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1.
Nat Commun ; 15(1): 5109, 2024 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-38877019

RESUMO

Positron emission tomography (PET) imaging of tau aggregation in Alzheimer's disease (AD) is helping to map and quantify the in vivo progression of AD pathology. To date, no high-affinity tau-PET radiopharmaceutical has been optimized for imaging non-AD tauopathies. Here we show the properties of analogues of a first-in-class 4R-tau lead, [18F]OXD-2115, using ligand-based design. Over 150 analogues of OXD-2115 were synthesized and screened in post-mortem brain tissue for tau affinity against [3H]OXD-2115, and in silico models were used to predict brain uptake. [18F]OXD-2314 was identified as a selective, high-affinity non-AD tau PET radiotracer with favorable brain uptake, dosimetry, and radiometabolite profiles in rats and non-human primate and is being translated for first-in-human PET studies.


Assuntos
Doença de Alzheimer , Encéfalo , Radioisótopos de Flúor , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos , Tauopatias , Proteínas tau , Tomografia por Emissão de Pósitrons/métodos , Animais , Humanos , Tauopatias/diagnóstico por imagem , Tauopatias/metabolismo , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Ligantes , Compostos Radiofarmacêuticos/química , Compostos Radiofarmacêuticos/farmacocinética , Compostos Radiofarmacêuticos/síntese química , Ratos , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/metabolismo , Radioisótopos de Flúor/química , Proteínas tau/metabolismo , Masculino
2.
ACS Chem Neurosci ; 12(4): 596-602, 2021 02 17.
Artigo em Inglês | MEDLINE | ID: mdl-33497190

RESUMO

CBD-2115 was selected from a library of 148 compounds based on a pyridinyl-indole scaffold as a first-in-class 4R-tau radiotracer. In vitro binding assays showed [3H]CBD-2115 had a KD value of 6.9 nM and a nominal Bmax of 500 nM in 4R-tau expressing P301L transgenic mouse tissue. In binding assays with human brain tissue homogenates, [3H]CBD-2115 has a higher affinity (4.9 nM) for progressive supranuclear palsy specific 4R-tau deposits than [3H]flortaucipir (45 nM) or [3H]MK-6240 (>50 nM). [18F]CBD-2115 was reliably synthesized (3-11% radiochemical yield with molar activity of 27-111 GBq/µmol and >97% radiochemical purity). Dynamic PET imaging was conducted in mice, rats, and nonhuman primates, and all species showed initial brain uptake of 0.5-0.65 standardized uptake value with fast clearance from normal tissues. [3H]CBD-2115 could be a useful lead radioligand for further research in 4R-tauopathies, and PET radiotracer development will focus on improving brain uptake and binding affinity.


Assuntos
Tauopatias , Animais , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Camundongos , Tomografia por Emissão de Pósitrons , Radioquímica , Compostos Radiofarmacêuticos , Ratos , Proteínas tau/metabolismo
3.
Comput Biol Med ; 104: 291-298, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30458961

RESUMO

BACKGROUND: Spiral waves are considered to be one of the potential mechanisms that maintain complex arrhythmias such as atrial and ventricular fibrillation. The aim of the present study was to quantify the complex dynamics of spiral waves as the organizing manifolds of information flow at multiple scales. METHOD: We simulated spiral waves using a numerical model of cardiac excitation in a two-dimensional (2-D) lattice. We created a renormalization group by coarse graining and re-scaling the original time series in multiple spatiotemporal scales, and quantified the Lagrangian coherent structures (LCS) of the information flow underlying the spiral waves. To quantify the scale-invariant structures, we compared the value of the finite-time Lyapunov exponent between the corresponding components of the 2-D lattice in each spatiotemporal scale of the renormalization group with that of the original scale. RESULTS: Both the repelling and the attracting LCS changed across the different spatial and temporal scales of the renormalization group. However, despite the change across the scales, some LCS were scale-invariant. The patterns of those scale-invariant structures were not obvious from the trajectory of the spiral waves based on voltage mapping of the lattice. CONCLUSIONS: Some Lagrangian coherent structures of information flow underlying spiral waves are preserved across multiple spatiotemporal scales.


Assuntos
Arritmias Cardíacas/fisiopatologia , Simulação por Computador , Modelos Cardiovasculares , Átrios do Coração/fisiopatologia , Humanos
4.
J Med Chem ; 56(8): 3177-90, 2013 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-23516963

RESUMO

We have developed two parallel series, A and B, of CX3CR1 antagonists for the treatment of multiple sclerosis. By modifying the substituents on the 7-amino-5-thio-thiazolo[4,5-d]pyrimidine core structure, we were able to achieve compounds with high selectivity for CX3CR1 over the closely related CXCR2 receptor. The structure-activity relationships showed that a leucinol moiety attached to the core-structure in the 7-position together with α-methyl branched benzyl derivatives in the 5-position displayed promising affinity, and selectivity as well as physicochemical properties, as exemplified by compounds 18a and 24h. We show the preparation of the first potent and selective orally available CX3CR1 antagonists.


