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1.
Bioorg Med Chem Lett ; 25(4): 908-13, 2015 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-25582600

RESUMO

Herein we describe design strategies that led to the discovery of novel pyridopyrazine-1,6-dione γ-secretase modulators (GSMs) incorporating an indole motif as a heterocyclic replacement for a naphthyl moiety that was present in the original lead 9. Tactics involving parallel medicinal chemistry and in situ monomer synthesis to prepare focused libraries are discussed. Optimized indole GSM 29 exhibited good alignment of in vitro potency and physicochemical properties, and moderate reduction of brain Aß42 was achieved in a rat efficacy model when dosed orally at 30mg/kg. Labeling experiments using a clickable, indole-derived GSM photoaffinity probe demonstrated that this series binds to the presenilin N-terminal fragment (PS1-NTF) of the γ-secretase complex.


Assuntos
Secretases da Proteína Precursora do Amiloide/efeitos dos fármacos , Descoberta de Drogas , Indóis/farmacologia , Presenilinas/efeitos dos fármacos , Pirazinas/química , Animais , Indóis/química , Ratos
2.
J Med Chem ; 67(12): 10248-10262, 2024 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-38848667

RESUMO

Herein, we describe the design and synthesis of γ-secretase modulator (GSM) clinical candidate PF-06648671 (22) for the treatment of Alzheimer's disease. A key component of the design involved a 2,5-cis-tetrahydrofuran (THF) linker to impart conformational rigidity and lock the compound into a putative bioactive conformation. This effort was guided using a pharmacophore model since crystallographic information was not available for the membrane-bound γ-secretase protein complex at the time of this work. PF-06648671 achieved excellent alignment of whole cell in vitro potency (Aß42 IC50 = 9.8 nM) and absorption, distribution, metabolism, and excretion (ADME) parameters. This resulted in favorable in vivo pharmacokinetic (PK) profile in preclinical species, and PF-06648671 achieved a human PK profile suitable for once-a-day dosing. Furthermore, PF-06648671 was found to have favorable brain availability in rodent, which translated into excellent central exposure in human and robust reduction of amyloid ß (Aß) 42 in cerebrospinal fluid (CSF).


Assuntos
Doença de Alzheimer , Secretases da Proteína Precursora do Amiloide , Peptídeos beta-Amiloides , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Secretases da Proteína Precursora do Amiloide/metabolismo , Doença de Alzheimer/tratamento farmacológico , Humanos , Animais , Peptídeos beta-Amiloides/metabolismo , Ratos , Relação Estrutura-Atividade , Camundongos , Masculino , Descoberta de Drogas , Furanos/farmacologia , Furanos/farmacocinética , Furanos/síntese química , Furanos/química , Furanos/uso terapêutico , Ratos Sprague-Dawley , Encéfalo/metabolismo
3.
Bioorg Med Chem Lett ; 23(7): 1961-6, 2013 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-23466229

RESUMO

The structure-based design, synthesis, and biological evaluation of a new pyrazole series of irreversible KAT II inhibitors are described herein. The modification of the inhibitor scaffold of 1 and 2 from a dihydroquinolinone core to a tetrahydropyrazolopyridinone core led to discovery of a new series of potent KAT II inhibitors with excellent physicochemical properties. Compound 20 is the most potent and lipophilically efficient of these new pyrazole analogs, with a k(inact)/K(i) value of 112,000 M(-1)s(-1) and lipophilic efficiency (LipE) of 8.53. The X-ray crystal structure of 20 with KAT II demonstrates key features that contribute to this remarkable potency and binding efficiency.


