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1.
J Med Chem ; 66(11): 7534-7552, 2023 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-37235865

RESUMO

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.


Assuntos
Doença de Alzheimer , Diabetes Mellitus Tipo 2 , Camundongos , Animais , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Proteínas tau/metabolismo , Quinase 3 da Glicogênio Sintase/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismo , Camundongos Transgênicos , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Fosforilação
2.
Bioorg Med Chem Lett ; 81: 129143, 2023 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-36669575

RESUMO

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.


Assuntos
Doença de Alzheimer , Quinase 3 da Glicogênio Sintase , Camundongos , Animais , Relação Estrutura-Atividade , Camundongos Transgênicos , Amidas/farmacologia , Glicogênio Sintase Quinase 3 beta , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/química
3.
J Med Chem ; 65(6): 4534-4564, 2022 03 24.
Artigo em Inglês | MEDLINE | ID: mdl-35261239

RESUMO

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.


Assuntos
Anestésicos Gerais , Neuralgia , Animais , Éteres/uso terapêutico , Camundongos , Neuralgia/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Ratos , Medula Espinal , Relação Estrutura-Atividade
4.
J Med Chem ; 65(6): 4457-4480, 2022 03 24.
Artigo em Inglês | MEDLINE | ID: mdl-35257579

RESUMO

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).


Assuntos
Aminas , Neuralgia , Animais , Encéfalo , Camundongos , Neuralgia/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Ratos , Medula Espinal
5.
Bioorg Med Chem Lett ; 43: 128077, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-33932522

RESUMO

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.


Assuntos
Azepinas/farmacologia , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina/farmacologia , Receptores de Peptídeo Relacionado com o Gene de Calcitonina/metabolismo , Azepinas/síntese química , Azepinas/química , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina/síntese química , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina/química , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Relação Estrutura-Atividade
7.
J Med Chem ; 62(2): 831-856, 2019 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-30576602

RESUMO

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.


Assuntos
Indazóis/química , Indóis/química , Canal de Sódio Disparado por Voltagem NAV1.7/química , Neuralgia/tratamento farmacológico , Sulfonamidas/química , Bloqueadores do Canal de Sódio Disparado por Voltagem/uso terapêutico , Animais , Avaliação Pré-Clínica de Medicamentos , Células HEK293 , Meia-Vida , Humanos , Hiperalgesia/tratamento farmacológico , Hiperalgesia/patologia , Masculino , Camundongos , Canal de Sódio Disparado por Voltagem NAV1.7/metabolismo , Neuralgia/patologia , Técnicas de Patch-Clamp , Relação Estrutura-Atividade , Sulfonamidas/metabolismo , Sulfonamidas/uso terapêutico , Bloqueadores do Canal de Sódio Disparado por Voltagem/química , Bloqueadores do Canal de Sódio Disparado por Voltagem/metabolismo
8.
Bioorg Med Chem ; 25(20): 5490-5505, 2017 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-28818462

RESUMO

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.


Assuntos
Descoberta de Drogas , Modelos Biológicos , Canal de Sódio Disparado por Voltagem NAV1.7/metabolismo , Neurônios/efeitos dos fármacos , Nociceptividade/efeitos dos fármacos , Sulfonamidas/farmacologia , Administração Oral , Animais , Dor Crônica/induzido quimicamente , Dor Crônica/tratamento farmacológico , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Adjuvante de Freund , Células HEK293 , Humanos , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Masculino , Camundongos , Estrutura Molecular , Neurônios/metabolismo , Relação Estrutura-Atividade , Sulfonamidas/administração & dosagem , Sulfonamidas/química
9.
J Org Chem ; 82(7): 3710-3720, 2017 04 07.
Artigo em Inglês | MEDLINE | ID: mdl-28306261

RESUMO

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.


Assuntos
Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina , Compostos de Epóxi/química , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Hidrólise , Análise Espectral/métodos
10.
J Med Chem ; 59(3): 1041-51, 2016 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-26751161

RESUMO

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.


