RESUMEN
HIV integrase strand transfer inhibitors (InSTIs) represent an important class of antiviral therapeutics with proven efficacy and excellent tolerability for the treatment of HIV infections. In 2007, Raltegravir became the first marketed strand transfer inhibitor pioneering the way to a first-line therapy for treatment-naïve patients. Challenges with this class of therapeutics remain, including frequency of the dosing regimen and the genetic barrier to resistance. To address these issues, research towards next-generation integrase inhibitors has focused on imparting potency against RAL-resistent mutants and improving pharmacokinetic profiles. Herein, we detail medicinal chemistry efforts on a novel class of 2-pyridinone aminal InSTIs, inpsired by MK-0536, which led to the discovery of important lead molecules for our program. Systematic optimization carried out at the amide and aminal positions on the periphery of the core provided the necessary balance of antiviral activity and physiochemical properties. These efforts led to a novel aminal lead compound with the desired virological profile and preclinical pharmacokinetic profile to support a once-daily human dose prediction.
Asunto(s)
Inhibidores de Integrasa VIH/química , Inhibidores de Integrasa VIH/farmacología , Integrasa de VIH/metabolismo , VIH-1/enzimología , Piridonas/química , Piridonas/farmacología , Animales , Perros , Infecciones por VIH/tratamiento farmacológico , Inhibidores de Integrasa VIH/farmacocinética , VIH-1/efectos de los fármacos , Humanos , Simulación del Acoplamiento Molecular , Piridonas/farmacocinéticaRESUMEN
Herein, we present the identification of a novel class of pyrazolopyrimidine phosphodiesterase 10A (PDE10A) inhibitors. Beginning with a lead molecule (1) identified through a fragment-based drug discovery (FBDD) effort, lead optimization was enabled by rational design, X-ray crystallography, metabolic and off-target profiling, and fragment scaffold-hopping. We highlight the discovery of PyP-1, a potent, highly selective, and orally bioavailable pyrazolopyrimidine inhibitor of PDE10A. PyP-1 exhibits sub-nanomolar potency (PDE10A Ki=0.23nM), excellent pharmacokinetic (PK) and physicochemical properties, and a clean off-target profile. It displays dose-dependent efficacy in numerous pharmacodynamic (PD) assays that measure potential for anti-psychotic activity and cognitive improvement. PyP-1 also has a clean preclinical profile with respect to cataleptic potential in rats, prolactin secretion, and weight gain, common adverse events associated with currently marketed therapeutics. Further, PyP-1 displays in vivo preclinical target engagement as measured by PET enzyme occupancy in concert with [(11)C]MK-8193, a novel PDE10A PET tracer.
Asunto(s)
Descubrimiento de Drogas , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Inhibidores de Fosfodiesterasa/farmacología , Hidrolasas Diéster Fosfóricas/metabolismo , Esquizofrenia/tratamiento farmacológico , Animales , Cristalografía por Rayos X , Perros , Relación Dosis-Respuesta a Droga , Compuestos Heterocíclicos de 4 o más Anillos/síntesis química , Compuestos Heterocíclicos de 4 o más Anillos/química , Humanos , Macaca mulatta , Modelos Moleculares , Estructura Molecular , Inhibidores de Fosfodiesterasa/síntesis química , Inhibidores de Fosfodiesterasa/química , Ratas , Ratas Wistar , Esquizofrenia/enzimología , Relación Estructura-ActividadRESUMEN
Orexin receptor antagonists have demonstrated clinical utility for the treatment of insomnia. The majority of clinical efforts to date have focused on the development of dual orexin receptor antagonists (DORAs), small molecules that antagonize both the orexin 1 and orexin 2 receptors. Our group has recently disclosed medicinal chemistry efforts to identify highly potent, orally bioavailable selective orexin 2 receptor antagonists (2-SORAs) that possess acceptable profiles for clinical development. Herein we report additional SAR studies within the 'triaryl' amide 2-SORA series focused on improvements in compound stability in acidic media and time-dependent inhibition of CYP3A4. These studies resulted in the discovery of 2,5-disubstituted isonicotinamide 2-SORAs such as compound 24 that demonstrated improved stability and TDI profiles as well as excellent sleep efficacy across species.