Assuntos
Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Pirazóis/farmacologia , Transaminases/antagonistas & inibidores , Domínio Catalítico/efeitos dos fármacos , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Interações Hidrofóbicas e Hidrofílicas/efeitos dos fármacos , Modelos Moleculares , Estrutura Molecular , Pirazóis/síntese química , Pirazóis/química , Relação Estrutura-Atividade , Transaminases/metabolismo
4.
J Org Chem ; 76(9): 3484-97, 2011 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-21452845

RESUMO

We describe a generalized approach to stereocontrolled synthesis of substituted cyclic hydroxamic acids (3-amino-1-hydroxy-3,4-dihydroquinolinones) by selective reduction of substituted 2-nitrophenylalanine substrates. Compounds in this series have antibacterial properties and have also recently been reported as KAT II inhibitors. The key nitrophenyl alanine intermediates are prepared enantioselectively in excellent yield by phase transfer catalyzed alkylation of the corresponding nitrobenzyl bromides. The scope and limitations of the reductive cyclization transformation have been explored with attention to the effects of substitution pattern and electronics on reaction efficiency and byproduct formation. In addition, a novel activated trifluoroethyl ester cyclization strategy has been developed as an alternate approach to the most sterically demanding systems in this series.


Assuntos
Ácidos Hidroxâmicos/química , Ácidos Hidroxâmicos/síntese química , Nitrocompostos/química , Ciclização , Ésteres , Oxirredução , Fenilalanina/análogos & derivados , Fenilalanina/síntese química , Fenilalanina/química , Acetato de Sódio/química , Especificidade por Substrato , Compostos de Estanho/química
5.
Cell Chem Biol ; 28(2): 148-157.e7, 2021 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-32997975

RESUMO

Utilizing a phenotypic screen, we identified chemical matter that increased astrocytic apoE secretion in vitro. We designed a clickable photoaffinity probe based on a pyrrolidine lead compound and carried out probe-based quantitative chemical proteomics in human astrocytoma CCF-STTG1 cells to identify liver x receptor ß (LXRß) as the target. Binding of the small molecule ligand stabilized LXRß, as shown by cellular thermal shift assay (CETSA). In addition, we identified a probe-modified peptide by mass spectrometry and proposed a model where the photoaffinity probe is bound in the ligand-binding pocket of LXRß. Taken together, our findings demonstrated that the lead chemical matter bound directly to LXRß, and our results highlight the power of chemical proteomic approaches to identify the target of a phenotypic screening hit. Additionally, the LXR photoaffinity probe and lead compound described herein may serve as valuable tools to further evaluate the LXR pathway.


Assuntos
Apolipoproteínas E/metabolismo , Astrócitos/metabolismo , Receptores X do Fígado/metabolismo , Astrócitos/citologia , Linhagem Celular , Humanos , Ligantes , Ligação Proteica , Proteômica
6.
Org Lett ; 20(3): 812-815, 2018 02 02.
Artigo em Inglês | MEDLINE | ID: mdl-29327935

RESUMO

The design, synthesis, and application of [4-(acetylamino)phenyl]imidodisulfuryl difluoride (AISF), a shelf-stable, crystalline reagent for the synthesis of sulfur(VI) fluorides, is described. The utility of AISF is demonstrated in the synthesis of a diverse array of aryl fluorosulfates and sulfamoyl fluorides under mild conditions. Additionally, a single-step preparation of AISF was developed that installed the bis(fluorosulfonyl)imide group on acetanilide utilizing an oxidative C-H functionalization protocol.

7.
Medchemcomm ; 8(4): 730-743, 2017 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30108792

RESUMO

Herein we describe the discovery of a novel series of cyclopropyl chromane-derived pyridopyrazine-1,6-dione γ-secretase modulators for the treatment of Alzheimer's disease (AD). Using ligand-based design tactics such as conformational analysis and molecular modeling, a cyclopropyl chromane unit was identified as a suitable heterocyclic replacement for a naphthyl moiety that was present in the preliminary lead 4. The optimized lead molecule 44 achieved good central exposure resulting in robust and sustained reduction of brain amyloid-ß42 (Aß42) when dosed orally at 10 mg kg-1 in a rat time-course study. Application of the unpaced isolated heart Langendorff model enabled efficient differentiation of compounds with respect to cardiovascular safety, highlighting how minor structural changes can greatly impact the safety profile within a series of compounds.

