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1.
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
2.
J Health Commun ; 28(10): 699-705, 2023 10 03.
Artigo em Inglês | MEDLINE | ID: mdl-37752882

RESUMO

This paper outlines lessons learned from tailoring communication campaigns to increase demand for, and reduce stigma toward, evidence-based practices to reduce opioid overdose deaths in 66 communities participating in the HEALing (Helping to End Addiction Long-termSM) Communities Study (HCS). We present nine lessons gathered about how to engage local communities in both virtual and in-person opioid messaging and distribution between February 2019 and June 2022. The research team created four communication campaigns and did extensive, tailored marketing and promotion to assist communities in implementing evidence-based clinical activities to reduce opioid overdose mortality. Various strategies and venues were used to amplify HCS messages, using free and paid outlets for message distribution, focusing primarily on social media due to the COVID-19 pandemic. Increasing the availability of medications for opioid use disorder and naloxone, as HCS attempted, is not enough; getting people to accept and use them depends on communication efforts. This paper focuses on the process of preparing communities for communication campaign activities, which we hope can help guide other communities preparing for opioid or substance-related campaigns in the future.


Assuntos
Comunicação , Promoção da Saúde , Overdose de Opiáceos , Humanos , Analgésicos Opioides/efeitos adversos , COVID-19/epidemiologia , Overdose de Opiáceos/prevenção & controle , Pandemias
3.
Bioorg Med Chem Lett ; 25(9): 1856-63, 2015 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-25845281

RESUMO

Glycogen synthase kinase-3 (GSK-3) has been proposed to play a crucial role in the pathogenesis of many diseases including cancer, stroke, bipolar disorders, diabetes and neurodegenerative diseases. GSK-3 inhibition has been a major area of pharmaceutical interest over the last two decades. A plethora of reports appeared recently on selective inhibitors and their co-crystal structures in GSK-3ß. We identified several series of promising new GSK-3ß inhibitors from a coherent design around a pyrrolopyridinone core structure. A systematic exploration of the chemical space around the central spacer led to potent single digit and sub-nanomolar GSK-3ß inhibitors. When dosed orally in a transgenic mouse model of Alzheimer's disease (AD), an exemplary compound showed significant lowering of Tau phosphorylation at one of the GSK-3 phosphorylating sites, Ser396. X-ray crystallography greatly aided in validating the binding hypotheses.


Assuntos
Aminopiridinas/farmacologia , Descoberta de Drogas , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Piridonas/química , Pirróis/química , Aminopiridinas/administração & dosagem , Aminopiridinas/química , Animais , Cristalografia por Raios X , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Quinase 3 da Glicogênio Sintase/metabolismo , Humanos , Camundongos , Camundongos Transgênicos , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade
4.
J Med Chem ; 66(6): 4231-4252, 2023 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-36950863

RESUMO

Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase that regulates numerous cellular processes, including metabolism, proliferation, and cell survival. Due to its multifaceted role, GSK-3 has been implicated in a variety of diseases, including Alzheimer's disease, type 2 diabetes, cancer, and mood disorders. GSK-3ß has been linked to the formation of the neurofibrillary tangles associated with Alzheimer's disease that arise from the hyperphosphorylation of tau protein. The design and synthesis of a series of imidazo[1,2-b]pyridazine derivatives that were evaluated as GSK-3ß inhibitors are described herein. Structure-activity relationship studies led to the identification of potent GSK-3ß inhibitors. In vivo studies with 47 in a triple-transgenic mouse Alzheimer's disease model showed that this compound is a brain-penetrant, orally bioavailable GSK-3ß inhibitor that significantly lowered levels of phosphorylated tau.


Assuntos
Doença de Alzheimer , Diabetes Mellitus Tipo 2 , Camundongos , Animais , Doença de Alzheimer/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismo , Quinase 3 da Glicogênio Sintase/metabolismo , Proteínas tau/metabolismo , Camundongos Transgênicos , Encéfalo/metabolismo , Relação Estrutura-Atividade , Fosforilação
5.
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
6.
Mol Ther Nucleic Acids ; 29: 625-642, 2022 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-36090761

RESUMO

Tau is a microtubule-associated protein (MAPT, tau) implicated in the pathogenesis of tauopathies, a spectrum of neurodegenerative disorders characterized by accumulation of hyperphosphorylated, aggregated tau. Because tau pathology can be distinct across diseases, a pragmatic therapeutic approach may be to intervene at the level of the tau transcript, as it makes no assumptions to mechanisms of tau toxicity. Here we performed a large library screen of locked-nucleic-acid (LNA)-modified antisense oligonucleotides (ASOs), where careful tiling of the MAPT locus resulted in the identification of hot spots for activity in the 3' UTR. Further modifications to the LNA design resulted in the generation of ASO-001933, which selectively and potently reduces tau in primary cultures from hTau mice, monkey, and human neurons. ASO-001933 was well tolerated and produced a robust, long-lasting reduction in tau protein in both mouse and cynomolgus monkey brain. In monkey, tau protein reduction was maintained in brain for 20 weeks post injection and corresponded with tau protein reduction in the cerebrospinal fluid (CSF). Our results demonstrate that LNA-ASOs exhibit excellent drug-like properties and sustained efficacy likely translating to infrequent, intrathecal dosing in patients. These data further support the development of LNA-ASOs against tau for the treatment of tauopathies.