Asunto(s)
Descubrimiento de Drogas , Antagonistas de los Receptores de Orexina , Piridinas/farmacología , Trastornos del Inicio y del Mantenimiento del Sueño/tratamiento farmacológico , Tiazoles/farmacología , Animales , Perros , Relación Dosis-Respuesta a Droga , Humanos , Ratones , Estructura Molecular , Piridinas/síntesis química , Piridinas/química , Ratas , Relación Estructura-Actividad , Tiazoles/síntesis química , Tiazoles/químicaRESUMEN
Dual Orexin Receptor Antagonists (DORA) bind to both the Orexin 1 and 2 receptors. High resolution crystal structures of the Orexin 1 and 2 receptors, both class A GPCRs, were not available at the time of this study, and thus, ligand-based analyses were invoked and successfully applied to the design of DORAs. Computational analysis, ligand based superposition, unbound small-molecule X-ray crystal structures and NMR analysis were utilized to understand the conformational preferences of key DORAs and excellent agreement between these orthogonal approaches was seen in the majority of compounds examined. The predominantly face-to-face (F2F) interaction observed between the distal aromatic rings was the core 3D shape motif in our design principle and was used in the development of compounds. A notable exception, however, was seen between computation and experiment for suvorexant where the molecule exhibits an extended conformation in the unbound small-molecule X-ray structure. Even taking into account solvation effects explicitly in our calculations, we nevertheless find support that the F2F conformation is the bioactive conformation. Using a dominant states approximation for the partition function, we made a comprehensive assessment of the free energies required to adopt both an extended and a F2F conformation of a number of DORAs. Interestingly, we find that only a F2F conformation is consistent with the activities reported.
Asunto(s)
Azepinas/química , Cristalografía por Rayos X , Receptores de Orexina/química , Triazoles/química , Humanos , Ligandos , Espectroscopía de Resonancia Magnética , Conformación Molecular , Estructura Molecular , Antagonistas de los Receptores de OrexinaRESUMEN
As SARS-CoV-2 continues to circulate, antiviral treatments are needed to complement vaccines. The virus's main protease, 3CLPro, is an attractive drug target in part because it recognizes a unique cleavage site, which features a glutamine residue at the P1 position and is not utilized by human proteases. Herein, we report the invention of MK-7845, a novel reversible covalent 3CLPro inhibitor. While most covalent inhibitors of SARS-CoV-2 3CLPro reported to date contain an amide as a Gln mimic at P1, MK-7845 bears a difluorobutyl substituent at this position. SAR analysis and X-ray crystallographic studies indicate that this group interacts with His163, the same residue that forms a hydrogen bond with the amide substituents typically found at P1. In addition to promising in vivo efficacy and an acceptable projected human dose with unboosted pharmacokinetics, MK-7845 exhibits favorable properties for both solubility and absorption that may be attributable to the unusual difluorobutyl substituent.
Asunto(s)
COVID-19 , Glutamina , Humanos , Glutamina/química , SARS-CoV-2 , Cisteína Endopeptidasas/química , Invenciones , Inhibidores de Proteasas/farmacología , Amidas , Antivirales/farmacología , Antivirales/químicaRESUMEN
We describe the discovery of potent and orally bioavailable tetrahydropyridopyrimidine inhibitors of phosphodiesterase 10A by systematic optimization of a novel HTS lead. Lead compound THPP-1 exhibits nanomolar potencies, excellent pharmacokinetic properties, and a clean off-target profile. It displays in vivo target engagement as measured by increased rat striatal cGMP levels upon oral dosing. It shows dose-dependent efficacy in a key pharmacodynamic assay predictive of antipsychotic activity, the psychostimulant-induced rat hyperlocomotion assay. Further, THPP-1 displays significantly fewer preclinical adverse events in assays measuring prolactin secretion, catalepsy, and weight gain, in contrast to the typical and atypical antipsychotics haloperidol and olanzapine.
Asunto(s)
Descubrimiento de Drogas , Inhibidores de Fosfodiesterasa/uso terapéutico , Piridinas/farmacología , Pirimidinas/farmacología , Esquizofrenia/tratamiento farmacológico , Administración Oral , Animales , GMP Cíclico/análisis , Relación Dosis-Respuesta a Droga , Humanos , Estructura Molecular , Inhibidores de Fosfodiesterasa/administración & dosificación , Inhibidores de Fosfodiesterasa/química , Hidrolasas Diéster Fosfóricas/metabolismo , Piridinas/administración & dosificación , Piridinas/química , Pirimidinas/administración & dosificación , Pirimidinas/química , Ratas , Relación Estructura-ActividadRESUMEN
A robust and general catalyst system facilitates the alkoxylation of activated heteroaryl halides with primary, secondary, and select tertiary alcohols without the need for an excess of either coupling partner. This catalyst system displays broad functional-group tolerance and excellent regioselectivity, and is insensitive to the order of reagent addition.
