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1.
ACS Med Chem Lett ; 12(2): 302-308, 2021 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-33603979

RESUMO

The MEK1 kinase plays a critical role in key cellular processes, and as such, its dysfunction is strongly linked to several human diseases, particularly cancer. MEK1 has consequently received considerable attention as a drug target, and a significant number of small-molecule inhibitors of this kinase have been reported. The majority of these inhibitors target an allosteric pocket proximal to the ATP binding site which has proven to be highly druggable, with four allosteric MEK1 inhibitors approved to date. Despite the significant attention that the MEK1 allosteric site has received, chemotypes which have been shown structurally to bind to this site are limited. With the aim of discovering novel allosteric MEK1 inhibitors using a fragment-based approach, we report here a screening method which resulted in the discovery of multiple allosteric MEK1 binders, one series of which was optimized to sub-µM affinity for MEK1 with promising physicochemical and ADMET properties.

2.
J Med Chem ; 64(18): 13807-13829, 2021 09 23.
Artigo em Inglês | MEDLINE | ID: mdl-34464130

RESUMO

Inverse agonists of the nuclear receptor RORC2 have been widely pursued as a potential treatment for a variety of autoimmune diseases. We have discovered a novel series of isoindoline-based inverse agonists of the nuclear receptor RORC2, derived from our recently disclosed RORC2 inverse agonist 2. Extensive structure-activity relationship (SAR) studies resulted in AZD0284 (20), which combined potent inhibition of IL-17A secretion from primary human TH17 cells with excellent metabolic stability and good PK in preclinical species. In two preclinical in vivo studies, compound 20 reduced thymocyte numbers in mice and showed dose-dependent reduction of IL-17A containing γδ-T cells and of IL-17A and IL-22 RNA in the imiquimod induced inflammation model. Based on these data and a favorable safety profile, 20 was progressed to phase 1 clinical studies.


Assuntos
Anti-Inflamatórios/uso terapêutico , Inflamação/tratamento farmacológico , Isoindóis/uso terapêutico , Receptores Nucleares Órfãos/agonistas , Sulfonas/uso terapêutico , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/farmacocinética , Cães , Agonismo Inverso de Drogas , Feminino , Humanos , Imiquimode , Inflamação/induzido quimicamente , Isoindóis/líquido cefalorraquidiano , Isoindóis/síntese química , Isoindóis/farmacocinética , Masculino , Camundongos Endogâmicos C57BL , Estrutura Molecular , Ratos Wistar , Relação Estrutura-Atividade , Sulfonas/líquido cefalorraquidiano , Sulfonas/síntese química , Sulfonas/farmacocinética , Células Th17 , Timócitos/efeitos dos fármacos
3.
ACS Med Chem Lett ; 10(6): 972-977, 2019 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-31223457

RESUMO

The further optimization of a recently disclosed series of inverse agonists of the nuclear receptor RORC2 is described. Investigations into the left-hand side of compound 1, guided by X-ray crystal structures, led to the substitution of the 4-aryl-thiophenyl residue with the hexafluoro-2-phenyl-propan-2-ol moiety. This change resulted in to compound 28, which combined improved drug-like properties with good cell potency and a significantly lower dose, using an early dose to man prediction. Target engagement in vivo was demonstrated in the thymus of mice by a reduction in the number of double positive T cells after oral dosing.

4.
J Med Chem ; 61(17): 7796-7813, 2018 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-30095900

RESUMO

Retinoic acid receptor related orphan receptor γt (RORγt), has been identified as the master regulator of TH17-cell function and development, making it an attractive target for the treatment of autoimmune diseases by a small-molecule approach. Herein, we describe our investigations on a series of 4-aryl-thienyl acetamides, which were guided by insights from X-ray cocrystal structures. Efforts in targeting the cofactor-recruitment site from the 4-aryl group on the thiophene led to a series of potent binders with nanomolar activity in a primary human-TH17-cell assay. The observation of a DMSO molecule binding in a subpocket outside the LBD inspired the introduction of an acetamide into the benzylic position of these compounds. Hereby, a hydrogen-bond interaction of the introduced acetamide oxygen with the backbone amide of Glu379 was established. This greatly enhanced the cellular activity of previously weakly cell-active compounds. The best compounds combined potent inhibition of IL-17 release with favorable PK in rodents, with compound 32 representing a promising starting point for future investigations.


Assuntos
Acetamidas/farmacologia , Desenho de Fármacos , Agonismo Inverso de Drogas , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/agonistas , Conformação Proteica , Células Th17/efeitos dos fármacos , Células Th17/metabolismo , Acetamidas/administração & dosagem , Acetamidas/química , Acetamidas/farmacocinética , Administração Oral , Animais , Sítios de Ligação , Disponibilidade Biológica , Células Cultivadas , Cristalografia por Raios X , Humanos , Interleucina-17/metabolismo , Modelos Moleculares , Estrutura Molecular , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/química , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Ligação Proteica , Roedores , Relação Estrutura-Atividade , Células Th17/imunologia , Distribuição Tecidual
5.
ChemMedChem ; 11(2): 207-16, 2016 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-26553345

RESUMO

RORγt, an isoform of the retinoic acid-related orphan receptor gamma (RORc, RORγ), has been identified as the master regulator of T-helper 17 (TH 17) cell function and development, making it an attractive target for the treatment of autoimmune diseases. Validation for this target comes from antibodies targeting interleukin-17 (IL-17), the signature cytokine produced by TH 17 cells, which have shown impressive results in clinical trials. Through focused screening of our compound collection, we identified a series of N-sulfonylated benzoxazepines, which displayed micromolar affinity for the RORγ ligand-binding domain (LBD) in a radioligand binding assay. Optimization of these initial hits resulted in potent binders, which dose-dependently decreased the ability of the RORγ-LBD to interact with a peptide derived from steroid receptor coactivator 1, and inhibited the release of IL-17 secretion from isolated and cultured human TH 17 cells with nanomolar potency. A cocrystal structure of inverse agonist 15 (2-chloro-6-fluoro-N-(4-{[3-(trifluoromethyl)phenyl]sulfonyl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)benzamide) bound to the RORγ-LBD illustrated that both hydrophobic interactions, leading to an induced fit around the substituted benzamide moiety of 15, as well as a hydrogen bond from the amide NH to His479 seemed to be important for the mechanism of action. This structure is compared with the structure of agonist 25 (N-(2-fluorophenyl)-4-[(4-fluorophenyl)sulfonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-6-amine ) and structures of other known RORγ modulators.


Assuntos
Interleucina-17/metabolismo , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Oxazepinas/farmacologia , Células Th17/efeitos dos fármacos , Células Th17/metabolismo , Sítios de Ligação/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Interleucina-17/imunologia , Modelos Moleculares , Estrutura Molecular , Oxazepinas/síntese química , Oxazepinas/química , Ligação Proteica/efeitos dos fármacos , Relação Estrutura-Atividade , Células Th17/imunologia
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