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1.
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
2.
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
3.
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
4.
ACS Med Chem Lett ; 13(6): 972-980, 2022 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-35707159

RESUMO

Allosteric HIV-1 integrase inhibitors (ALLINIs) have been of interest recently because of their novel mechanism of action. Strategic modifications to the C5 moiety of a class of 4-(4,4-dimethylpiperidinyl)-2,6-dimethylpyridinyl ALLINIs led to the identification of a tetrahydroisoquinoline heterocycle as a suitable spacer element to project the distal hydrophobic aryl ring. Subsequent optimization of the aryl substitutions identified 12 as an ALLINI with single-digit nanomolar inhibitory potency and low clearance across preclinical species. In preclinical toxicology studies with 12 in rats, lipid hepatocellular vacuolation was observed. Removal of the C6 methyl group resulted in GSK3839919 (22), which exhibited a reduced incidence and severity of lipid vacuolation in both in vitro assays and in vivo studies while maintaining the potency and pharmacokinetic (PK) properties of the prototype. The virology, PK, and toxicology profiles of 22 are discussed.

5.
Bioorg Med Chem ; 67: 116833, 2022 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-35605346

RESUMO

Allosteric integrase inhibitors (ALLINIs) of HIV-1 may hold promise as a novel mechanism for HIV therapeutics and cure. Scaffold modifications to the 4-(4,4-dimethylpiperidinyl) 2,6-dimethylpyridinyl class of ALLINIs provided a series of potent compounds with differentiated 5/6 fused ring systems. Notably, inhibitors containing the 1,2,4-triazolopyridine and imidazopyridine core exhibited single digit nM antiviral potency and low to moderate clearance after intravenous (IV) dosing in rat pharmacokinetic (PK) studies. The 1,2,4-triazolopyridines showed a higher oral exposure when compared to the imidazopyridines. Further modifications to the C5 substituent of the 1,2,4-triazolopyridines resulted in a new lead compound, which had improved rat IV/PO PK compared to the former lead compound GSK3739936, while maintaining antiviral potency. Structure-activity relationships (SAR) and rat pharmacokinetic profiles of this series are discussed.


Assuntos
Fármacos Anti-HIV , Inibidores de Integrase de HIV , Integrase de HIV , HIV-1 , Regulação Alostérica , Animais , Fármacos Anti-HIV/farmacologia , Integrase de HIV/metabolismo , Inibidores de Integrase de HIV/farmacologia , HIV-1/metabolismo , Ratos
6.
J Med Chem ; 65(6): 4949-4971, 2022 03 24.
Artigo em Inglês | MEDLINE | ID: mdl-35235334

RESUMO

Allosteric HIV-1 integrase inhibitors (ALLINIs) have garnered special interest because of their novel mechanism of action: they inhibit HIV-1 replication by promoting aberrant integrase multimerization, leading to the production of replication-deficient viral particles. The binding site of ALLINIs is in a well-defined pocket formed at the interface of two integrase monomers that is characterized by conserved residues along with two polymorphic amino acids at residues 124 and 125. The design, synthesis, and optimization of pyridine-based allosteric integrase inhibitors are reported here. Optimization was conducted with a specific emphasis on the inhibition of the 124/125 polymorphs such that the designed compounds showed excellent potency in vitro against majority of the 124/125 variants. In vivo profiling of promising preclinical lead 29 showed that it exhibited a good pharmacokinetic (PK) profile in preclinical species, which resulted in a low predicted human efficacious dose. However, findings in rat toxicology studies precluded further development of 29.


Assuntos
Inibidores de Integrase de HIV , Integrase de HIV , HIV-1 , Regulação Alostérica , Animais , Integrase de HIV/metabolismo , Inibidores de Integrase de HIV/química , Inibidores de Integrase de HIV/farmacologia , HIV-1/fisiologia , Ratos
7.
ACS Med Chem Lett ; 11(3): 266-271, 2020 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-32184955

RESUMO

Necroptosis has been implicated in a variety of disease states, and RIPK3 is one of the kinases identified to play a critical role in this signaling pathway. In an effort to identify RIPK3 kinase inhibitors with a novel profile, mechanistic studies were incorporated at the hit triage stage. Utilization of these assays enabled identification of a Type II DFG-out inhibitor for RIPK3, which was confirmed by protein crystallography. Structure-based drug design on the inhibitors targeting this previously unreported conformation enabled an enhancement in selectivity against key off-target kinases.