Asunto(s)
Alcoholes/química , Halógenos/química , Compuestos Heterocíclicos/química , Carbono/química , Catálisis , Cobre/química , Oxígeno/química , Paladio/química , EstereoisomerismoRESUMEN
Orexins are neuropeptides that regulate wakefulness and arousal. Small molecule antagonists of orexin receptors may provide a novel therapy for the treatment of insomnia and other sleep disorders. In this Letter we describe the design and synthesis of conformationally constrained N,N-disubstituted 1,4-diazepanes as orexin receptor antagonists. The design of these constrained analogs was guided by an understanding of the preferred solution and solid state conformation of the diazepane central ring.
Asunto(s)
Azepinas/química , Azepinas/farmacología , Receptores Acoplados a Proteínas G/antagonistas & inhibidores , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Neuropéptido/antagonistas & inhibidores , Receptores de Neuropéptido/metabolismo , Animales , Azepinas/síntesis química , Azepinas/farmacocinética , Cristalografía por Rayos X , Perros , Humanos , Modelos Moleculares , Receptores de Orexina , Ratas , Ratas Sprague-Dawley , Trastornos del Sueño-Vigilia/tratamiento farmacológicoRESUMEN
Orexins are excitatory neuropeptides that regulate arousal and sleep. Orexin receptor antagonists promote sleep and offer potential as a new therapy for the treatment of insomnia. In this Letter, we describe the synthesis of constrained diazepanes having a 3,9 diazabicyclo[4.2.1]nonane bicyclic core with good oral bioavailability and sleep-promoting activity in a rat EEG model.
Asunto(s)
Alcanos/farmacología , Descubrimiento de Drogas , Hipnóticos y Sedantes/farmacología , Receptores Acoplados a Proteínas G/antagonistas & inhibidores , Receptores de Neuropéptido/antagonistas & inhibidores , Alcanos/química , Alcanos/farmacocinética , Animales , Compuestos Aza/química , Compuestos Aza/farmacocinética , Compuestos Aza/farmacología , Disponibilidad Biológica , Compuestos Bicíclicos con Puentes/química , Compuestos Bicíclicos con Puentes/farmacocinética , Compuestos Bicíclicos con Puentes/farmacología , Electroencefalografía , Hipnóticos y Sedantes/química , Hipnóticos y Sedantes/farmacocinética , Receptores de Orexina , Ratas , Ratas Sprague-DawleyRESUMEN
The search for new molecular constructs that resemble the critical two-metal binding pharmacophore required for HIV integrase strand transfer inhibition represents a vibrant area of research within drug discovery. Here we present the discovery of a new class of HIV integrase strand transfer inhibitors based on the 2-pyridinone core of MK-0536. These efforts led to the identification of two lead compounds with excellent antiviral activity and preclinical pharmacokinetic profiles to support a once-daily human dose prediction. Dose escalating PK studies in dog revealed significant issues with limited oral absorption and required an innovative prodrug strategy to enhance the high-dose plasma exposures of the parent molecules.
Asunto(s)
Inhibidores de Integrasa VIH/síntesis química , Inhibidores de Integrasa VIH/farmacología , Piridonas/síntesis química , Piridonas/farmacología , Animales , Área Bajo la Curva , Perros , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Integrasa de VIH/efectos de los fármacos , Integrasa de VIH/metabolismo , Inhibidores de Integrasa VIH/farmacocinética , VIH-1/efectos de los fármacos , VIH-1/enzimología , VIH-1/genética , Humanos , Modelos Moleculares , Profármacos , Piridonas/farmacocinética , RatasRESUMEN
The field of small-molecule orexin antagonist research has evolved rapidly in the last 15 years from the discovery of the orexin peptides to clinical proof-of-concept for the treatment of insomnia. Clinical programs have focused on the development of antagonists that reversibly block the action of endogenous peptides at both the orexin 1 and orexin 2 receptors (OX1 R and OX2 R), termed dual orexin receptor antagonists (DORAs), affording late-stage development candidates including Merck's suvorexant (new drug application filed 2012). Full characterization of the pharmacology associated with antagonism of either OX1 R or OX2 R alone has been hampered by the dearth of suitable subtype-selective, orally bioavailable ligands. Herein, we report the development of a selective orexin 2 antagonist (2-SORA) series to afford a potent, orally bioavailable 2-SORA ligand. Several challenging medicinal chemistry issues were identified and overcome during the development of these 2,5-disubstituted nicotinamides, including reversible CYP inhibition, physiochemical properties, P-glycoprotein efflux and bioactivation. This article highlights structural modifications the team utilized to drive compound design, as well as in vivo characterization of our 2-SORA clinical candidate, 5''-chloro-N-[(5,6-dimethoxypyridin-2-yl)methyl]-2,2':5',3''-terpyridine-3'-carboxamide (MK-1064), in mouse, rat, dog, and rhesus sleep models.