8.
ACS Med Chem Lett ; 4(1): 37-40, 2013 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-24900560

RESUMO

A series of aryl hydroxamates recently have been disclosed as irreversible inhibitors of kynurenine amino transferase II (KAT II), an enzyme that may play a role in schizophrenia and other psychiatric and neurological disorders. The utilization of structure-activity relationships (SAR) in conjunction with X-ray crystallography led to the discovery of hydroxamate 4, a disubstituted analogue that has a significant potency enhancement due to a novel interaction with KAT II. The use of k inact/K i to assess potency was critical for understanding the SAR in this series and for identifying compounds with improved pharmacodynamic profiles.

9.
ACS Med Chem Lett ; 3(3): 187-92, 2012 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-24900455

RESUMO

Kynurenine aminotransferase (KAT) II has been identified as a potential new target for the treatment of cognitive impairment associated with schizophrenia and other psychiatric disorders. Following a high-throughput screen, cyclic hydroxamic acid PF-04859989 was identified as a potent and selective inhibitor of human and rat KAT II. An X-ray crystal structure and (13)C NMR studies of PF-04859989 bound to KAT II have demonstrated that this compound forms a covalent adduct with the enzyme cofactor, pyridoxal phosphate (PLP), in the active site. In vivo pharmacokinetic and efficacy studies in rat show that PF-04859989 is a brain-penetrant, irreversible inhibitor and is capable of reducing brain kynurenic acid by 50% at a dose of 10 mg/kg (sc). Preliminary structure-activity relationship investigations have been completed and have identified the positions on this scaffold best suited to modification for further optimization of this novel series of KAT II inhibitors.

10.
J Med Chem ; 53(3): 1222-37, 2010 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-20043678

RESUMO

A novel alpha 7 nAChR agonist, 4-(5-methyloxazolo[4,5-b]pyridin-2-yl)-1,4-diazabicyclo[3.2.2]nonane (24, CP-810,123), has been identified as a potential treatment for cognitive deficits associated with psychiatric or neurological conditions including schizophrenia and Alzheimer's disease. Compound 24 is a potent and selective compound with excellent pharmaceutical properties. In rodent, the compound displays high oral bioavailability and excellent brain penetration affording high levels of receptor occupancy and in vivo efficacy in auditory sensory gating and novel object recognition. The structural diversity of this compound and its preclinical in vitro and in vivo package support the hypothesis that alpha 7 nAChR agonists may have potential as a pharmacotherapy for the treatment of cognitive deficits in schizophrenia.


Assuntos
Compostos Azabicíclicos/síntese química , Compostos Azabicíclicos/farmacologia , Transtornos Cognitivos/tratamento farmacológico , Agonistas Nicotínicos/síntese química , Agonistas Nicotínicos/farmacologia , Nootrópicos/síntese química , Nootrópicos/farmacologia , Oxazóis/síntese química , Oxazóis/farmacologia , Receptores Nicotínicos/química , Esquizofrenia/tratamento farmacológico , Animais , Compostos Azabicíclicos/química , Disponibilidade Biológica , Células Cultivadas , Células Epiteliais/efeitos dos fármacos , Feminino , Hipocampo/efeitos dos fármacos , Humanos , Rim/citologia , Rim/efeitos dos fármacos , Microssomos Hepáticos/efeitos dos fármacos , Agonistas Nicotínicos/química , Nootrópicos/química , Oócitos/efeitos dos fármacos , Oxazóis/química , Ratos , Pele/citologia , Pele/efeitos dos fármacos , Relação Estrutura-Atividade , Xenopus laevis/crescimento & desenvolvimento , Receptor Nicotínico de Acetilcolina alfa7
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