RESUMEN
Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase that serves as an important regulator of a broad range of cellular functions. It has been linked to Alzheimer's disease as well as various other diseases, including mood disorders, type 2 diabetes, and cancer. There is considerable evidence indicating that GSK-3ß in the central nervous system plays a role in the production of abnormal, hyperphosphorylated, microtubule-associated tau protein found in neurofibrillary tangles associated with Alzheimer's disease. A series of analogues containing a pyrimidine-based hinge-binding heterocycle was synthesized and evaluated, leading to the identification of highly potent GSK-3 inhibitors with excellent kinase selectivity. Further evaluation of 34 and 40 in vivo demonstrated that these compounds are orally bioavailable, brain-penetrant GSK-3 inhibitors that lowered levels of phosphorylated tau in a triple-transgenic mouse Alzheimer's disease model.
Asunto(s)
Enfermedad de Alzheimer , Diabetes Mellitus Tipo 2 , Ratones , Animales , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Proteínas tau/metabolismo , Glucógeno Sintasa Quinasa 3/metabolismo , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Ratones Transgénicos , Pirimidinas/farmacología , Pirimidinas/uso terapéutico , FosforilaciónRESUMEN
In our continuing efforts to explore structure-activity relationships around the novel class of potent, isonicotinamide-based GSK3 inhibitors described in our previous report, we extensively explored structural variations around both 4/5-pyridine substitutions and the amide group. Some analogs were found to have greatly improved pTau lowering potency while retaining high kinase selectivity. In contrast to previous active compounds 1a-c, a close analog 3h did not show in vivo efficacy in a triple-transgenic mouse Alzheimer's disease model. In general, these 2pyridinyl amide derivatives were prone to amidase mediated hydrolysis in mouse plasma.
Asunto(s)
Enfermedad de Alzheimer , Glucógeno Sintasa Quinasa 3 , Ratones , Animales , Relación Estructura-Actividad , Ratones Transgénicos , Amidas/farmacología , Glucógeno Sintasa Quinasa 3 beta , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/químicaRESUMEN
Recent mouse knockout studies identified adapter protein-2-associated kinase 1 (AAK1) as a viable target for treating neuropathic pain. BMS-986176/LX-9211 (4), as a highly selective, CNS-penetrable, and potent AAK1 inhibitor, has advanced into phase II human trials. On exploring the structure-activity relationship (SAR) around this biaryl alkyl ether chemotype, several additional compounds were found to be highly selective and potent AAK1 inhibitors with good druglike properties. Among these, compounds 43 and 58 showed very good efficacy in two neuropathic pain rat models and had excellent CNS penetration and spinal cord target engagement. Both compounds also exhibited favorable physicochemical and oral pharmacokinetic (PK) properties. Compound 58, a central pyridine isomer of BMS-986176/LX-9211 (4), was 4-fold more potent than 4 in vitro and showed lower plasma exposure needed to achieve similar efficacy compared to 4 in the CCI rat model. However, both 43 and 58 showed an inferior preclinical toxicity profile compared to 4.
Asunto(s)
Anestésicos Generales , Neuralgia , Animales , Éteres/uso terapéutico , Ratones , Neuralgia/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Ratas , Médula Espinal , Relación Estructura-ActividadRESUMEN
Recent mouse knockout studies identified adapter protein-2 associated kinase 1 (AAK1) as a viable target for treating neuropathic pain. Potent small-molecule inhibitors of AAK1 have been identified and show efficacy in various rodent pain models. (S)-1-((2',6-Bis(difluoromethyl)-[2,4'-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine (BMS-986176/LX-9211) (34) was identified as a highly selective, CNS penetrant, potent AAK1 inhibitor from a novel class of bi(hetero)aryl ethers. BMS-986176/LX9211 (34) showed excellent efficacy in two rodent neuropathic pain models and excellent central nervous system (CNS) penetration and target engagement at the spinal cord with an average brain to plasma ratio of 20 in rat. The compound exhibited favorable physicochemical and pharmacokinetic properties, had an acceptable preclinical toxicity profile, and was chosen for clinical trials. BMS-986176/LX9211 (34) completed phase I trials with good human pharmacokinetics and minimum adverse events and is currently in phase II clinical trials for diabetic peripheral neuropathic pain (ClinicalTrials.gov identifier: NCT04455633) and postherpetic neuralgia (ClinicalTrials.gov identifier: NCT04662281).
