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1.
Proc Natl Acad Sci U S A ; 121(6): e2317756121, 2024 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-38300868

RESUMO

Fibroblast growth factor receptor (FGFR) kinase inhibitors have been shown to be effective in the treatment of intrahepatic cholangiocarcinoma and other advanced solid tumors harboring FGFR2 alterations, but the toxicity of these drugs frequently leads to dose reduction or interruption of treatment such that maximum efficacy cannot be achieved. The most common adverse effects are hyperphosphatemia caused by FGFR1 inhibition and diarrhea due to FGFR4 inhibition, as current therapies are not selective among the FGFRs. Designing selective inhibitors has proved difficult with conventional approaches because the orthosteric sites of FGFR family members are observed to be highly similar in X-ray structures. In this study, aided by analysis of protein dynamics, we designed a selective, covalent FGFR2 inhibitor. In a key initial step, analysis of long-timescale molecular dynamics simulations of the FGFR1 and FGFR2 kinase domains allowed us to identify differential motion in their P-loops, which are located adjacent to the orthosteric site. Using this insight, we were able to design orthosteric binders that selectively and covalently engage the P-loop of FGFR2. Our drug discovery efforts culminated in the development of lirafugratinib (RLY-4008), a covalent inhibitor of FGFR2 that shows substantial selectivity over FGFR1 (~250-fold) and FGFR4 (~5,000-fold) in vitro, causes tumor regression in multiple FGFR2-altered human xenograft models, and was recently demonstrated to be efficacious in the clinic at doses that do not induce clinically significant hyperphosphatemia or diarrhea.


Assuntos
Neoplasias dos Ductos Biliares , Colangiocarcinoma , Hiperfosfatemia , Humanos , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/química , Ductos Biliares Intra-Hepáticos/metabolismo , Diarreia , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/química
2.
Cancer Discov ; 14(2): 240-257, 2024 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-37916956

RESUMO

PIK3CA (PI3Kα) is a lipid kinase commonly mutated in cancer, including ∼40% of hormone receptor-positive breast cancer. The most frequently observed mutants occur in the kinase and helical domains. Orthosteric PI3Kα inhibitors suffer from poor selectivity leading to undesirable side effects, most prominently hyperglycemia due to inhibition of wild-type (WT) PI3Kα. Here, we used molecular dynamics simulations and cryo-electron microscopy to identify an allosteric network that provides an explanation for how mutations favor PI3Kα activation. A DNA-encoded library screen leveraging electron microscopy-optimized constructs, differential enrichment, and an orthosteric-blocking compound led to the identification of RLY-2608, a first-in-class allosteric mutant-selective inhibitor of PI3Kα. RLY-2608 inhibited tumor growth in PIK3CA-mutant xenograft models with minimal impact on insulin, a marker of dysregulated glucose homeostasis. RLY-2608 elicited objective tumor responses in two patients diagnosed with advanced hormone receptor-positive breast cancer with kinase or helical domain PIK3CA mutations, with no observed WT PI3Kα-related toxicities. SIGNIFICANCE: Treatments for PIK3CA-mutant cancers are limited by toxicities associated with the inhibition of WT PI3Kα. Molecular dynamics, cryo-electron microscopy, and DNA-encoded libraries were used to develop RLY-2608, a first-in-class inhibitor that demonstrates mutant selectivity in patients. This marks the advance of clinical mutant-selective inhibition that overcomes limitations of orthosteric PI3Kα inhibitors. See related commentary by Gong and Vanhaesebroeck, p. 204 . See related article by Varkaris et al., p. 227 . This article is featured in Selected Articles from This Issue, p. 201.


Assuntos
Neoplasias da Mama , Hiperinsulinismo , Humanos , Feminino , Inibidores de Fosfoinositídeo-3 Quinase/uso terapêutico , Microscopia Crioeletrônica , Neoplasias da Mama/tratamento farmacológico , Classe I de Fosfatidilinositol 3-Quinases/genética , Hiperinsulinismo/tratamento farmacológico , Hiperinsulinismo/genética , DNA
3.
J Med Chem ; 66(19): 13384-13399, 2023 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-37774359

RESUMO

Protein tyrosine phosphatase SHP2 mediates RAS-driven MAPK signaling and has emerged in recent years as a target of interest in oncology, both for treating with a single agent and in combination with a KRAS inhibitor. We were drawn to the pharmacological potential of SHP2 inhibition, especially following the initial observation that drug-like compounds could bind an allosteric site and enforce a closed, inactive state of the enzyme. Here, we describe the identification and characterization of GDC-1971 (formerly RLY-1971), a SHP2 inhibitor currently in clinical trials in combination with KRAS G12C inhibitor divarasib (GDC-6036) for the treatment of solid tumors driven by a KRAS G12C mutation.

