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1.
J Med Chem ; 62(7): 3228-3250, 2019 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-30893553

RESUMO

Bruton's tyrosine kinase (BTK), a non-receptor tyrosine kinase, is a member of the Tec family of kinases and is essential for B cell receptor (BCR) mediated signaling. BTK also plays a critical role in the downstream signaling pathways for the Fcγ receptor in monocytes, the Fcε receptor in granulocytes, and the RANK receptor in osteoclasts. As a result, pharmacological inhibition of BTK is anticipated to provide an effective strategy for the clinical treatment of autoimmune diseases such as rheumatoid arthritis and lupus. This article will outline the evolution of our strategy to identify a covalent, irreversible inhibitor of BTK that has the intrinsic potency, selectivity, and pharmacokinetic properties necessary to provide a rapid rate of inactivation systemically following a very low dose. With excellent in vivo efficacy and a very desirable tolerability profile, 5a (branebrutinib, BMS-986195) has advanced into clinical studies.

2.
ACS Med Chem Lett ; 9(11): 1117-1122, 2018 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-30429955

RESUMO

The multifunctional cytokine TGFß plays a central role in regulating antitumor immunity. It has been postulated that inhibition of TGFß signaling in concert with checkpoint blockade will provide improved and durable immune response against tumors. Herein, we describe a novel series of 4-azaindole TGFß receptor kinase inhibitors with excellent selectivity for TGFß receptor 1 kinase. The combination of compound 3f and an antimouse-PD-1 antibody demonstrated significantly improved antitumor efficacy compared to either treatment alone in a murine tumor model.

3.
Bioorg Med Chem ; 26(5): 1026-1034, 2018 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-29422332

RESUMO

The TGFß-TGFßR signaling pathway has been reported to play a protective role in the later stages of tumorigenesis via increasing immunosuppressive Treg cells and facilitating the epithelial to mesenchymal transition (EMT). Therefore, inhibition of TGFßR has the potential to enhance antitumor immunity. Herein we disclose the identification and optimization of novel heterobicyclic inhibitors of TGFßRI that demonstrate potent inhibition of SMAD phosphorylation. Application of structure-based drug design to the novel pyrrolotriazine chemotype resulted in improved binding affinity (Ki apparent = 0.14 nM), long residence time (T1/2 > 120 min) and significantly improved potency in the PSMAD cellular assay (IC50 = 24 nM). Several analogs inhibited phosphorylation of SMAD both in vitro and in vivo. Additionally, inhibition of TGFß-stimulated phospho-SMAD was observed in primary human T cells.


Assuntos
Compostos Bicíclicos com Pontes/química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Receptores de Fatores de Crescimento Transformadores beta/antagonistas & inibidores , Sítios de Ligação , Compostos Bicíclicos com Pontes/síntese química , Compostos Bicíclicos com Pontes/farmacologia , Células Cultivadas , Cristalografia por Raios X , Desenho de Drogas , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Humanos , Simulação de Dinâmica Molecular , Fosforilação , Ligação Proteica , Estrutura Terciária de Proteína , Proteínas Serina-Treonina Quinases/metabolismo , Pirróis/síntese química , Pirróis/química , Pirróis/metabolismo , Receptor do Fator de Crescimento Transformador beta Tipo I , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Proteínas Smad/metabolismo , Relação Estrutura-Atividade , Linfócitos T/citologia , Linfócitos T/metabolismo , Tiazinas/síntese química , Tiazinas/química , Tiazinas/metabolismo
4.
Bioorg Med Chem Lett ; 27(23): 5267-5271, 2017 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-29102228

RESUMO

Macrocyclic pyrrolobenzodiazepine dimers were designed and evaluated for use as antibody-drug conjugate payloads. Initial structure-activity exploration established that macrocyclization could increase the potency of PBD dimers compared with non-macrocyclic analogs. Further optimization overcame activity-limiting solubility issues, leading to compounds with highly potent (picomolar) activity against several cancer cell lines. High levels of in vitro potency and specificity were demonstrated with an anti-mesothelin conjugate.