Asunto(s)
Diseño de Fármacos , Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Neuropéptidos/antagonistas & inhibidores , Piridinas/química , Piridinas/farmacología , Trastornos del Inicio y del Mantenimiento del Sueño/tratamiento farmacológico , Animales , Perros , Humanos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Macaca mulatta , Masculino , Ratones , Ratones Endogámicos C57BL , Neuropéptidos/metabolismo , Orexinas , Ratas , Ratas Sprague-Dawley , Trastornos del Inicio y del Mantenimiento del Sueño/metabolismoRESUMEN
Phosphodiesterase 10A (PDE10A) is a novel target for the treatment of schizophrenia that may address multiple symptomatic domains associated with this disorder. PDE10A is highly expressed in the brain and functions to metabolically inactivate the important second messengers cAMP and cGMP. Here we describe effects of a potent and orally bioavailable PDE10A inhibitor [2-(6-chloropyridin-3-yl)-4-(2-methoxyethoxy)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl](imidazo[1,5-a]pyridin-1-yl)methanone] (THPP-1) on striatal signaling pathways, in behavioral tests that predict antipsychotic potential, and assays that measure episodic-like memory in rat and executive function in rhesus monkey. THPP-1 exhibits nanomolar potency on the PDE10A enzyme, demonstrates excellent pharmacokinetic properties in multiple preclinical animal species, and is selective for PDE10A over other PDE families of enzymes. THPP-1 significantly increased phosphorylation of proteins in the striatum involved in synaptic plasticity, including the a-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid receptor (AMPA) GluR1 subunit, extracellular receptor kinase (ERK), and cAMP-response element binding protein (CREB). THPP-1 produced dose-dependent effects in preclinical assays predictive of antipsychotic activity including attenuation of MK-801-induced psychomotor activation and condition avoidance responding in rats. At similar plasma exposures, THPP-1 significantly increased object recognition memory in rat and attenuated a ketamine-induced deficit in the object retrieval detour task in rhesus monkey. These findings suggest that PDE10A inhibitors have the potential to impact multiple symptomatic domains of schizophrenia including positive symptoms and cognitive impairment. This article is part of a Special Issue entitled 'Cognitive Enhancers'.