4.
J Chem Inf Model ; 63(9): 2644-2650, 2023 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-37086179

RESUMO

Fragment-based drug discovery has led to six approved drugs, but the small sizes of the chemical fragments used in such methods typically result in only weak interactions between the fragment and its target molecule, which makes it challenging to experimentally determine the three-dimensional poses fragments assume in the bound state. One computational approach that could help address this difficulty is long-timescale molecular dynamics (MD) simulations, which have been used in retrospective studies to recover experimentally known binding poses of fragments. Here, we present the results of long-timescale MD simulations that we used to prospectively discover binding poses for two series of fragments in allosteric pockets on a difficult and important pharmaceutical target, protein tyrosine phosphatase 1b (PTP1b). Our simulations reversibly sampled the fragment association and dissociation process. One of the binding pockets found in the simulations has not to our knowledge been previously observed with a bound fragment, and the other pocket adopted a very rare conformation. We subsequently obtained high-resolution crystal structures of members of each fragment series bound to PTP1b, and the experimentally observed poses confirmed the simulation results. To the best of our knowledge, our findings provide the first demonstration that MD simulations can be used prospectively to determine fragment binding poses to previously unidentified pockets.


Assuntos
Simulação de Dinâmica Molecular , Proteína Tirosina Fosfatase não Receptora Tipo 1 , Proteína Tirosina Fosfatase não Receptora Tipo 1/química , Cristalografia por Raios X , Estudos Retrospectivos , Descoberta de Drogas/métodos , Ligação Proteica , Sítios de Ligação
5.
ACS Med Chem Lett ; 13(4): 681-686, 2022 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-35450368

RESUMO

Thiazolidinedione PPARγ agonists such as rosiglitazone and pioglitazone are effective antidiabetic drugs, but side effects have limited their use. It has been posited that their positive antidiabetic effects are mainly mediated by the inhibition of the CDK5-mediated Ser273 phosphorylation of PPARγ, whereas the side effects are linked to classical PPARγ agonism. Thus compounds that inhibit PPARγ Ser273 phosphorylation but lack classical PPARγ agonism have been sought as safer antidiabetic therapies. Herein we report the discovery by virtual screening of 10, which is a potent PPARγ binder and in vitro inhibitor of the CDK5-mediated phosphorylation of PPARγ Ser273 and displays negligible PPARγ agonism in a reporter gene assay. The pharmacokinetic properties of 10 are compatible with oral dosing, enabling preclinical in vivo testing, and a 7 day treatment demonstrated an improvement in insulin sensitivity in the ob/ob diabetic mouse model.

6.
J Am Chem Soc ; 144(6): 2501-2510, 2022 02 16.
Artigo em Inglês | MEDLINE | ID: mdl-35130691

RESUMO

Intrinsically disordered proteins (IDPs) are implicated in many human diseases. They have generally not been amenable to conventional structure-based drug design, however, because their intrinsic conformational variability has precluded an atomic-level understanding of their binding to small molecules. Here we present long-time-scale, atomic-level molecular dynamics (MD) simulations of monomeric α-synuclein (an IDP whose aggregation is associated with Parkinson's disease) binding the small-molecule drug fasudil in which the observed protein-ligand interactions were found to be in good agreement with previously reported NMR chemical shift data. In our simulations, fasudil, when bound, favored certain charge-charge and π-stacking interactions near the C terminus of α-synuclein but tended not to form these interactions simultaneously, rather breaking one of these interactions and forming another nearby (a mechanism we term dynamic shuttling). Further simulations with small molecules chosen to modify these interactions yielded binding affinities and key structural features of binding consistent with subsequent NMR experiments, suggesting the potential for MD-based strategies to facilitate the rational design of small molecules that bind with disordered proteins.