Asunto(s)
Aminas , Neuralgia , Animales , Encéfalo , Ratones , Neuralgia/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Ratas , Médula EspinalRESUMEN
In our efforts to identify orally bioavailable CGRP receptor antagonists, we previously discovered a novel series of orally available azepinone derivatives that unfortunately also exhibited the unwanted property of potent time-dependent human CYP3A4 inhibition. Through heterocyclic replacement of the indazole ring, we discovered a series of heterocycle derivatives as high-affinity CGRP receptor antagonists. Some of them showed reasonable oral exposures, and the imidazolone derivatives that showed good oral exposure also exhibited substantially reduced time-dependent CYP3A4 inhibition. Several compounds showed strong in vivo efficacy in our marmoset facial blood flow assay with up to 87% inhibition of CGRP-induced activity. However, oral bioavailability generally remained low, emphasizing the challenges we and others encountered in discovering clinical development candidates for this difficult Class B GPCR target.
Asunto(s)
Azepinas/farmacología , Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina/farmacología , Receptores de Péptido Relacionado con el Gen de Calcitonina/metabolismo , Azepinas/síntesis química , Azepinas/química , Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina/síntesis química , Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina/química , Relación Dosis-Respuesta a Droga , Humanos , Estructura Molecular , Relación Estructura-ActividadRESUMEN
3-Aryl-indole and 3-aryl-indazole derivatives were identified as potent and selective Nav1.7 inhibitors. Compound 29 was shown to be efficacious in the mouse formalin assay and also reduced complete Freund's adjuvant (CFA)-induced thermal hyperalgesia and chronic constriction injury (CCI) induced cold allodynia and models of inflammatory and neuropathic pain, respectively, following intraperitoneal (IP) doses of 30 mg/kg. The observed efficacy could be correlated with the mouse dorsal root ganglion exposure and NaV1.7 potency associated with 29.
Asunto(s)
Indazoles/química , Indoles/química , Canal de Sodio Activado por Voltaje NAV1.7/química , Neuralgia/tratamiento farmacológico , Sulfonamidas/química , Bloqueadores del Canal de Sodio Activado por Voltaje/uso terapéutico , Animales , Evaluación Preclínica de Medicamentos , Células HEK293 , Semivida , Humanos , Hiperalgesia/tratamiento farmacológico , Hiperalgesia/patología , Masculino , Ratones , Canal de Sodio Activado por Voltaje NAV1.7/metabolismo , Neuralgia/patología , Técnicas de Placa-Clamp , Relación Estructura-Actividad , Sulfonamidas/metabolismo , Sulfonamidas/uso terapéutico , Bloqueadores del Canal de Sodio Activado por Voltaje/química , Bloqueadores del Canal de Sodio Activado por Voltaje/metabolismoRESUMEN
Since zwitterionic benzenesulfonamide Nav1.7 inhibitors suffer from poor membrane permeability, we sought to eliminate this characteristic by replacing the basic moiety with non-basic bicyclic acetals and monocyclic ethers. These efforts led to the discovery of the non-zwitterionic aryl sulfonamide 49 as a selective Nav1.7 inhibitor with improved membrane permeability. Despite its moderate cellular activity, 49 exhibited robust efficacy in mouse models of neuropathic and inflammatory pain and modulated translational electromyogram measures associated with activation of nociceptive neurons.
Asunto(s)
Descubrimiento de Drogas , Modelos Biológicos , Canal de Sodio Activado por Voltaje NAV1.7/metabolismo , Neuronas/efectos de los fármacos , Nocicepción/efectos de los fármacos , Sulfonamidas/farmacología , Administración Oral , Animales , Dolor Crónico/inducido químicamente , Dolor Crónico/tratamiento farmacológico , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Adyuvante de Freund , Células HEK293 , Humanos , Inflamación/inducido químicamente , Inflamación/tratamiento farmacológico , Masculino , Ratones , Estructura Molecular , Neuronas/metabolismo , Relación Estructura-Actividad , Sulfonamidas/administración & dosificación , Sulfonamidas/químicaRESUMEN
An asymmetric synthesis of the major metabolite of the calcitonin gene-related peptide recepotor antagonist BMS-846372 is presented. The variously substituted cyclohepta[b]pyridine ring system represents an underexplored ring system and showed some unexpected chemistry. Reactivities of epoxide and ketone functional groups on the cycloheptane ring were extensively controlled by a remote bulky TIPS group. The rate difference of the hydrogenolysis between two diastereomeric epoxide intermediates shed some light on the mechanism of epoxide hydrogenolysis, and further, deuterium labeling studies revealed more mechanistic details on this well-known chemical transformation for the first time.