8.
J Med Chem ; 63(5): 2620-2637, 2020 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-32081010

RESUMO

The standard of care for HIV-1 infection, highly active antiretroviral therapy (HAART), combines two or more drugs from at least two classes. Even with the success of HAART, new drugs with novel mechanisms are needed to combat viral resistance, improve adherence, and mitigate toxicities. Active site inhibitors of HIV-1 integrase are clinically validated for the treatment of HIV-1 infection. Here we describe allosteric inhibitors of HIV-1 integrase that bind to the LEDGF/p75 interaction site and disrupt the structure of the integrase multimer that is required for the HIV-1 maturation. A series of pyrazolopyrimidine-based inhibitors was developed with a vector in the 2-position that was optimized by structure-guided compound design. This resulted in the discovery of pyrazolopyrimidine 3, which was optimized at the 2- and 7-positions to afford 26 and 29 as potent allosteric inhibitors of HIV-1 integrase that exhibited low nanomolar antiviral potency in cell culture and encouraging PK properties.


Assuntos
Regulação Alostérica/efeitos dos fármacos , Inibidores de Integrase de HIV/química , Inibidores de Integrase de HIV/farmacologia , HIV-1/efeitos dos fármacos , Pirazóis/química , Pirazóis/farmacologia , Piridinas/química , Piridinas/farmacologia , Administração Oral , Animais , Descoberta de Drogas , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Integrase de HIV/metabolismo , Inibidores de Integrase de HIV/administração & dosagem , Inibidores de Integrase de HIV/farmacocinética , Humanos , Masculino , Simulação de Acoplamento Molecular , Pirazóis/administração & dosagem , Pirazóis/farmacocinética , Piridinas/administração & dosagem , Piridinas/farmacocinética , Ratos Sprague-Dawley
9.
J Med Chem ; 62(3): 1348-1361, 2019 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-30609350

RESUMO

A series of 5,6,7,8-tetrahydro-1,6-naphthyridine derivatives targeting the allosteric lens-epithelium-derived-growth-factor-p75 (LEDGF/p75)-binding site on HIV-1 integrase, an attractive target for antiviral chemotherapy, was prepared and screened for activity against HIV-1 infection in cell culture. Small molecules that bind within the LEDGF/p75-binding site promote aberrant multimerization of the integrase enzyme and are of significant interest as HIV-1-replication inhibitors. Structure-activity-relationship studies and rat pharmacokinetic studies of lead compounds are presented.


Assuntos
Inibidores de Integrase de HIV/farmacologia , HIV-1/efeitos dos fármacos , Naftiridinas/farmacologia , Sítio Alostérico , Cristalografia por Raios X , Infecções por HIV/tratamento farmacológico , Inibidores de Integrase de HIV/química , Inibidores de Integrase de HIV/uso terapêutico , HIV-1/enzimologia , HIV-1/fisiologia , Humanos , Naftiridinas/química , Naftiridinas/uso terapêutico , Replicação Viral/efeitos dos fármacos
10.
ACS Med Chem Lett ; 9(2): 143-148, 2018 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-29456803

RESUMO

The design and synthesis of potent, tripeptidic acylsulfonamide inhibitors of HCV NS3 protease that contain a difluoromethyl cyclopropyl amino acid at P1 are described. A cocrystal structure of 18 with a NS3/4A protease complex suggests the presence of a H-bond between the polarized C-H of the CHF2 moiety and the backbone carbonyl of Leu135 of the enzyme. Structure-activity relationship studies indicate that this H-bond enhances enzyme inhibitory potency by 13- and 17-fold compared to the CH3 and CF3 analogues, respectively, providing insight into the deployment of this unique amino acid.

11.
ACS Med Chem Lett ; 9(12): 1217-1222, 2018 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-30613329

RESUMO

In solving the P-gp and BCRP transporter-mediated efflux issue in a series of benzofuran-derived pan-genotypic palm site inhibitors of the hepatitis C virus NS5B replicase, it was found that close attention to physicochemical properties was essential. In these compounds, where both molecular weight (MW >579) and TPSA (>110 Å2) were high, attenuation of polar surface area together with weakening of hydrogen bond acceptor strength of the molecule provided a higher intrinsic membrane permeability and more desirable Caco-2 parameters, as demonstrated by trifluoroacetamide 11 and the benchmark N-ethylamino analog 12. In addition, the tendency of these inhibitors to form intramolecular hydrogen bonds potentially contributes favorably to the improved membrane permeability and absorption. The functional group minimization that resolved the efflux problem simultaneously maintained potent inhibitory activity toward a gt-2 HCV replicon due to a switching of the role of substituents in interacting with the Gln414 binding pocket, as observed in gt-2a NS5B/inhibitor complex cocrystal structures, thus increasing the efficiency of the optimization. Noteworthy, a novel intermolecular S=O···C=O n → π* type interaction between the ligand sulfonamide oxygen atom and the carbonyl moiety of the side chain of Gln414 was observed. The insights from these structure-property studies and crystallography information provided a direction for optimization in a campaign to identify second generation pan-genotypic NS5B inhibitors.