Assuntos
1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/análogos & derivados , Proteínas Intrinsicamente Desordenadas/metabolismo , alfa-Sinucleína/metabolismo , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/química , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/metabolismo , Sequência de Aminoácidos , Ligação de Hidrogênio , Proteínas Intrinsicamente Desordenadas/química , Ligantes , Conformação Molecular , Simulação de Dinâmica Molecular , Ligação Proteica , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/metabolismo
7.
J Crohns Colitis ; 15(11): 1943-1958, 2021 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-33891001

RESUMO

BACKGROUND AND AIMS: The potassium channel Kv1.3 is a potentially attractive therapeutic target in T cell-mediated inflammatory diseases, as the activity of antigen-activated T cells is selectively impeded by Kv1.3 inhibition. In this study, we examined Kv1.3 as a potential therapeutic intervention point for ulcerative colitis [UC], and studied the efficacy of DES1, a small-molecule inhibitor of Kv1.3, in vitro and in vivo. METHODS: Kv1.3 expression on T cells in peripheral blood mononuclear cells [PBMCs] isolated from donors with and without UC was examined by flow cytometry. In biopsies from UC patients, Kv1.3-expressing CD4+ T cells were detected by flow cytometry and immunohistochemistry. In vitro, we determined the ability of DES1 to inhibit anti-CD3-driven activation of T cells. In vivo, the efficacy of DES1 was determined in a humanised mouse model of UC and compared with infliximab and tofacitinib in head-to-head studies. RESULTS: Kv1.3 expression was elevated in PBMCs from UC patients and correlated with the prevalence of TH1 and TH2 T cells. Kv1.3 expression was also detected on T cells from biopsies of UC patients. In vitro, DES1 suppressed anti-CD3-driven activation of T cells in a concentration-dependent manner. In vivo, DES1 significantly ameliorated inflammation in the UC model and most effectively so when PBMCs from donors with higher levels of activated T cells were selected for reconstitution. The efficacy of DES1 was comparable to that of either infliximab or tofacitinib. CONCLUSION: Inhibition of Kv1.3 [by DES1, for instance] appears to be a potential therapeutic intervention strategy for UC patients.


Assuntos
Colite Ulcerativa/complicações , Inflamação/tratamento farmacológico , Canal de Potássio Kv1.3/antagonistas & inibidores , Proteínas de Membrana/uso terapêutico , Oxirredutases/uso terapêutico , Animais , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/fisiopatologia , Modelos Animais de Doenças , Alemanha , Inflamação/fisiopatologia , Leucócitos Mononucleares/efeitos dos fármacos , Proteínas de Membrana/farmacologia , Camundongos , Oxirredutases/farmacologia
8.
J Med Chem ; 62(7): 3381-3394, 2019 04 11.
Artigo em Inglês | MEDLINE | ID: mdl-30875465

RESUMO

A "fragment hit", a molecule of low molecular weight that has been validated to bind to a target protein, can be an effective chemical starting point for a drug discovery project. Our ability to find and progress fragment hits could potentially be improved by enhancing our understanding of their binding properties, which to date has largely been based on tacit knowledge and reports from individual projects. In the work reported here, we systematically analyzed the molecular and binding properties of fragment hits using 489 published protein-fragment complexes. We identified a number of notable features that these hits tend to have in common, including preferences in buried surface area upon binding, hydrogen bonding and other directional interactions with the protein targets, structural topology, functional-group occurrence, and degree of carbon saturation. In the future, taking account of these preferences in designing and selecting fragments to screen against protein targets may increase the chances of success in fragment screening campaigns.


Assuntos
Descoberta de Drogas/métodos , Bibliotecas de Moléculas Pequenas/química , Cristalografia por Raios X , Ligação de Hidrogênio , Ligantes , Ligação Proteica
9.
J Med Chem ; 62(5): 2720-2737, 2019 03 14.
Artigo em Inglês | MEDLINE | ID: mdl-30786203

RESUMO

Antibiotic resistance is posing a continuous threat to global public health and represents a huge burden for society as a whole. In the past decade, the interference with bacterial quorum sensing (QS) (i.e., cell-cell communication) mechanisms has extensively been investigated as a valid therapeutic approach in the pursuit of a next generation of antimicrobials. ( S)-4,5-Dihydroxy-2,3-pentanedione, commonly known as ( S)-DPD, a small signaling molecule that modulates QS in both Gram-negative and Gram-positive bacteria, is phosphorylated by LsrK, and the resulting phospho-DPD activates QS. We designed and prepared a small library of DPD derivatives, characterized by five different scaffolds, and evaluated their LsrK inhibition in the context of QS interference. SAR studies highlighted the pyrazole moiety as an essential structural element for LsrK inhibition. Particularly, four compounds were found to be micromolar LsrK inhibitors (IC50 ranging between 100 µM and 500 µM) encouraging further exploration of novel analogues as potential new antimicrobials.