Assuntos
Anticorpos/metabolismo , Antineoplásicos/farmacologia , Benzodiazepinas/farmacologia , Compostos Macrocíclicos/farmacologia , Pirróis/farmacologia , Anticorpos/química , Antineoplásicos/síntese química , Antineoplásicos/química , Benzodiazepinas/síntese química , Benzodiazepinas/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Dimerização , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Compostos Macrocíclicos/síntese química , Compostos Macrocíclicos/química , Estrutura Molecular , Pirróis/síntese química , Pirróis/química , Solubilidade , Relação Estrutura-Atividade
5.
J Med Chem ; 59(17): 7915-35, 2016 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-27531604

RESUMO

Bruton's tyrosine kinase (BTK) belongs to the TEC family of nonreceptor tyrosine kinases and plays a critical role in multiple cell types responsible for numerous autoimmune diseases. This article will detail the structure-activity relationships (SARs) leading to a novel second generation series of potent and selective reversible carbazole inhibitors of BTK. With an excellent pharmacokinetic profile as well as demonstrated in vivo activity and an acceptable safety profile, 7-(2-hydroxypropan-2-yl)-4-[2-methyl-3-(4-oxo-3,4-dihydroquinazolin-3-yl)phenyl]-9H-carbazole-1-carboxamide 6 (BMS-935177) was selected to advance into clinical development.


Assuntos
Antirreumáticos/química , Carbazóis/química , Proteínas Tirosina Quinases/antagonistas & inibidores , Quinazolinonas/química , Administração Oral , Tirosina Quinase da Agamaglobulinemia , Animais , Antirreumáticos/síntese química , Antirreumáticos/farmacocinética , Antirreumáticos/farmacologia , Artrite Experimental/tratamento farmacológico , Artrite Experimental/patologia , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/patologia , Disponibilidade Biológica , Carbazóis/síntese química , Carbazóis/farmacocinética , Carbazóis/farmacologia , Linhagem Celular , Cristalografia por Raios X , Cães , Humanos , Macaca fascicularis , Camundongos , Microssomos Hepáticos/metabolismo , Permeabilidade , Proteínas Tirosina Quinases/química , Quinazolinonas/síntese química , Quinazolinonas/farmacocinética , Quinazolinonas/farmacologia , Relação Estrutura-Atividade
6.
J Med Chem ; 59(13): 6248-64, 2016 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-27309907

RESUMO

Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid metabolite that regulates a multitude of physiological processes such as lymphocyte trafficking, cardiac function, vascular development, and inflammation. Because of the ability of S1P1 receptor agonists to suppress lymphocyte egress, they have great potential as therapeutic agents in a variety of autoimmune diseases. In this article, the discovery of selective, direct acting S1P1 agonists utilizing an ethanolamine scaffold containing a terminal carboxylic acid is described. Potent S1P1 agonists such as compounds 18a and 19a which have greater than 1000-fold selectivity over S1P3 are described. These compounds efficiently reduce blood lymphocyte counts in rats through 24 h after single doses of 1 and 0.3 mpk, respectively. Pharmacodynamic properties of both compounds are discussed. Compound 19a was further studied in two preclinical models of disease, exhibiting good efficacy in both the rat adjuvant arthritis model (AA) and the mouse experimental autoimmune encephalomyelitis model (EAE).


Assuntos
Etanolamina/química , Etanolamina/farmacologia , Linfócitos/efeitos dos fármacos , Receptores de Lisoesfingolipídeo/agonistas , Animais , Artrite/tratamento farmacológico , Cães , Encefalomielite Autoimune Experimental/tratamento farmacológico , Etanolamina/farmacocinética , Etanolamina/uso terapêutico , Feminino , Haplorrinos , Humanos , Contagem de Linfócitos , Linfócitos/citologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ratos , Ratos Endogâmicos Lew , Receptores de Lisoesfingolipídeo/metabolismo , Relação Estrutura-Atividade
7.
Acta Crystallogr D Struct Biol ; 72(Pt 5): 658-74, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-27139629

RESUMO

The cytokine TGF-ß modulates a number of cellular activities and plays a critical role in development, hemostasis and physiology, as well as in diseases including cancer and fibrosis. TGF-ß signals through two transmembrane serine/threonine kinase receptors: TGFßR1 and TGFßR2. Multiple structures of the TGFßR1 kinase domain are known, but the structure of TGFßR2 remains unreported. Wild-type TGFßR2 kinase domain was refractory to crystallization, leading to the design of two mutated constructs: firstly, a TGFßR1 chimeric protein with seven ATP-site residues mutated to their counterparts in TGFßR2, and secondly, a reduction of surface entropy through mutation of six charged residues on the surface of the TGFßR2 kinase domain to alanines. These yielded apo and inhibitor-bound crystals that diffracted to high resolution (<2 Å). Comparison of these structures with those of TGFßR1 reveal shared ligand contacts as well as differences in the ATP-binding sites, suggesting strategies for the design of pan and selective TGFßR inhibitors.