12.
J Med Chem ; 60(10): 4369-4385, 2017 05 25.
Artigo em Inglês | MEDLINE | ID: mdl-28430437

RESUMO

The hepatitis C virus (HCV) NS5B replicase is a prime target for the development of direct-acting antiviral drugs for the treatment of chronic HCV infection. Inspired by the overlay of bound structures of three structurally distinct NS5B palm site allosteric inhibitors, the high-throughput screening hit anthranilic acid 4, the known benzofuran analogue 5, and the benzothiadiazine derivative 6, an optimization process utilizing the simple benzofuran template 7 as a starting point for a fragment growing approach was pursued. A delicate balance of molecular properties achieved via disciplined lipophilicity changes was essential to achieve both high affinity binding and a stringent targeted absorption, distribution, metabolism, and excretion profile. These efforts led to the discovery of BMS-929075 (37), which maintained ligand efficiency relative to early leads, demonstrated efficacy in a triple combination regimen in HCV replicon cells, and exhibited consistently high oral bioavailability and pharmacokinetic parameters across preclinical animal species. The human PK properties from the Phase I clinical studies of 37 were better than anticipated and suggest promising potential for QD administration.


Assuntos
Antivirais/farmacologia , Antivirais/farmacocinética , Benzofuranos/farmacologia , Benzofuranos/farmacocinética , Hepacivirus/efeitos dos fármacos , Hepatite C/tratamento farmacológico , Proteínas não Estruturais Virais/antagonistas & inibidores , Regulação Alostérica/efeitos dos fármacos , Sítio Alostérico/efeitos dos fármacos , Animais , Antivirais/química , Benzofuranos/química , Cães , Descoberta de Drogas , Haplorrinos , Hepatite C/virologia , Humanos , Masculino , Simulação de Acoplamento Molecular , Ratos , Ratos Sprague-Dawley , Proteínas não Estruturais Virais/química , Proteínas não Estruturais Virais/metabolismo
13.
Medchemcomm ; 8(4): 796-806, 2017 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30108798

RESUMO

The development of a series of novel 7-azabenzofurans exhibiting pan-genotype inhibition of HCV NS5B polymerase via binding to the primer grip site is presented. Many challenges, including poor oral bioavailability, high clearance, bioactivation, high human serum shift, and metabolic stability were encountered and overcome through SAR studies. This work culminated in the selection of BMS-986139 (43) as a preclinical candidate.

14.
J Med Chem ; 59(17): 8042-60, 2016 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-27564532

RESUMO

The discovery of a back-up to the hepatitis C virus NS3 protease inhibitor asunaprevir (2) is described. The objective of this work was the identification of a drug with antiviral properties and toxicology parameters similar to 2, but with a preclinical pharmacokinetic (PK) profile that was predictive of once-daily dosing. Critical to this discovery process was the employment of an ex vivo cardiovascular (CV) model which served to identify compounds that, like 2, were free of the CV liabilities that resulted in the discontinuation of BMS-605339 (1) from clinical trials. Structure-activity relationships (SARs) at each of the structural subsites in 2 were explored with substantial improvement in PK through modifications at the P1 site, while potency gains were found with small, but rationally designed structural changes to P4. Additional modifications at P3 were required to optimize the CV profile, and these combined SARs led to the discovery of BMS-890068 (29).


Assuntos
Antivirais/química , Hepacivirus/efeitos dos fármacos , Isoquinolinas/uso terapêutico , Oligopeptídeos/química , Sulfonamidas/química , Proteínas não Estruturais Virais/antagonistas & inibidores , Animais , Antivirais/administração & dosagem , Antivirais/farmacocinética , Antivirais/farmacologia , Cães , Esquema de Medicação , Farmacorresistência Viral , Hepacivirus/genética , Macaca fascicularis , Masculino , Modelos Moleculares , Oligopeptídeos/administração & dosagem , Oligopeptídeos/farmacocinética , Oligopeptídeos/farmacologia , Coelhos , Ratos Sprague-Dawley , Replicon , Estereoisomerismo , Relação Estrutura-Atividade , Sulfonamidas/administração & dosagem , Sulfonamidas/farmacocinética , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico
15.
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
16.
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
17.
J Lab Autom ; 19(6): 517-27, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25117530