Assuntos
Antibacterianos/farmacologia , Descoberta de Drogas , Farmacorresistência Bacteriana/efeitos dos fármacos , Proteínas de Escherichia coli/antagonistas & inibidores , Escherichia coli/efeitos dos fármacos , Pentanos/química , Fosfotransferases (Aceptor do Grupo Álcool)/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Modelos Moleculares , Inibidores de Proteínas Quinases/química , Percepção de Quorum/efeitos dos fármacos , Relação Estrutura-Atividade
10.
Molecules ; 23(10)2018 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-30301207

RESUMO

Resistance to antibiotics is an increasingly serious threat to global public health and its management translates to significant health care costs. The validation of new Gram-negative antibacterial targets as sources for potential new antibiotics remains a challenge for all the scientists working in this field. The interference with bacterial Quorum Sensing (QS) mechanisms represents a potentially interesting approach to control bacterial growth and pursue the next generation of antimicrobials. In this context, our research is focused on the discovery of novel compounds structurally related to (S)-4,5-dihydroxy-2,3-pentanedione, commonly known as (S)-DPD, a small signaling molecule able to modulate bacterial QS in both Gram-negative and Gram-positive bacteria. In this study, a practical and versatile synthesis of racemic DPD is presented. Compared to previously reported syntheses, the proposed strategy is short and robust: it requires only one purification step and avoids the use of expensive or hazardous starting materials as well as the use of specific equipment. It is therefore well suited to the synthesis of derivatives for pharmaceutical research, as demonstrated by four series of novel DPD-related compounds described herein.


Assuntos
Antibacterianos/síntese química , Bactérias/efeitos dos fármacos , Pentanos/síntese química , Percepção de Quorum/efeitos dos fármacos , Antibacterianos/química , Antibacterianos/farmacologia , Bactérias/patogenicidade , Humanos , Cetonas , Lactonas/química , Lactonas/farmacologia , Pentanos/química , Pentanos/farmacologia , Transdução de Sinais/efeitos dos fármacos
11.
ACS Med Chem Lett ; 9(7): 594-599, 2018 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-30034585

RESUMO

In order to assess the potential of sPLA2-X as a therapeutic target for atherosclerosis, novel sPLA2 inhibitors with improved type X selectivity are required. To achieve the objective of identifying such compounds, we embarked on a lead generation effort that resulted in the identification of a novel series of indole-2-carboxamides as selective sPLA2-X inhibitors with excellent potential for further optimization.

12.
ACS Med Chem Lett ; 9(7): 600-605, 2018 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-30034586

RESUMO

A lead generation campaign identified indole-based sPLA2-X inhibitors with a promising selectivity profile against other sPLA2 isoforms. Further optimization of sPLA2 selectivity and metabolic stability resulted in the design of (-)-17, a novel, potent, and selective sPLA2-X inhibitor with an exquisite pharmacokinetic profile characterized by high absorption and low clearance, and low toxicological risk. Compound (-)-17 was tested in an ApoE-/- murine model of atherosclerosis to evaluate the effect of reversible, pharmacological sPLA2-X inhibition on atherosclerosis development. Despite being well tolerated and achieving adequate systemic exposure of mechanistic relevance, (-)-17 did not significantly affect circulating lipid and lipoprotein biomarkers and had no effect on coronary function or histological markers of atherosclerosis.

13.
Eur J Med Chem ; 155: 229-243, 2018 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-29886325

RESUMO

Recently we identified cycloguanil-like dihydrotriazine derivatives, which provided host-factor directed antiviral activity against influenza viruses and respiratory syncytial virus (RSV), by targeting the human dihydrofolate reductase (hDHFR) enzyme. In this context we deemed interesting to further investigate the structure activity relationship (SAR) of our first series of cycloguanil-like dihydrotriazines, designing two novel azaspiro dihydrotriazine scaffolds. The present study allowed the exploration of the potential chemical space, around these new scaffolds, that are well tolerated for maintaining the antiviral effect by means of interaction with the hDHFR enzyme. The new derivatives confirmed their inhibitory profile against influenza viruses, especially type B. In particular, the two best compounds shared potent antiviral activity (4: EC50 = 0.29 µM; 6: EC50 = 0.19 µM), which was comparable to that of zanamivir (EC50 = 0.14 µM), and better than that of ribavirin (EC50 = 3.2 µM). In addition, these two compounds proved to be also effective against RSV (4: EC50 = 0.40 µM, SI ≥ 250; 6: EC50 = 1.8 µM, SI ≥ 56), surpassing the potency and selectivity index (SI) of ribavirin (EC50 = 5.8 µM, SI > 43). By a perspective of these results, the above adequately substituted azaspiro dihydrotriazines may represent valuable hit compounds worthy of further structural optimization to develop improved host DHFR-directed antiviral agents.