Asunto(s)
Antipsicóticos/uso terapéutico , Trastornos del Conocimiento/prevención & control , Terapia Molecular Dirigida , Nootrópicos/uso terapéutico , Inhibidores de Fosfodiesterasa/uso terapéutico , Hidrolasas Diéster Fosfóricas/metabolismo , Esquizofrenia/tratamiento farmacológico , Animales , Antipsicóticos/administración & dosificación , Antipsicóticos/sangre , Antipsicóticos/farmacocinética , Conducta Animal/efectos de los fármacos , Trastornos del Conocimiento/etiología , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/enzimología , Cuerpo Estriado/metabolismo , Relación Dosis-Respuesta a Droga , Función Ejecutiva/efectos de los fármacos , Macaca mulatta , Masculino , Memoria Episódica , Proteínas del Tejido Nervioso/antagonistas & inhibidores , Proteínas del Tejido Nervioso/metabolismo , Neuronas/efectos de los fármacos , Neuronas/enzimología , Neuronas/metabolismo , Nootrópicos/administración & dosificación , Nootrópicos/sangre , Nootrópicos/farmacocinética , Inhibidores de Fosfodiesterasa/administración & dosificación , Inhibidores de Fosfodiesterasa/sangre , Inhibidores de Fosfodiesterasa/farmacocinética , Hidrolasas Diéster Fosfóricas/química , Fosforilación/efectos de los fármacos , Procesamiento Proteico-Postraduccional/efectos de los fármacos , Piridinas/administración & dosificación , Piridinas/sangre , Piridinas/farmacocinética , Piridinas/uso terapéutico , Pirimidinas/administración & dosificación , Pirimidinas/sangre , Pirimidinas/farmacocinética , Pirimidinas/uso terapéutico , Distribución Aleatoria , Ratas , Ratas Wistar , Esquizofrenia/sangre , Esquizofrenia/metabolismo , Esquizofrenia/fisiopatologíaRESUMEN
Orexin (hypocretin) neuropeptides promote wakefulness by signaling through two G-protein coupled receptors, Orexin 1 Receptor (OX(1)R) and Orexin 2 Receptor (OX(2)R). MK-6096 is an orally bioavailable potent and selective reversible antagonist of OX(1)R and OX(2)R currently in clinical development for insomnia. In radioligand binding and functional cell based assays MK-6096 demonstrated potent binding and antagonism of both human OX(1)R and OX(2)R (<3 nM in binding, 11 nM in FLIPR), with no significant off-target activities against a panel of >170 receptors and enzymes. MK-6096 occupies 90% of human OX(2)Rs expressed in transgenic rats at a plasma concentration of 142 nM, and dose-dependently reduced locomotor activity and significantly increased sleep in rats (3-30 mg/kg) and dogs (0.25 and 0.5 mg/kg). DORA-22, an analog of MK-6096, exhibits similar sleep promoting properties that are absent OX(1/2)R double knockouts, demonstrating the mechanism of action and specificity of these effects. These findings with a novel, structurally distinct class of OxR antagonists provide further validation of the orexin pathway as an effective target to promote normal sleep. Comparative analysis of the biochemical and pharmacokinetic properties of these compounds relative to other OXR antagonists provides a basis for understanding the attributes critical for in vivo efficacy. This mechanism is distinct from current standard of care such that MK-6096 represents a novel and selective therapeutic for the treatment of insomnia. This article is part of a Special Issue entitled 'Post-Traumatic Stress Disorder'.
Asunto(s)
Piperidinas/farmacología , Pirimidinas/farmacología , Receptores Acoplados a Proteínas G/antagonistas & inhibidores , Receptores de Neuropéptido/antagonistas & inhibidores , Trastornos del Inicio y del Mantenimiento del Sueño/tratamiento farmacológico , Sueño/efectos de los fármacos , Animales , Perros , Ratones , Receptores de Orexina , RatasRESUMEN
Insomnia is a common disorder that can be comorbid with other physical and psychological illnesses. Traditional management of insomnia relies on general central nervous system (CNS) suppression using GABA modulators. Many of these agents fail to meet patient needs with respect to sleep onset, maintenance, and next-day residual effects and have issues related to tolerance, memory disturbances, and balance. Orexin neuropeptides are central regulators of wakefulness, and orexin antagonism has been identified as a novel mechanism for treating insomnia with clinical proof of concept. Herein we describe the discovery of a series of α-methylpiperidine carboxamide dual orexinâ 1 and orexinâ 2 receptor (OX(1) R/OX(2) R) antagonists (DORAs). The design of these molecules was inspired by earlier work from this laboratory in understanding preferred conformational properties for potent orexin receptor binding. Minimization of 1,3-allylic strain interactions was used as a design principle to synthesize 2,5-disubstituted piperidine carboxamides with axially oriented substituents including DORA 28. DORA 28 (MK-6096) has exceptional inâ vivo activity in preclinical sleep models, and has advanced into phaseâ II clinical trials for the treatment of insomnia.