Assuntos
Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/química , Receptores de Fatores de Crescimento Transformadores beta/antagonistas & inibidores , Receptores de Fatores de Crescimento Transformadores beta/química , Trifosfato de Adenosina/metabolismo , Sítios de Ligação , Cristalografia por Raios X , Humanos , Ligantes , Modelos Moleculares , Ligação Proteica , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/química , Isoformas de Proteínas/metabolismo , Inibidores de Proteínas Quinases/química , Proteínas Serina-Treonina Quinases/metabolismo , Receptor do Fator de Crescimento Transformador beta Tipo I , Receptor do Fator de Crescimento Transformador beta Tipo II , Receptores de Fatores de Crescimento Transformadores beta/metabolismo
8.
ACS Med Chem Lett ; 7(1): 40-5, 2016 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-26819663

RESUMO

Efforts to identify a potent, reversible, nonsteroidal CYP17A1 lyase inhibitor with good selectivity over CYP17A1 hydroxylase and CYPs 11B1 and 21A2 for the treatment of castration-resistant prostate cancer (CRPC) culminated in the discovery of BMS-351 (compound 18), a pyridyl biaryl benzimidazole with an excellent in vivo profile. Biological evaluation of BMS-351 at a dose of 1.5 mg in castrated cynomolgus monkeys revealed a remarkable reduction in testosterone levels with minimal glucocorticoid and mineralcorticoid perturbation. Based on a favorable profile, BMS-351 was selected as a candidate for further preclinical evaluation.

10.
ACS Med Chem Lett ; 6(4): 439-44, 2015 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-25893046

RESUMO

We describe the hybridization of our previously reported acyclic and cyclic CC chemokine receptor 2 (CCR2) antagonists to lead to a new series of dual antagonists of CCR2 and CCR5. Installation of a γ-lactam as the spacer group and a quinazoline as a benzamide mimetic improved oral bioavailability markedly. These efforts led to the identification of 13d, a potent and orally bioavailable dual antagonist suitable for use in both murine and monkey models of inflammation.

11.
J Mol Biol ; 427(4): 924-942, 2015 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-25579995

RESUMO

The human pregnane X receptor (PXR) is a promiscuous nuclear receptor that functions as a sensor to a wide variety of xenobiotics and regulates expression of several drug metabolizing enzymes and transporters. We have generated "Adnectins", derived from 10th fibronectin type III domain ((10)Fn3), that target the PXR ligand binding domain (LBD) interactions with the steroid receptor co-activator-1 (SRC-1) peptide, displacing SRC-1 binding. Adnectins are structurally homologous to the immunoglobulin superfamily. Three different co-crystal structures of PXR LBD with Adnectin-1 and CCR1 (CC chemokine receptor-1) antagonist Compound-1 were determined. This structural information was used to modulate PXR affinity for a related CCR1 antagonist compound that entered into clinical trials for rheumatoid arthritis. The structures of PXR with Adnectin-1 reveal specificity of Adnectin-1 in not only targeting the interface of the SRC-1 interactions but also engaging the same set of residues that are involved in binding of SRC-1 to PXR. Substituting SRC-1 with Adnectin-1 does not alter the binding conformation of Compound-1 in the ligand binding pocket. The structure also reveals the possibility of using Adnectins as crystallization chaperones to generate structures of PXR with compounds of interest.


Assuntos
Coativador 1 de Receptor Nuclear/química , Receptores CCR1/antagonistas & inibidores , Receptores de Esteroides/química , Ureia/análogos & derivados , Valina/análogos & derivados , Sequência de Aminoácidos , Sítios de Ligação , Cristalografia por Raios X , Humanos , Lignanas/metabolismo , Modelos Moleculares , Dados de Sequência Molecular , Receptor de Pregnano X , Ligação Proteica , Estrutura Terciária de Proteína , Receptores CCR1/metabolismo , Alinhamento de Sequência , Ressonância de Plasmônio de Superfície , Ureia/química , Ureia/metabolismo , Ureia/farmacologia , Valina/química , Valina/metabolismo , Valina/farmacologia
12.
J Chem Inf Model ; 54(10): 2680-96, 2014 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-25233464