Assuntos
Antivirais/farmacologia , Compostos Aza/farmacologia , Antagonistas do Ácido Fólico/farmacologia , Orthomyxoviridae/efeitos dos fármacos , Compostos de Espiro/farmacologia , Tetra-Hidrofolato Desidrogenase/metabolismo , Triazinas/farmacologia , Antivirais/síntese química , Antivirais/química , Compostos Aza/síntese química , Compostos Aza/química , Relação Dose-Resposta a Droga , Antagonistas do Ácido Fólico/síntese química , Antagonistas do Ácido Fólico/química , Modelos Moleculares , Estrutura Molecular , Orthomyxoviridae/enzimologia , Compostos de Espiro/síntese química , Compostos de Espiro/química , Relação Estrutura-Atividade , Triazinas/síntese química , Triazinas/química
14.
Future Med Chem ; 9(17): 2029-2051, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-29076758

RESUMO

Effective therapies for multiple sclerosis (MS) are still missing. This neurological disease affects more than 2.5 million people worldwide. To date, biological immunomodulatory drugs are effective and safe during short-term treatment, but they are suitable only for parenteral administration and they are expensive. Accordingly, academic and industrial environments are still focusing their efforts toward the development of new MS drugs. Considering that neurodegeneration is a contributory factor in the onset of MS, herein we will focus on the crucial role played by sigma 1 receptors (S1Rs) in MS. A pilot study was performed, evaluating the effect of the S1R agonist (R)-RC33 on rat dorsal root ganglia experimental model. The encouraging results support the potential of S1R agonists for MS treatment.


Assuntos
Compostos de Bifenilo/farmacologia , Esclerose Múltipla/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Piperidinas/farmacologia , Receptores sigma/agonistas , Animais , Compostos de Bifenilo/química , Modelos Animais de Doenças , Imunomodulação , Modelos Moleculares , Conformação Molecular , Esclerose Múltipla/imunologia , Fármacos Neuroprotetores/química , Piperidinas/química , Ratos , Receptores sigma/imunologia , Receptores sigma/metabolismo , Receptor Sigma-1
15.
J Med Chem ; 60(21): 8801-8815, 2017 11 09.
Artigo em Inglês | MEDLINE | ID: mdl-28991465

RESUMO

In modern cancer therapy, the use of small organic molecules against receptor tyrosine kinases (RTKs) has been shown to be a valuable strategy. The association of cancer cells with dysregulated signaling pathways linked to RTKs represents a key element in targeted cancer therapies. The tyrosine kinase mast/stem cell growth factor receptor KIT is an example of a clinically relevant RTK. KIT is targeted for cancer therapy in gastrointestinal stromal tumors (GISTs) and chronic myelogenous leukemia (CML). However, acquired resistance mutations within the catalytic domain decrease the efficacy of this strategy and are the most common cause of failed therapy. Here, we present the structure-based design and synthesis of novel type II kinase inhibitors to overcome these mutations in KIT. Biochemical and cellular studies revealed promising molecules for the inhibition of mutated KIT.


Assuntos
Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Mutação , Inibidores de Proteínas Quinases/síntese química , Proteínas Proto-Oncogênicas c-kit/antagonistas & inibidores , Resistencia a Medicamentos Antineoplásicos/genética , Neoplasias Gastrointestinais/tratamento farmacológico , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Proteínas Proto-Oncogênicas c-kit/genética , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Relação Estrutura-Atividade
16.
ACS Med Chem Lett ; 8(2): 139-142, 2017 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-28197301

RESUMO

Design strategies centered on intramolecular hydrogen bonds are sometime used in drug discovery, but their general applicability has not been addressed beyond scattered examples or circumstantial evidence. A total of 1053 matched molecular pairs where only one of the two molecules is able to form an intramolecular hydrogen bond via monatomic transformations have been identified across the ChEMBL database. These pairs were used to investigate the effect of intramolecular hydrogen bonds on biological activity. While cases of extreme, conflicting variation of effect emerge, the mean biological activity difference for a pair is close to zero and does not exceed ±0.5 log biological activity for over 50% of the analyzed sample.