RESUMO

A scheduler has been developed for an integrated laboratory robot system that operates in an always-on mode. The integrated system is designed for imaging plates containing protein crystallization experiments, and it allows crystallographers to enter plates at any time and request that they be imaged at multiple time points in the future. The scheduler must rearrange tasks within the time it takes to image one plate, trading off the quality of the schedule for the speed of the computation. For this reason, the scheduler was based on a simulated annealing algorithm with an objective function that makes use of a linear programming solver. To optimize the scheduler, extensive computational simulations were performed involving a difficult but representative scheduling problem. The simulations explore multiple configurations of the simulated annealing algorithm, including both geometric and adaptive annealing schedules, 3 neighborhood functions, and 20 neighborhood diameters. An optimal configuration was found that produced the best results in less than 60 seconds, well within the window necessary to dynamically reschedule imaging tasks as new plates are entered into the system.


Assuntos
Automação Laboratorial/métodos , Pesquisa Biomédica/organização & administração , Robótica/métodos , Algoritmos , Simulação por Computador , Cristalização/métodos , Imagem Óptica/métodos
18.
J Med Chem ; 57(5): 1730-52, 2014 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-24564672

RESUMO

The discovery of asunaprevir (BMS-650032, 24) is described. This tripeptidic acylsulfonamide inhibitor of the NS3/4A enzyme is currently in phase III clinical trials for the treatment of hepatitis C virus infection. The discovery of 24 was enabled by employing an isolated rabbit heart model to screen for the cardiovascular (CV) liabilities (changes to HR and SNRT) that were responsible for the discontinuation of an earlier lead from this chemical series, BMS-605339 (1), from clinical trials. The structure-activity relationships (SARs) developed with respect to CV effects established that small structural changes to the P2* subsite of the molecule had a significant impact on the CV profile of a given compound. The antiviral activity, preclincial PK profile, and toxicology studies in rat and dog supported clinical development of BMS-650032 (24).


Assuntos
Antivirais/uso terapêutico , Hepatite C/tratamento farmacológico , Isoquinolinas/uso terapêutico , Inibidores de Proteases/uso terapêutico , Sulfonamidas/uso terapêutico , Proteínas não Estruturais Virais/antagonistas & inibidores , Animais , Antivirais/sangue , Antivirais/química , Cães , Humanos , Isoquinolinas/sangue , Isoquinolinas/química , Modelos Moleculares , Inibidores de Proteases/sangue , Inibidores de Proteases/química , Coelhos , Ratos , Sulfonamidas/sangue , Sulfonamidas/química
19.
J Med Chem ; 56(18): 7343-57, 2013 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-23964740

RESUMO

Optimization of a 5-oxopyrrolopyridine series based upon structure-activity relationships (SARs) developed from our previous efforts on a number of related bicyclic series yielded compound 2s (BMS-767778) with an overall activity, selectivity, efficacy, PK, and developability profile suitable for progression into the clinic. SAR in the series and characterization of 2s are described.


Assuntos
Acetamidas/química , Acetamidas/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/química , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/química , Inibidores da Dipeptidil Peptidase IV/farmacologia , Desenho de Fármacos , Pirróis/química , Pirróis/farmacologia , Acetamidas/síntese química , Animais , Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Domínio Catalítico , Dipeptidil Peptidase 4/química , Inibidores da Dipeptidil Peptidase IV/síntese química , Teste de Tolerância a Glucose , Humanos , Masculino , Camundongos , Modelos Moleculares , Pirróis/síntese química , Especificidade por Substrato
20.
Bioorg Med Chem Lett ; 23(14): 4120-6, 2013 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-23746475

RESUMO

A novel series of p38 MAP kinase inhibitors with high selectivity for the p38α isoform over the other family members including the highly homologous p38ß isoform has been identified. X-ray co-crystallographic studies have revealed an unprecedented kinase binding mode in p38α for representative analogs, 5c and 9d, in which a Leu108/Met109 peptide flip occurs within the p38α hinge region. Based on these findings, a general strategy for the rational design of additional promising p38α isoform selective inhibitors by targeting this novel binding mode is proposed.


Assuntos
Proteína Quinase 14 Ativada por Mitógeno/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Sítios de Ligação , Cristalografia por Raios X , Humanos , Ligação de Hidrogênio , Proteína Quinase 14 Ativada por Mitógeno/metabolismo , Simulação de Dinâmica Molecular , Ligação Proteica , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/metabolismo , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/metabolismo , Estrutura Terciária de Proteína , Relação Estrutura-Atividade
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