActividadRESUMEN
A novel class of 4-alkoxy-[1'-cyclobutyl-spiro(3,4-dihydrobenzopyran-2,4'-piperidine)] analogues were designed and synthesized as H(3)R antagonists. Structure-activity relationship identified sulfone 27 with excellent H(3)R affinities in both humans and rats, and acceptable pharmacokinetic properties. Further, compound 28 achieved single digit nanomolar H(3)R affinities in both species with minimum hERG activity.
Asunto(s)
Antagonistas de los Receptores Histamínicos/química , Piperidinas/química , Receptores Histamínicos H3/química , Compuestos de Espiro/síntesis química , Animales , Química Farmacéutica/métodos , Diseño de Fármacos , Interacciones Farmacológicas , Canal de Potasio ERG1 , Canales de Potasio Éter-A-Go-Go/antagonistas & inhibidores , Humanos , Concentración 50 Inhibidora , Cinética , Hígado/metabolismo , Ratones , Modelos Químicos , Ratas , Compuestos de Espiro/farmacología , Relación Estructura-ActividadRESUMEN
Optimization of the R(2) and R(6) positions of (5-{4-[3-(R)-2-methylpyrrolin-1-yl-propoxy]phenyl}-2H-pyridazin-3-one) 2a with constrained phenoxypiperidines led to the identification of 5-[4-(cyclobutyl-piperidin-4-yloxy)-phenyl]-6-methyl-2H-pyridazin-3-one 8b as a potent, selective histamine H(3) receptor antagonist with favorable pharmacokinetic properties. Compound 8b had an excellent safety genotoxocity profile for a CNS-active compound in the Ames and micronucleus tests, also displayed potent H(3)R antagonist activity in the brain in the rat dipsogenia model and robust wake activity in the rat EEG/EMG model.
Asunto(s)
Piperidinas/farmacología , Piridazinas/farmacología , Receptores Histamínicos H3/química , Animales , Humanos , Estructura Molecular , Piperidinas/síntesis química , Piperidinas/química , Piridazinas/síntesis química , Piridazinas/química , Ratas , Receptores Histamínicos H3/metabolismo , Relación Estructura-ActividadRESUMEN
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
H(3)R structure-activity relationships for a new class of 4,5-dihydropyridazin-3-one H(3)R antagonists/inverse agonists are disclosed. Modification of the 4,5-dihydropyridazinone moiety to block in vivo metabolism identified 4,4-dimethyl-6-{4-[3-((R)-2-methyl-pyrrolidin-1-yl)-propoxy]-phenyl}-4,5-dihydro-2H-pyridazin-3-one 22 as a lead candidate demonstrating potent in vivo functional H(3)R antagonism in the rat dipsogenia model and robust wake promoting activity in the rat EEG/EMG model.
Asunto(s)
Agonistas de los Receptores Histamínicos/síntesis química , Piridazinas/química , Receptores Histamínicos H3/química , Animales , Área Bajo la Curva , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Electroencefalografía/métodos , Electromiografía/métodos , Agonistas de los Receptores Histamínicos/farmacología , Cinética , Modelos Químicos , Piridazinas/síntesis química , Piridazinas/farmacología , Ratas , Estereoisomerismo , Relación Estructura-Actividad , Factores de TiempoRESUMEN
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 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
Structure-activity relationships for a series of phenoxypiperidine pyridazin-3-one H(3)R antagonists/inverse agonists are disclosed. The search for compounds with improved hERG and DAT selectivity without the formation of in vivo active metabolites identified 6-[4-(1-cyclobutyl-piperidin-4-yloxy)-phenyl]-4,4-dimethyl-4,5-dihydro-2H-pyridazin-3-one 17b. Compound 17b met discovery flow criteria, demonstrated potent H(3)R functional antagonism in vivo in the rat dipsogenia model and potent wake activity in the rat EEG/EMG model at doses as low as 0.1 mg/kg ip.
Asunto(s)
Antagonistas de los Receptores Histamínicos/química , Antagonistas de los Receptores Histamínicos/farmacología , Piperidinas/química , Piridazinas/química , Receptores Histamínicos H3 , Vigilia/efectos de los fármacos , Animales , Modelos Animales de Enfermedad , Modelos Moleculares , Estructura Molecular , Piperidinas/farmacología , Piridazinas/farmacología , RatasRESUMEN
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
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
The elaboration of a novel scaffold for the inhibition of JAK2 and FAK kinases was targeted in order to provide a dual inhibitor that could target divergent pathways for tumor cell progression.
Asunto(s)
Proteína-Tirosina Quinasas de Adhesión Focal/química , Janus Quinasa 2/química , Inhibidores de Proteínas Quinasas/farmacología , Animales , Línea Celular Tumoral , Química Farmacéutica/métodos , Progresión de la Enfermedad , Diseño de Fármacos , Humanos , Concentración 50 Inhibidora , Ratones , Modelos Químicos , Mutación , Neoplasias/genética , Neoplasias/patología , Inhibidores de Proteínas Quinasas/síntesis química , Ratas , Ratas Sprague-Dawley , Transducción de Señal , Factores de TiempoRESUMEN
A novel series of 4-pyridazin-3-one and 5-pyridazin-3-one analogues were designed and synthesized as H(3)R antagonists. Structure-activity relationship revealed the 5-pyridazin-3-ones 8a and S-methyl 8b had excellent human and rat H(3)R affinities, and acceptable pharmacokinetic properties. In vivo evaluation of 8a showed potent activity in the rat dipsogenia model and robust wake-promoting activity in the rat EEG/EMG model.