Assuntos
Esclerose Múltipla/tratamento farmacológico , Pirimidinas/farmacologia , Receptores de Quimiocinas/antagonistas & inibidores , Tiazóis/farmacologia , Amino Álcoois/síntese química , Amino Álcoois/farmacocinética , Amino Álcoois/farmacologia , Animais , Receptor 1 de Quimiocina CX3C , Células CACO-2 , Humanos , Pirimidinas/síntese química , Pirimidinas/química , Pirimidinas/farmacocinética , Ratos , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/química , Tiazóis/farmacocinética
5.
Bioorg Med Chem Lett ; 22(22): 6888-95, 2012 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-23058884

RESUMO

A novel indolizine class of compounds was identified as TRPV1 antagonist from an HTS campaign. However, this indolizine class proved to be unstable and reacted readily with glutathione when exposed to light and oxygen. Reactivity was reduced by the introduction of a nitrogen atom alpha to the indolizine nitrogen. The pyrrolopyridazine core obtained proved to be inert to the action of light and oxygen. The synthesis route followed the one used for the indolizine compounds, and the potency and ADMET profile proved to be similar.


Assuntos
Piridazinas/química , Pirróis/química , Canais de Cátion TRPV/antagonistas & inibidores , Animais , Células CACO-2 , Permeabilidade da Membrana Celular/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Humanos , Indolizidinas/química , Microssomos Hepáticos/metabolismo , Piridazinas/síntese química , Piridazinas/farmacocinética , Pirróis/síntese química , Pirróis/farmacocinética , Ratos , Relação Estrutura-Atividade , Canais de Cátion TRPV/metabolismo
6.
Bioorg Med Chem Lett ; 22(17): 5485-92, 2012 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-22868228

RESUMO

A series of potent antagonists of the ion channel transient receptor potential A1 (TRPA1) was developed by modifying lead structure 16 that was discovered by high-throughput screening. Based on lead compound 16, a SAR was established, showing a narrow region at the nitro-aromatic R(1) moiety and at the warhead, while the R(2) side had a much wider scope including ureas and carbamates. Compound 16 inhibits Ca(2+)-activated TRPA1 currents reversibly in whole cell patch clamp experiments, indicating that under in vivo conditions, it does not react covalently, despite its potentially electrophilic ketone.


Assuntos
Amidas/química , Amidas/farmacologia , Proteínas do Tecido Nervoso/antagonistas & inibidores , Canais de Potencial de Receptor Transitório/antagonistas & inibidores , Cálcio/metabolismo , Canais de Cálcio/metabolismo , Carbamatos/química , Carbamatos/farmacologia , Humanos , Proteínas do Tecido Nervoso/metabolismo , Técnicas de Patch-Clamp , Relação Estrutura-Atividade , Canal de Cátion TRPA1 , Canais de Potencial de Receptor Transitório/metabolismo , Ureia/química , Ureia/farmacologia
7.
Bioorg Med Chem Lett ; 20(6): 1976-80, 2010 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-20153963

RESUMO

The syntheses and SAR of new series of beta-amyloid binding agents are reported. The effort to optimize signal-to-background ratios for these ligands are described. Compounds 8, 21 and 30 displayed desirable lipophilicity and pharmacokinetic properties. Compounds 8 and 21 were evaluated with in vitro autoradiographic studies and in vivo in APP/PS1 transgenic mice. It is shown that it was possible to increase the signal-to-background ratios compared to PIB 1, as demonstrated by compounds 8 and 21.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Benzofuranos/síntese química , Benzofuranos/farmacocinética , Benzotiazóis/síntese química , Benzotiazóis/farmacocinética , Benzoxazóis/síntese química , Benzoxazóis/farmacocinética , Tomografia por Emissão de Pósitrons , Animais , Radioisótopos de Carbono , Meia-Vida , Camundongos , Camundongos Transgênicos , Ensaio Radioligante , Relação Estrutura-Atividade
9.
J Med Chem ; 47(16): 3927-30, 2004 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-15267230

RESUMO

The understanding of the physiological role of the G-protein coupled serotonin 5-HT(7) receptor is largely rudimentary. Therefore, selective and potent pharmacological tools will add to the understanding of serotonergic effects mediated through this receptor. In this report, we describe two compound classes, chromans and tetralins, encompassing compounds with nanomolar affinity for the 5-HT(7) receptor and with good selectivity. Within theses classes, we have discovered both agonists and antagonists that can be used for further understanding of the pharmacology of the 5-HT(7) receptor.


Assuntos
Cromanos/síntese química , Receptores de Serotonina/efeitos dos fármacos , Antagonistas da Serotonina/síntese química , Agonistas do Receptor de Serotonina/síntese química , Tetra-Hidronaftalenos/síntese química , Animais , Células CHO , Cromanos/química , Cromanos/farmacologia , Cricetinae , AMP Cíclico/biossíntese , Ligantes , Receptores de Serotonina/metabolismo , Antagonistas da Serotonina/química , Antagonistas da Serotonina/farmacologia , Agonistas do Receptor de Serotonina/química , Agonistas do Receptor de Serotonina/farmacologia , Estereoisomerismo , Relação Estrutura-Atividade , Tetra-Hidronaftalenos/química , Tetra-Hidronaftalenos/farmacologia
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