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1.
Bioorg Med Chem Lett ; 23(12): 3592-8, 2013 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-23642482

RESUMO

The identification of a novel fused triazolo-pyrrolopyridine scaffold, optimized derivatives of which display nanomolar inhibition of Janus kinase 1, is described. Prototypical example 3 demonstrated lower cell potency shift, better permeability in cells and higher oral exposure in rat than the corresponding, previously reported, imidazo-pyrrolopyridine analogue 2. Examples 6, 7 and 18 were subsequently identified from an optimization campaign and demonstrated modest selectivity over JAK2, moderate to good oral bioavailability in rat with overall pharmacokinetic profiles comparable to that reported for an approved pan-JAK inhibitor (tofacitinib).


Assuntos
Janus Quinase 1/antagonistas & inibidores , Piridinas/farmacologia , Animais , Cristalografia por Raios X , Janus Quinase 1/química , Janus Quinase 2/antagonistas & inibidores , Janus Quinase 2/química , Cinética , Modelos Moleculares , Piridinas/química , Pirróis/química , Pirróis/farmacologia , Ratos
2.
J Med Chem ; 65(24): 16589-16621, 2022 12 22.
Artigo em Inglês | MEDLINE | ID: mdl-36455032

RESUMO

Small molecule inhibitors that target the phosphatidylinositol 3-kinase (PI3K) signaling pathway have received significant interest for the treatment of cancers. The class I isoform PI3Kα is most commonly associated with solid tumors via gene amplification or activating mutations. However, inhibitors demonstrating both PI3K isoform and mutant specificity have remained elusive. Herein, we describe the optimization and characterization of a series of benzoxazepin-oxazolidinone ATP-competitive inhibitors of PI3Kα which also induce the selective degradation of the mutant p110α protein, the catalytic subunit of PI3Kα. Structure-based design informed isoform-specific interactions within the binding site, leading to potent inhibitors with greater than 300-fold selectivity over the other Class I PI3K isoforms. Further optimization of pharmacokinetic properties led to excellent in vivo exposure and efficacy and the identification of clinical candidate GDC-0077 (inavolisib, 32), which is now under evaluation in a Phase III clinical trial as a treatment for patients with PIK3CA-mutant breast cancer.


Assuntos
Neoplasias da Mama , Fosfatidilinositol 3-Quinases , Humanos , Feminino , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Inibidores de Fosfoinositídeo-3 Quinase/uso terapêutico , Fosfatidilinositol 3-Quinases/metabolismo , Classe I de Fosfatidilinositol 3-Quinases/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Mutação
3.
Magn Reson Chem ; 46(1): 1-8, 2008 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-18041011

RESUMO

A general and unambiguous approach has been developed for structural elucidation of modified purine nucleosides using NMR spectroscopy. Systematic assignment of proton and carbon signals of modified nucleosides was firmly established by COSY and the anomerism of the glycosidic linkage of synthetic nucleosides clearly elucidated by NOESY experiments. Characteristic properties of 15N-isotopic labelling at specific positions of nucleosides were also employed for structural studies. The reported approach is applicable to other modified nucleosides and nucleotides, as well as nucleobases.


Assuntos
Espectroscopia de Ressonância Magnética/métodos , Nucleosídeos de Purina/química , Nucleotídeos de Purina/química , Carboidratos/química , Conformação de Ácido Nucleico , Prótons
4.
Nucleic Acids Res ; 33(6): 1767-78, 2005.
Artigo em Inglês | MEDLINE | ID: mdl-15788749

RESUMO

Site-specific modification of the N1-position of purine was explored at the nucleoside and oligomer levels. 2'-deoxyinosine was converted into an N1-2,4-dinitrophenyl derivative 2 that was readily transformed to the desired N1-substituted 2'-deoxyinosine analogues. This approach was used to develop a post-synthetic method for the modification of the endocyclic N1-position of purine at the oligomer level. The phosphoramidite monomer of N1-(2,4-dinitrophenyl)-2'-deoxyinosine 9 was prepared from 2'-deoxyinosine in four steps and incorporated into oligomers using an automated DNA synthesizer. The modified base, N1-(2,4-dinitrophenyl)-hypoxanthine, in synthesized oligomers, upon treatment with respective agents, was converted into corresponding N1-substituted hypoxanthines, including N1-15N-hypoxanthine, N1-methylhypoxanthine and N1-(2-aminoethyl)-hypoxanthine. These modified oligomers can be easily separated and high purity oligomers obtained. Melting curve studies show the oligomer containing N1-methylhypoxanthine or N1-(2-aminoethyl)-hypoxanthine has a reduced thermostability with no particular pairing preference to either cytosine or thymine. The developed method could be adapted for the preparation of oligomers containing mutagenic N1-beta-hydroxyalkyl-hypoxanthines and the availability of the rare base-modified oligomers should offer novel tools for biological and structural studies.


Assuntos
2,4-Dinitrofenol/análogos & derivados , 2,4-Dinitrofenol/química , Hipoxantina/química , Hipoxantinas , Inosina/análogos & derivados , Inosina/química , Oligodesoxirribonucleotídeos/síntese química , 2,4-Dinitrofenol/síntese química , DNA/química , Hipoxantinas/química , Inosina/síntese química , Nitrogênio/química , Nucleosídeos/química , Oligodesoxirribonucleotídeos/química , Oligodesoxirribonucleotídeos/isolamento & purificação
5.
Fitoterapia ; 78(6): 446-7, 2007 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-17616261

RESUMO

A new trimethoxychalcone (1) was isolated from the aerial parts of Crotalaria ramosissima. The structure was elucidated on the basis of (1)H NMR, (13)C NMR and MS methods.