Asunto(s)
Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina , Compuestos Epoxi/química , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Hidrólisis , Análisis Espectral/métodosRESUMEN
GSK-3 is a serine/threonine kinase that has numerous substrates. Many of these proteins are involved in the regulation of diverse cellular functions, including metabolism, differentiation, proliferation, and apoptosis. Inhibition of GSK-3 may be useful in treating a number of diseases including Alzheimer's disease (AD), type II diabetes, mood disorders, and some cancers, but the approach poses significant challenges. Here, we present a class of isonicotinamides that are potent, highly kinase-selective GSK-3 inhibitors, the members of which demonstrated oral activity in a triple-transgenic mouse model of AD. The remarkably high kinase selectivity and straightforward synthesis of these compounds bode well for their further exploration as tool compounds and therapeutics.
Asunto(s)
Encéfalo/metabolismo , Descubrimiento de Drogas , Glucógeno Sintasa Quinasa 3/antagonistas & inhibidores , Niacinamida/farmacología , Niacinamida/farmacocinética , Inhibidores de Proteínas Quinasas/farmacología , Administración Oral , Animales , Encéfalo/efectos de los fármacos , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Glucógeno Sintasa Quinasa 3/metabolismo , Glucógeno Sintasa Quinasa 3 beta , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Modelos Moleculares , Estructura Molecular , Niacinamida/administración & dosificación , Niacinamida/química , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacocinética , Relación Estructura-ActividadRESUMEN
An asymmetric synthesis of novel heterocyclic analogue of the CGRP receptor antagonist rimegepant (BMS-927711, 3) is reported. The cycloheptane ring was constructed by an intramolecular Heck reaction. The application of Hayashi-Miyaura and Ellman reactions furnished the aryl and the amine chiral centers, while the separable diastereomeric third chiral center alcohols led to both carbamate and urea analogues. This synthetic approach was applicable to both 6- and 5-membered heterocycles as exemplified by pyrazine and thiazole derivatives.
Asunto(s)
Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina , Cicloheptanos/síntesis química , Cicloheptanos/farmacología , Trastornos Migrañosos/tratamiento farmacológico , Piperidinas/síntesis química , Piperidinas/farmacología , Piridinas/síntesis química , Piridinas/farmacología , Cicloheptanos/química , Estructura Molecular , Piperidinas/química , Piridinas/química , EstereoisomerismoRESUMEN
A convergent synthesis route for the heterocyclic modification of a novel bicyclo[3.1.0]hexane NPY1 antagonist 2 was developed and the structure activity relationship of these modifications on NPY1 binding is reported. Two heterocyclic analogs 9 and 10 showed comparable Y1 binding potency to 2, but with improved aqueous solubility. Compound 9 demonstrated reduced spontaneous nocturnal food intake in a rat model when dosed ip. Compound 9 was also shown to be orally bioavailable and brain penetrable.
Asunto(s)
Compuestos Bicíclicos con Puentes/farmacología , Compuestos Heterocíclicos/farmacología , Receptores de Neuropéptido Y/antagonistas & inhibidores , Administración Oral , Animales , Compuestos Bicíclicos con Puentes/administración & dosificación , Compuestos Bicíclicos con Puentes/química , Relación Dosis-Respuesta a Droga , Compuestos Heterocíclicos/administración & dosificación , Compuestos Heterocíclicos/química , Masculino , Estructura Molecular , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
Calcitonin gene-related peptide (CGRP) receptor antagonists have demonstrated clinical efficacy in the treatment of acute migraine. Herein, we describe the design, synthesis, and preclinical characterization of a highly potent, oral CGRP receptor antagonist BMS-927711 (8). Compound 8 has good oral bioavailability in rat and cynomolgus monkey, attractive overall preclinical properties, and shows dose-dependent activity in a primate model of CGRP-induced facial blood flow. Compound 8 is presently in phase II clinical trials.
Asunto(s)
Péptido Relacionado con Gen de Calcitonina/antagonistas & inhibidores , Descubrimiento de Drogas , Trastornos Migrañosos/tratamiento farmacológico , Piperidinas/química , Piperidinas/uso terapéutico , Piridinas/química , Piridinas/uso terapéutico , Administración Oral , Ensayos Clínicos como Asunto , Humanos , Espectroscopía de Resonancia Magnética , Piperidinas/farmacología , Piridinas/farmacologíaRESUMEN
An enantioselective synthesis of the CGRP antagonist BMS-846372, amenable to large scale preparation, is presented. This new synthesis showcases a chemo- and enantioselective reduction of a cyclohepta[b]pyridine-5,9-dione as well as a Pd-catalyzed alpha-arylation reaction to form the key carbon-carbon bond and set the absolute and relative stereochemistry.