RESUMO

Sampling low energy conformations of macrocycles is challenging due to the large size of many of these molecules and the constraints imposed by the macrocycle. We present a new conformational search method (implemented in MacroModel) that uses brief MD simulations followed by minimization and normal-mode search steps. The method was parametrized using a set of 100 macrocycles from the PDB and CSD. It was then tested on a publicly available data set for which there are published results using alternative methods; we found that when the same force field is used (in this case MMFFs in vacuum), our method tended to identify conformations with lower energies than what the other methods identified. The performance on a new set of 50 macrocycles from the PDB and CSD was also quite good; the mean and median RMSD values for just the ring atoms were 0.60 and 0.33 Å, respectively. However, the RMSD values for macrocycles with more than 30 ring-atoms were quite a bit larger compared to the smaller macrocycles. Possible origins for this and ideas for improving the performance on very large macrocycles are discussed.


Assuntos
Ciclodextrinas/química , Peptídeos Cíclicos/química , Peptídeos/química , Software , Algoritmos , Conformação Molecular , Simulação de Dinâmica Molecular , Proteínas/química , Termodinâmica
13.
J Med Chem ; 57(18): 7550-64, 2014 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-25101488
14.
Bioorg Med Chem Lett ; 23(13): 3833-40, 2013 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-23707259

RESUMO

A series of compounds which exhibited good human CCR1 binding and functional potency was modified resulting in the discovery of a novel series of high affinity, functionally potent antagonists of the CCR1 receptor. Issues of PXR activity, ion-channel potency, and poor metabolic stability were addressed by the addition of a hydroxyl group to an otherwise lipophilic area in the molecule resulting in the discovery of preclinical candidate BMS-457 for the treatment of rheumatoid arthritis.


Assuntos
Descoberta de Drogas , Piperidinas/farmacologia , Receptores CCR1/antagonistas & inibidores , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Piperidinas/síntese química , Piperidinas/química , Relação Estrutura-Atividade
15.
J Med Chem ; 55(22): 9643-53, 2012 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-23075267

RESUMO

A series of novel, potent CCR1 inhibitors was developed from a moderately active hit using an iterative parallel synthesis approach. The initial hit (composed of three subunits: an amine, a central amino acid, and an N-terminal cap) became the basis for a series of parallel chemical libraries designed to generate SAR data. Libraries were synthesized that explored each of the three subunits; the CCR1 binding data obtained revealed the following: (1) changes to the amine are not well tolerated; (2) small alkylamino acids are preferred in the center of the molecule; (3) substitutions at the N-terminus are generally well tolerated. These data were used to drive the optimization of the series, ultimately providing a lead with a CCR1 binding IC(50) of 28 nM (48). This lead demonstrates high selectivity for CCR1 over other CCR-family members, high microsomal stability, and good pharmacokinetics in mice.


Assuntos
Quimiotaxia/efeitos dos fármacos , Microssomos Hepáticos/efeitos dos fármacos , Monócitos/efeitos dos fármacos , Piperidinas/farmacologia , Receptores CCR/antagonistas & inibidores , Animais , Cálcio/metabolismo , Células Cultivadas , Humanos , Camundongos , Monócitos/citologia , Técnicas de Patch-Clamp , Piperidinas/síntese química , Piperidinas/farmacocinética , Ligação Proteica , Coelhos , Ratos , Receptores CCR/metabolismo , Relação Estrutura-Atividade , Distribuição Tecidual
16.
J Med Chem ; 55(21): 9208-23, 2012 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-23030502

RESUMO

This report describes the discovery and optimization of a BACE-1 inhibitor series containing an unusual acyl guanidine chemotype that was originally synthesized as part of a 6041-membered solid-phase library. The synthesis of multiple follow-up solid- and solution-phase libraries facilitated the optimization of the original micromolar hit into a single-digit nanomolar BACE-1 inhibitor in both radioligand binding and cell-based functional assay formats. The X-ray structure of representative inhibitors bound to BACE-1 revealed a number of key ligand:protein interactions, including a hydrogen bond between the side chain amide of flap residue Gln73 and the acyl guanidine carbonyl group, and a cation-π interaction between Arg235 and the isothiazole 4-methoxyphenyl substituent. Following subcutaneous administration in rats, an acyl guanidine inhibitor with single-digit nanomolar activity in cells afforded good plasma exposures and a dose-dependent reduction in plasma Aß levels, but poor brain exposure was observed (likely due to Pgp-mediated efflux), and significant reductions in brain Aß levels were not obtained.


Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Guanidinas/síntese química , Bibliotecas de Moléculas Pequenas , Secretases da Proteína Precursora do Amiloide/química , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Animais , Ácido Aspártico Endopeptidases/química , Encéfalo/metabolismo , Linhagem Celular , Cristalografia por Raios X , Guanidinas/farmacocinética , Guanidinas/farmacologia , Humanos , Isoxazóis/síntese química , Isoxazóis/farmacocinética , Isoxazóis/farmacologia , Modelos Moleculares , Estrutura Molecular , Mutação , Fragmentos de Peptídeos/metabolismo , Ligação Proteica , Ensaio Radioligante , Ratos , Técnicas de Síntese em Fase Sólida , Soluções , Relação Estrutura-Atividade
17.
Bioorg Med Chem Lett ; 22(9): 3311-6, 2012 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-22475558

RESUMO

We describe an isostere-driven approach to improve upon a previously-described series of capped dipeptide antagonists of CC Chemokine Receptor 2 (CCR2). Modification of the substitution around the isostere was combined with additional changes in a distal aromatic substituent to provide single-digit nanomolar antagonists of CCR2. These studies led to the identification of 18, a compound that was suitable for studies in murine models of CCR2 activity.


Assuntos
Amino Álcoois/química , Receptores CCR2/antagonistas & inibidores , Amino Álcoois/farmacologia , Animais , Disponibilidade Biológica , Camundongos
18.
Bioorg Med Chem Lett ; 22(3): 1384-7, 2012 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-22225639

RESUMO

We report the synthesis of 3-phenylsulfonylmethyl cyclohexylaminobenzamides (4) as CCR2 inhibitors for the potential treatment of inflammatory diseases. Several of the compounds display nanomolar binding affinity for CCR2. The in vitro structure-activity relationships of 4 are described, and are also reconciled with those from the related 2-phenylsulfonylmethyl series.


Assuntos
Amidas/síntese química , Aminobenzoatos/síntese química , Modelos Moleculares , Receptores CCR2/antagonistas & inibidores , Enxofre/química , Amidas/química , Amidas/farmacologia , Aminobenzoatos/química , Aminobenzoatos/farmacologia , Animais , Ciclização , Humanos , Concentração Inibidora 50 , Camundongos , Microssomos/enzimologia , Estrutura Molecular , Ligação Proteica/efeitos dos fármacos , Ratos , Estereoisomerismo , Relação Estrutura-Atividade , Especificidade por Substrato , Enxofre/farmacologia
19.
Bioorg Med Chem Lett ; 21(22): 6909-15, 2011 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-21974952
20.
Chem Biol Drug Des ; 78(5): 739-48, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21883956

RESUMO

Bone marrow kinase in the X chromosome, a member of the Tec family of tyrosine kinases, plays a role in both monocyte/macrophage trafficking as well as cytokine secretion. Although the structures of Tec family kinases Bruton's tyrosine kinase and IL-2-inducible T-cell kinase are known, the crystal structures of other Tec family kinases have remained elusive. We report the X-ray crystal structures of bone marrow kinase in the X chromosome in complex with dasatinib at 2.4 Å resolution and PP2 at 1.9 Å resolution. The bone marrow kinase in the X chromosome structures reveal a typical kinase protein fold; with well-ordered protein conformation that includes an open/extended activation loop and a stabilized DFG-motif rendering the kinase in an inactive conformation. Dasatinib and PP2 bind to bone marrow kinase in the X chromosome in the ATP binding pocket and display similar binding modes to that observed in other Tec and Src protein kinases. The bone marrow kinase in the X chromosome structures identify conformational elements of the DFG-motif that could potentially be utilized to design potent and/or selective bone marrow kinase in the X chromosome inhibitors.


Assuntos
Cromossomos Humanos X , Proteínas Tirosina Quinases/química , Tirosina Quinase da Agamaglobulinemia , Sítios de Ligação , Cristalografia por Raios X , Dasatinibe , Humanos , Ligação Proteica , Inibidores de Proteínas Quinases/química , Estrutura Terciária de Proteína , Proteínas Tirosina Quinases/metabolismo , Pirimidinas/química , Tiazóis/química , Quinases da Família src/química , Quinases da Família src/metabolismo
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