Assuntos
Crotalaria , Fitoterapia , Extratos Vegetais/química , Chalconas/química , Humanos , Espectroscopia de Ressonância Magnética , Espectrometria de Massas
6.
J Med Chem ; 58(12): 5053-74, 2015 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-25988399

RESUMO

Checkpoint kinase 1 (ChK1) plays a key role in the DNA damage response, facilitating cell-cycle arrest to provide sufficient time for lesion repair. This leads to the hypothesis that inhibition of ChK1 might enhance the effectiveness of DNA-damaging therapies in the treatment of cancer. Lead compound 1 (GNE-783), the prototype of the 1,7-diazacarbazole class of ChK1 inhibitors, was found to be a highly potent inhibitor of acetylcholine esterase (AChE) and unsuitable for development. A campaign of analogue synthesis established SAR delineating ChK1 and AChE activities and allowing identification of new leads with improved profiles. In silico docking using a model of AChE permitted rationalization of the observed SAR. Compounds 19 (GNE-900) and 30 (GNE-145) were identified as selective, orally bioavailable ChK1 inhibitors offering excellent in vitro potency with significantly reduced AChE activity. In combination with gemcitabine, these compounds demonstrate an in vivo pharmacodynamic effect and are efficacious in a mouse p53 mutant xenograft model.


Assuntos
Acetilcolinesterase/metabolismo , Carbazóis/química , Carbazóis/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Quinases/metabolismo , Acetilcolinesterase/química , Acetilcolinesterase/farmacocinética , Acetilcolinesterase/uso terapêutico , Animais , Compostos Aza/química , Compostos Aza/farmacocinética , Compostos Aza/farmacologia , Compostos Aza/uso terapêutico , Linhagem Celular Tumoral , Quinase 1 do Ponto de Checagem , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacocinética , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/uso terapêutico , Cristalografia por Raios X , Cães , Humanos , Camundongos , Camundongos Nus , Modelos Moleculares , Neoplasias/tratamento farmacológico , Neoplasias/enzimologia , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Quinases/química , Ratos
7.
J Med Chem ; 56(11): 4764-85, 2013 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-23659214

RESUMO

Herein we report on the structure-based discovery of a C-2 hydroxyethyl moiety which provided consistently high levels of selectivity for JAK1 over JAK2 to the imidazopyrrolopyridine series of JAK1 inhibitors. X-ray structures of a C-2 hydroxyethyl analogue in complex with both JAK1 and JAK2 revealed differential ligand/protein interactions between the two isoforms and offered an explanation for the observed selectivity. Analysis of historical data from related molecules was used to develop a set of physicochemical compound design parameters to impart desirable properties such as acceptable membrane permeability, potent whole blood activity, and a high degree of metabolic stability. This work culminated in the identification of a highly JAK1 selective compound (31) exhibiting favorable oral bioavailability across a range of preclinical species and robust efficacy in a rat CIA model.


Assuntos
Antirreumáticos/síntese química , Compostos Heterocíclicos com 3 Anéis/síntese química , Imidazóis/síntese química , Janus Quinase 1/antagonistas & inibidores , Janus Quinase 2/antagonistas & inibidores , Piridinas/síntese química , Pirróis/síntese química , Administração Oral , Animais , Antirreumáticos/química , Antirreumáticos/farmacologia , Artrite Experimental/tratamento farmacológico , Artrite Experimental/etiologia , Disponibilidade Biológica , Permeabilidade da Membrana Celular , Colágeno , Cristalografia por Raios X , Cães , Haplorrinos , Compostos Heterocíclicos com 3 Anéis/química , Compostos Heterocíclicos com 3 Anéis/farmacologia , Humanos , Imidazóis/química , Imidazóis/farmacologia , Isoenzimas/antagonistas & inibidores , Isoenzimas/química , Janus Quinase 1/química , Janus Quinase 2/química , Células Madin Darby de Rim Canino , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Estrutura Molecular , Piridinas/química , Piridinas/farmacologia , Pirróis/química , Pirróis/farmacologia , Ratos , Estereoisomerismo
8.
J Med Chem ; 55(12): 5901-21, 2012 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-22591402

RESUMO

A therapeutic rationale is proposed for the treatment of inflammatory diseases, such as rheumatoid arthritis (RA), by specific targeting of the JAK1 pathway. Examination of the preferred binding conformation of clinically effective, pan-JAK inhibitor 1 led to identification of a novel, tricyclic hinge binding scaffold 3. Exploration of SAR through a series of cycloamino and cycloalkylamino analogues demonstrated this template to be highly tolerant of substitution, with a predisposition to moderate selectivity for the JAK1 isoform over JAK2. This study culminated in the identification of subnanomolar JAK1 inhibitors such as 22 and 49, having excellent cell potency, good rat pharmacokinetic characteristics, and excellent kinase selectivity. Determination of the binding modes of the series in JAK1 and JAK2 by X-ray crystallography supported the design of analogues to enhance affinity and selectivity.


Assuntos
Imidazóis/química , Janus Quinase 1/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Piridinas/química , Piridinas/farmacologia , Animais , Linhagem Celular , Janus Quinase 1/química , Janus Quinase 2/antagonistas & inibidores , Janus Quinase 2/química , Modelos Moleculares , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacocinética , Estrutura Terciária de Proteína , Piridinas/síntese química , Piridinas/farmacocinética , Ratos , Especificidade por Substrato
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