7.
Artigo em Inglês | MEDLINE | ID: mdl-34733584

RESUMO

This article examines conceptualizations of the relationship between food insecurity and place. We use an ethnographically inspired and community-engaged approach to situate our analysis of fluid dynamics at work in a community with high levels of food insecurity. We propose that the relationship between place and people's experience of food insecurity is recursive, dialectical, and "whorled." This relationship reflects complex, interconnected, and multidimensional processes with consequences for the health of residents. Our research demonstrates the key nature of the health-place nexus by exploring how food insecurity articulates with place in unexpected ways that go beyond discussions of food, food environments, food access, food practices or food systems that have become common in the literature.

8.
J Clin Oncol ; 23(33): 8512-9, 2005 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-16260687

RESUMO

PURPOSE: To update the 2000 American Society of Clinical Oncology guideline on colorectal cancer surveillance. RECOMMENDATIONS: Based on results from three independently reported meta-analyses of randomized controlled trials that compared low-intensity and high-intensity programs of colorectal cancer surveillance, and on recent analyses of data from major clinical trials in colon and rectal cancer, the Panel recommends annual computed tomography (CT) of the chest and abdomen for 3 years after primary therapy for patients who are at higher risk of recurrence and who could be candidates for curative-intent surgery; pelvic CT scan for rectal cancer surveillance, especially for patients with several poor prognostic factors, including those who have not been treated with radiation; colonoscopy at 3 years after operative treatment, and, if results are normal, every 5 years thereafter; flexible proctosigmoidoscopy [corrected] every 6 months for 5 years for rectal cancer patients who have not been treated with pelvic radiation; history and physical examination every 3 to 6 months for the first 3 years, every 6 months during years 4 and 5, and subsequently at the discretion of the physician; and carcinoembryonic antigen every 3 months postoperatively for at least 3 years after diagnosis, if the patient is a candidate for surgery or systemic therapy. Chest x-rays, CBCs, and liver function tests are not recommended, and molecular or cellular markers should not influence the surveillance strategy based on available evidence.


Assuntos
Neoplasias Colorretais/prevenção & controle , Continuidade da Assistência ao Paciente , Biomarcadores Tumorais , Diagnóstico por Imagem , Humanos , Anamnese , Exame Físico , Guias de Prática Clínica como Assunto , Medição de Risco , Prevenção Secundária , Estados Unidos
9.
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
10.
Int J Alzheimers Dis ; 2014: 431858, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25097793

RESUMO

Alzheimer's disease is the most prevalent cause of dementia and is associated with accumulation of amyloid-ß peptide (Aß), particularly the 42-amino acid Aß1-42, in the brain. Aß1-42 levels can be decreased by γ-secretase modulators (GSM), which are small molecules that modulate γ-secretase, an enzyme essential for Aß production. BMS-869780 is a potent GSM that decreased Aß1-42 and Aß1-40 and increased Aß1-37 and Aß1-38, without inhibiting overall levels of Aß peptides or other APP processing intermediates. BMS-869780 also did not inhibit Notch processing by γ-secretase and lowered brain Aß1-42 without evidence of Notch-related side effects in rats. Human pharmacokinetic (PK) parameters were predicted through allometric scaling of PK in rat, dog, and monkey and were combined with the rat pharmacodynamic (PD) parameters to predict the relationship between BMS-869780 dose, exposure and Aß1-42 levels in human. Off-target and safety margins were then based on comparisons to the predicted exposure required for robust Aß1-42 lowering. Because of insufficient safety predictions and the relatively high predicted human daily dose of 700 mg, further evaluation of BMS-869780 as a potential clinical candidate was discontinued. Nevertheless, BMS-869780 demonstrates the potential of the GSM approach for robust lowering of brain Aß1-42 without Notch-related side effects.