Asunto(s)
Antagonistas de los Receptores Histamínicos/síntesis química , Antagonistas de los Receptores Histamínicos/farmacología , Propilaminas/farmacología , Piridazinas/farmacología , Receptores Histamínicos H3/metabolismo , Animales , Antagonistas de los Receptores Histamínicos/química , Humanos , Masculino , Datos de Secuencia Molecular , Estructura Molecular , Propilaminas/síntesis química , Propilaminas/química , Piridazinas/síntesis química , Piridazinas/química , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
There are numerous published studies establishing a link between reactive metabolite formation and toxicity of various drugs. Although the correlation between idiosyncratic reactions and reactive metabolite formation is not 1:1, the association between the two is such that many pharmaceutical companies now monitor for reactive metabolites as a standard part of drug candidate testing and selection. The most common method involves in vitro human microsomal incubations in the presence of a thiol trapping agent, such as glutathione (GSH), followed by LC/MS analysis. In this study, we describe several 2,7-disubstituted-pyrrolotriazine analogues that are extremely potent reactive metabolite precursors. Utilizing a UPLC/UV/MS method, unprecedented levels of GSH adducts were measured that are 5-10 times higher than previously reported for high reactive metabolite-forming compounds such as clozapine and troglitazone.
Asunto(s)
Química Farmacéutica , Glutatión/metabolismo , Microsomas Hepáticos/enzimología , Inhibidores de Proteínas Quinasas/metabolismo , Pirroles/metabolismo , Triazinas/metabolismo , Animales , Bilis/química , Biotransformación , Cromanos/metabolismo , Cromatografía Líquida de Alta Presión , Cromatografía Liquida , Clozapina/metabolismo , Perros , Haplorrinos , Humanos , Ratones , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/orina , Proteínas Quinasas/metabolismo , Pirroles/síntesis química , Pirroles/farmacocinética , Pirroles/orina , Ratas , Espectrometría de Masa por Ionización de Electrospray , Compuestos de Sulfhidrilo/metabolismo , Tiazolidinedionas/metabolismo , Triazinas/síntesis química , Triazinas/farmacocinética , Triazinas/orina , TroglitazonaRESUMEN
Three series of novel 4,5-fused pyridazinones were synthesized as histamine H(3) receptor antagonists. The 2,5,6,7-tetrahydrocyclopenta[d]pyridazin-1-one 5q and 5,6,7,8-tetrahydro-2H-phthalazin-1-one 5u displayed high affinity at both rat and human H(3) receptors, and showed potent antagonist and full inverse agonist activity in functional assays.
Asunto(s)
Antagonistas de los Receptores Histamínicos H3/química , Antagonistas de los Receptores Histamínicos H3/farmacología , Piridazinas/química , Piridazinas/farmacología , Receptores Histamínicos H3/metabolismo , Animales , Antagonistas de los Receptores Histamínicos H3/farmacocinética , Humanos , Piridazinas/farmacocinética , Ratas , Relación Estructura-ActividadRESUMEN
6-{4-[3-(R)-2-Methylpyrrolidin-1-yl)propoxy]-phenyl}-2H-pyridazin-3-one 6 (Irdabisant; CEP-26401) was recently reported as a potent H(3)R antagonist with excellent drug-like properties and in vivo activity that advanced into clinical evaluation. A series of pyridone analogs of 6 was synthesized and evaluated as H(3)R antagonists. Structure-activity relationships revealed that the 5-pyridone regiomer was optimal for H(3)R affinity. N-Methyl 9b showed excellent H(3)R affinity, acceptable pharmacokinetics and pharmaceutical properties. In vivo evaluation of 9b showed potent activity in the rat dipsogenia model and robust wake-promoting activity in the rat EEG model.
Asunto(s)
Antagonistas de los Receptores Histamínicos H3/síntesis química , Antagonistas de los Receptores Histamínicos H3/farmacología , Piridazinas/síntesis química , Piridazinas/farmacología , Pirrolidinas/síntesis química , Pirrolidinas/farmacología , Animales , Modelos Animales de Enfermedad , Antagonistas de los Receptores Histamínicos H3/química , Humanos , Estructura Molecular , Unión Proteica/efectos de los fármacos , Piridazinas/química , Pirrolidinas/química , Ratas , Relación Estructura-ActividadRESUMEN
The incorporation of R,R-1,2-diaminocyclohexane at C4 in a series of 2,4-diaminopyrimidines led to a number of ALK inhibitors in which optimized activity was achieved by conversion of the 2-amino group into a methanesulfonamide. Tumor growth inhibition was observed when an orally bioavailable analog was evaluated in a Karpas-299 tumor xenograft mouse model.