Assuntos
Encéfalo/metabolismo , Descoberta de Drogas , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Niacinamida/farmacologia , Niacinamida/farmacocinética , Inibidores de Proteínas Quinases/farmacologia , Administração Oral , Animais , Encéfalo/efeitos dos fármacos , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Quinase 3 da Glicogênio Sintase/metabolismo , Glicogênio Sintase Quinase 3 beta , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Modelos Moleculares , Estrutura Molecular , Niacinamida/administração & dosagem , Niacinamida/química , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacocinética , Relação Estrutura-Atividade
11.
Org Lett ; 17(24): 5982-5, 2015 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-26650258

RESUMO

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.


Assuntos
Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina , Cicloeptanos/síntese química , Cicloeptanos/farmacologia , Transtornos de Enxaqueca/tratamento farmacológico , Piperidinas/síntese química , Piperidinas/farmacologia , Piridinas/síntese química , Piridinas/farmacologia , Cicloeptanos/química , Estrutura Molecular , Piperidinas/química , Piridinas/química , Estereoisomerismo
12.
Bioorg Med Chem Lett ; 23(13): 3814-7, 2013 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-23726344

RESUMO

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.


Assuntos
Compostos Bicíclicos com Pontes/farmacologia , Compostos Heterocíclicos/farmacologia , Receptores de Neuropeptídeo Y/antagonistas & inibidores , Administração Oral , Animais , Compostos Bicíclicos com Pontes/administração & dosagem , Compostos Bicíclicos com Pontes/química , Relação Dose-Resposta a Droga , Compostos Heterocíclicos/administração & dosagem , Compostos Heterocíclicos/química , Masculino , Estrutura Molecular , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade
13.
J Med Chem ; 55(23): 10644-51, 2012 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-23153230

RESUMO

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.


Assuntos
Peptídeo Relacionado com Gene de Calcitonina/antagonistas & inibidores , Descoberta de Drogas , Transtornos de Enxaqueca/tratamento farmacológico , Piperidinas/química , Piperidinas/uso terapêutico , Piridinas/química , Piridinas/uso terapêutico , Administração Oral , Ensaios Clínicos como Assunto , Humanos , Espectroscopia de Ressonância Magnética , Piperidinas/farmacologia , Piridinas/farmacologia
14.
Org Lett ; 14(18): 4938-41, 2012 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-22954228

RESUMO

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.


Assuntos
Peptídeo Relacionado com Gene de Calcitonina/antagonistas & inibidores , Compostos Heterocíclicos de 4 ou mais Anéis/síntese química , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Catálise , Compostos Heterocíclicos de 4 ou mais Anéis/química , Estrutura Molecular , Estereoisomerismo
15.
Bioorg Med Chem Lett ; 22(8): 2917-21, 2012 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-22429470

RESUMO

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.


Assuntos
Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina , Piridinas/síntese química , Amidas/química , Amidas/farmacologia , Células CACO-2 , Humanos , Concentração Inibidora 50 , Transtornos de Enxaqueca/tratamento farmacológico , Estrutura Molecular , Ligação Proteica/efeitos dos fármacos , Piridinas/química , Piridinas/farmacologia
16.
Bioorg Med Chem Lett ; 22(8): 2912-6, 2012 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-22429471

RESUMO

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.


Assuntos
Ácido Aspártico/síntese química , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina , Succinatos/síntese química , Ácido Aspártico/química , Ácido Aspártico/farmacologia , Humanos , Indazóis/química , Indazóis/farmacologia , Concentração Inibidora 50 , Estrutura Molecular , Ligação Proteica/efeitos dos fármacos , Quinazolinonas/química , Quinazolinonas/farmacologia , Estereoisomerismo , Relação Estrutura-Atividade , Succinatos/química , Succinatos/farmacologia
17.
ACS Med Chem Lett ; 3(3): 222-6, 2012 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-24900458

RESUMO

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.

18.
ACS Med Chem Lett ; 3(4): 337-41, 2012 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-24900474

RESUMO

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.

19.
J Org Chem ; 71(14): 5392-5, 2006 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-16808535

RESUMO

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.


Assuntos
Indazóis/síntese química , Indazóis/química , Estrutura Molecular , Estereoisomerismo
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