Asunto(s)
Péptido Relacionado con Gen de Calcitonina/antagonistas & inhibidores , Compuestos Heterocíclicos de 4 o más Anillos/síntesis química , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Catálisis , Compuestos Heterocíclicos de 4 o más Anillos/química , Estructura Molecular , EstereoisomerismoRESUMEN
In our continuing efforts to identify CGRP receptor antagonists that can be dosed orally for the treatment of migraine headache, we have investigated a pyridine bioisosteric replacement of a polar amide portion of a previous lead compound, BMS-694153. Pyridine derivatives were discovered and their SAR was studied. Some of them showed excellent binding potency. However, oral bioavailability was low, even for compounds with good Caco-2 cell permeability.
Asunto(s)
Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina , Piridinas/síntesis química , Amidas/química , Amidas/farmacología , Células CACO-2 , Humanos , Concentración 50 Inhibidora , Trastornos Migrañosos/tratamiento farmacológico , Estructura Molecular , Unión Proteica/efectos de los fármacos , Piridinas/química , Piridinas/farmacologíaRESUMEN
Novel aspartate and succinate CGRP full antagonists were identified through core modification of a potent lead CGRP antagonist, BMS-694153. While aspartates were much less active and had a flat SAR, some of the succinates were very potent CGRP full antagonists and matched the potency of BMS-694153. The most potency resides in the S enantiomer as demonstrated through an asymmetric synthesis.
Asunto(s)
Ácido Aspártico/síntesis química , Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina , Succinatos/síntesis química , Ácido Aspártico/química , Ácido Aspártico/farmacología , Humanos , Indazoles/química , Indazoles/farmacología , Concentración 50 Inhibidora , Estructura Molecular , Unión Proteica/efectos de los fármacos , Quinazolinonas/química , Quinazolinonas/farmacología , Estereoisomerismo , Relación Estructura-Actividad , Succinatos/química , Succinatos/farmacologíaRESUMEN
A novel class of bicyclo[3.1.0]hexanylpiperazine neuropeptide Y (NPY) Y1 antagonists has been designed and synthesized. Scatchard binding analysis showed these compounds to be noncompetitive with [(125)I]PYY binding to the Y1 receptor. The most potent member, 1-((1α,3α,5α,6ß)-6-(3-ethoxyphenyl)-3-methylbicyclo[3.1.0]hexan-6-yl)-4-phenylpiperazine (2) had an IC50 = 62 nM and displayed excellent oral bioavailability in rat (% F po = 80), as well as good brain penetration (B/P ratio = 0.61). In a spontaneous nocturnal feeding study with male Sprague-Dawley rats, 2 significantly reduced food intake during a 12 h period.
RESUMEN
Calcitonin gene-related peptide (CGRP) receptor antagonists have been clinically shown to be effective in the treatment of migraine, but identification of potent and orally bioavailable compounds has been challenging. Herein, we describe the conceptualization, synthesis, and preclinical characterization of a potent, orally active CGRP receptor antagonist 5 (BMS-846372). Compound 5 has good oral bioavailability in rat, dog, and cynomolgus monkeys and overall attractive preclinical properties including strong (>50% inhibition) exposure-dependent in vivo efficacy in a marmoset migraine model.
RESUMEN
Indazoles are regioselectively protected at N-2 by a 2-(trimethylsilyl)ethoxymethyl (SEM) group using novel conditions. The SEM group can efficiently direct regioselective C-3 lithiation, and the resulting nucleophile can react with a wide range of electrophiles to generate novel indazole derivatives. The SEM group can be removed by treatment with TBAF in THF or aqueous HCl in EtOH.
Asunto(s)
Indazoles/síntesis química , Indazoles/química , Estructura Molecular , EstereoisomerismoRESUMEN
4-Amino-N-arylpiperidines serve as effective bioisosteres for N-arylpiperazines in the series of dihydropyridine NPY1 receptor antagonists. These were prepared by a ZnCl2-mediated reductive amination reaction between elaborated primary amines, 2 or 5, and 4-arylpiperidones.