Asunto(s)
Hipnóticos y Sedantes/síntesis química , Piperidinas/síntesis química , Piridinas/síntesis química , Receptores Acoplados a Proteínas G/antagonistas & inhibidores , Receptores de Neuropéptido/antagonistas & inhibidores , Trastornos del Inicio y del Mantenimiento del Sueño/tratamiento farmacológico , Triazoles/síntesis química , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Perros , Descubrimiento de Drogas , Humanos , Hipnóticos y Sedantes/farmacocinética , Hipnóticos y Sedantes/farmacología , Espectroscopía de Resonancia Magnética , Modelos Moleculares , Receptores de Orexina , Piperidinas/farmacocinética , Piperidinas/farmacología , Unión Proteica , Piridinas/farmacocinética , Piridinas/farmacología , Ratas , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Neuropéptido/metabolismo , Sueño , Trastornos del Inicio y del Mantenimiento del Sueño/metabolismo , Estereoisomerismo , Relación Estructura-Actividad , Triazoles/farmacocinética , Triazoles/farmacología , Vigilia/efectos de los fármacosRESUMEN
Despite increased understanding of the biological basis for sleep control in the brain, few novel mechanisms for the treatment of insomnia have been identified in recent years. One notable exception is inhibition of the excitatory neuropeptides orexins A and B by design of orexin receptor antagonists. Herein, we describe how efforts to understand the origin of poor oral pharmacokinetics in a leading HTS-derived diazepane orexin receptor antagonist led to the identification of compound 10 with a 7-methyl substitution on the diazepane core. Though 10 displayed good potency, improved pharmacokinetics, and excellent in vivo efficacy, it formed reactive metabolites in microsomal incubations. A mechanistic hypothesis coupled with an in vitro assay to assess bioactivation led to replacement of the fluoroquinazoline ring of 10 with a chlorobenzoxazole to provide 3 (MK-4305), a potent dual orexin receptor antagonist that is currently being tested in phase III clinical trials for the treatment of primary insomnia.
Asunto(s)
Azepinas/farmacología , Receptores Acoplados a Proteínas G/antagonistas & inhibidores , Receptores de Neuropéptido/antagonistas & inhibidores , Triazoles/farmacología , Animales , Azepinas/síntesis química , Azepinas/farmacocinética , Disponibilidad Biológica , Células CHO , Cricetinae , Cricetulus , Perros , Humanos , Técnicas In Vitro , Masculino , Microsomas Hepáticos/metabolismo , Receptores de Orexina , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Ratas Transgénicas , Receptores Acoplados a Proteínas G/genética , Receptores de Neuropéptido/genética , Sueño/efectos de los fármacos , Trastornos del Inicio y del Mantenimiento del Sueño/tratamiento farmacológico , Estereoisomerismo , Relación Estructura-Actividad , Telemetría , Triazoles/síntesis química , Triazoles/farmacocinética , Vigilia/efectos de los fármacosRESUMEN
Silent Night: Antagonism of the orexin (or hypocretin) system has recently been identified as a novel mechanism for the treatment of insomnia. Herein, we describe discovery of a dual (OX(1)R/OX(2)R) orexin receptor antagonist featuring a 1,4-diazepane central constraint that blocks orexin signaling in vivo. In telemetry-implanted rats, oral administration of this antagonist produced a decrease in wakefulness, while increasing REM and non-REM sleep.
Asunto(s)
Azepinas/química , Receptores Acoplados a Proteínas G/antagonistas & inhibidores , Receptores de Neuropéptido/antagonistas & inhibidores , Trastornos del Sueño-Vigilia/tratamiento farmacológico , Animales , Azepinas/farmacocinética , Azepinas/uso terapéutico , Sistema Nervioso Central/efectos de los fármacos , Receptores de Orexina , Ratas , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Neuropéptido/metabolismo , Relación Estructura-ActividadRESUMEN
Inspired by previous efforts in the pyrazolobenzoxazine class of KSP inhibitors, the design and synthesis of 1,4-diaryl-4,5-dihydropyrazole inhibitors of KSP are described. Crystallographic evidence of binding mode and in vivo potency data is also highlighted.
Asunto(s)
Diseño de Fármacos , Hidrógeno/química , Cinesinas/antagonistas & inhibidores , Cinesinas/metabolismo , Mitosis/efectos de los fármacos , Pirazoles/química , Pirazoles/farmacología , Sitios de Unión , Cristalografía por Rayos X , Humanos , Modelos Moleculares , Estructura Molecular , Pirazoles/síntesis química , Relación Estructura-ActividadRESUMEN
3,5-diaryl-4,5-dihydropyrazoles were discovered to be potent KSP inhibitors with excellent in vivo potency. These enzyme inhibitors possess desirable physical properties that can be readily modified by incorporation of a weakly basic amine. Careful adjustment of amine basicity was essential for preserving cellular potency in a multidrug resistant cell line while maintaining good aqueous solubility.