11.
J Med Chem ; 52(9): 3084-92, 2009 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-19361209

RESUMO

This report describes the syntheses and structure-activity relationships of 8-(substituted pyridyl)pyrazolo[1,5-a]-1,3,5-triazine corticotropin releasing factor receptor-1 (CRF(1)) receptor antagonists. These CRF(1) receptor antagonists may be potential anxiolytic or antidepressant drugs. This research resulted in the discovery of compound 13-15, which is a potent, selective CRF(1) antagonist (hCRF(1) IC(50) = 6.1 +/- 0.6 nM) with weak affinity for the CRF-binding protein and biogenic amine receptors. This compound also has a good pharmacokinetic profile in dogs. Analogue 13-15 is orally effective in two rat models of anxiety: the defensive withdrawal (situational anxiety) model and the elevated plus maze test. Analogue 13-15 has been advanced to clinical trials.


Assuntos
Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores , Triazinas/síntese química , Triazinas/farmacologia , Administração Oral , Animais , Comportamento Animal/efeitos dos fármacos , Disponibilidade Biológica , Ensaios Clínicos como Assunto , Cães , Concentração Inibidora 50 , Ratos , Solubilidade , Relação Estrutura-Atividade , Triazinas/administração & dosagem , Triazinas/farmacocinética , Água/química
12.
J Med Chem ; 52(9): 3073-83, 2009 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-19361210

RESUMO

This report describes the syntheses and structure-activity relationships of 8-(4-methoxyphenyl)pyrazolo[1,5-a]-1,3,5-triazine corticotropin releasing factor receptor-1 (CRF(1)) receptor antagonists. CRF(1) receptor antagonists may be potential anxiolytic or antidepressant drugs. This research culminated in the discovery of analogue 12-3, which is a potent, selective CRF(1) antagonist (hCRF(1) IC(50) = 4.7 +/- 2.0 nM) with weak affinity for the CRF-binding protein and biogenic amine receptors. This compound also has a good pharmacokinetic profile in dogs. Analogue 12-3 is orally effective in two rat models of anxiety: the defensive withdrawal (situational anxiety) model and the elevated plus maze test. Analogue 12-3 has been advanced to clinical trials.


Assuntos
Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores , Triazinas/química , Triazinas/farmacologia , Animais , Ansiolíticos/química , Ansiolíticos/farmacocinética , Ansiolíticos/farmacologia , Ansiolíticos/uso terapêutico , Ansiedade/tratamento farmacológico , Ensaios Clínicos como Assunto , Cães , Feminino , Concentração Inibidora 50 , Masculino , Ratos , Receptores de Amina Biogênica/metabolismo , Receptores de Hormônio Liberador da Corticotropina/metabolismo , Relação Estrutura-Atividade , Especificidade por Substrato , Triazinas/farmacocinética , Triazinas/uso terapêutico
13.
J Biol Chem ; 283(34): 22992-3003, 2008 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-18574238

RESUMO

The amyloid-beta (Abeta) peptide, which likely plays a key role in Alzheimer disease, is derived from the amyloid-beta precursor protein (APP) through consecutive proteolytic cleavages by beta-site APP-cleaving enzyme and gamma-secretase. Unexpectedly gamma-secretase inhibitors can increase the secretion of Abeta peptides under some circumstances. This "Abeta rise" phenomenon, the same inhibitor causing an increase in Abeta at low concentrations but inhibition at higher concentrations, has been widely observed. Here we show that the Abeta rise depends on the beta-secretase-derived C-terminal fragment of APP (betaCTF) or C99 levels with low levels causing rises. In contrast, the N-terminally truncated form of Abeta, known as "p3," formed by alpha-secretase cleavage, did not exhibit a rise. In addition to the Abeta rise, low betaCTF or C99 expression decreased gamma-secretase inhibitor potency. This "potency shift" may be explained by the relatively high enzyme to substrate ratio under conditions of low substrate because increased concentrations of inhibitor would be necessary to affect substrate turnover. Consistent with this hypothesis, gamma-secretase inhibitor radioligand occupancy studies showed that a high level of occupancy was correlated with inhibition of Abeta under conditions of low substrate expression. The Abeta rise was also observed in rat brain after dosing with the gamma-secretase inhibitor BMS-299897. The Abeta rise and potency shift are therefore relevant factors in the development of gamma-secretase inhibitors and can be evaluated using appropriate choices of animal and cell culture models. Hypothetical mechanisms for the Abeta rise, including the "incomplete processing" and endocytic models, are discussed.


Assuntos
Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/metabolismo , Regulação Enzimológica da Expressão Gênica , Animais , Encéfalo/metabolismo , Butiratos/farmacologia , Linhagem Celular , Inibidores Enzimáticos/farmacologia , Feminino , Humanos , Hidrocarbonetos Halogenados/farmacologia , Camundongos , Ligação Proteica , Estrutura Terciária de Proteína , Ratos , Especificidade por Substrato
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