17.
Bioorg Med Chem Lett ; 27(1): 24-29, 2017 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-27890378

RESUMO

Phosphodiesterase 4 (PDE4) inhibitors have attractive therapeutic potential in respiratory, inflammatory, metabolic and CNS disorders. The present work details the design, chemical exploration and biological profile of a novel PDE4 inhibitor chemotype. A diazepinone ring was identified as an under-represented heterocyclic system fulfilling a set of PDE4 structure-based design hypotheses. Rapid exploration of the structure activity relationships for the series was enabled by robust and scalable two/three-steps parallel chemistry protocols. The resulting compounds demonstrated PDE4 inhibitory activity in cell free and cell-based assays comparable to the Zardaverine control used, suggesting potential avenues for their further development.


Assuntos
Azepinas/farmacologia , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Desenho de Fármacos , Inibidores da Fosfodiesterase 4/farmacologia , Azepinas/síntese química , Azepinas/química , Relação Dose-Resposta a Droga , Humanos , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Estrutura Molecular , Inibidores da Fosfodiesterase 4/síntese química , Inibidores da Fosfodiesterase 4/química , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/biossíntese
18.
ACS Med Chem Lett ; 7(10): 884-889, 2016 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-27774123

RESUMO

Expedited structure-based optimization of the initial fragment hit 1 led to the design of (R)-7 (AZD2716) a novel, potent secreted phospholipase A2 (sPLA2) inhibitor with excellent preclinical pharmacokinetic properties across species, clear in vivo efficacy, and minimized safety risk. Based on accumulated profiling data, (R)-7 was selected as a clinical candidate for the treatment of coronary artery disease.

19.
ACS Comb Sci ; 18(6): 330-6, 2016 06 13.
Artigo em Inglês | MEDLINE | ID: mdl-27163646

RESUMO

The exploration of innovative chemical space is a critical step in the early phases of drug discovery. Bis-spirocyclic frameworks occur in natural products and other biologically relevant metabolites and show attractive features, such as molecular compactness, structural complexity, and three-dimensional character. A concise approach to the synthesis of bis-spirocyclic-based compound libraries starting from readily available commercial reagents and robust chemical transformations has been developed. A number of novel bis-spirocyclic scaffold examples, as implemented in the European Lead Factory project, is presented.


Assuntos
Desenho de Fármacos , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/farmacologia , Reação de Cicloadição , Ensaios de Triagem em Larga Escala , Indicadores e Reagentes , Modelos Moleculares , Conformação Molecular , Bibliotecas de Moléculas Pequenas , Estereoisomerismo
20.
Future Med Chem ; 8(6): 681-96, 2016 04.
Artigo em Inglês | MEDLINE | ID: mdl-27073990

RESUMO

In total, 47,500,000 people worldwide are affected by dementia and this number is estimated to double by 2030 and triple within 2050 resulting in a huge burden on public health. Alzheimer's disease (AD), a progressive neurodegenerative disorder, is the most common cause of dementia, accounting for 60-70% of all the cases. The cause of AD is still poorly understood but several brain abnormalities (e.g., loss of neuronal connections and neuronal death) have been identified in affected patients. In addition to the accumulation of ß-amyloid plaques in the brain tissue, aberrant phosphorylation of tau proteins has proved to increase neuronal death. DYRK1A phosphorylates tau on 11 different Ser/Thr residues, resulting in the formation of aggregates called 'neurofibrillary tangles' which, together with amyloid plaques, could be responsible for dementia, neuronal degeneration and cell death. Small molecule inhibition of DYRK1A could thus represent an interesting approach toward the treatment of Alzheimer's and other neurodegenerative diseases. Herein we review the current progress in the identification and development of DYRK1A inhibitors.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/antagonistas & inibidores , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Morte Celular , Descoberta de Drogas , Humanos , Neurônios/patologia , Fosforilação , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Tirosina Quinases/metabolismo , Relação Estrutura-Atividade , Proteínas tau/metabolismo , Quinases Dyrk
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