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1.
J Med Chem ; 64(7): 3843-3869, 2021 04 08.
Artigo em Inglês | MEDLINE | ID: mdl-33749283

RESUMO

Transient receptor potential ankyrin 1 (TRPA1) is a nonselective calcium-permeable ion channel highly expressed in the primary sensory neurons functioning as a polymodal sensor for exogenous and endogenous stimuli and has generated widespread interest as a target for inhibition due to its implication in neuropathic pain and respiratory disease. Herein, we describe the optimization of a series of potent, selective, and orally bioavailable TRPA1 small molecule antagonists, leading to the discovery of a novel tetrahydrofuran-based linker. Given the balance of physicochemical properties and strong in vivo target engagement in a rat AITC-induced pain assay, compound 20 was progressed into a guinea pig ovalbumin asthma model where it exhibited significant dose-dependent reduction of inflammatory response. Furthermore, the structure of the TRPA1 channel bound to compound 21 was determined via cryogenic electron microscopy to a resolution of 3 Å, revealing the binding site and mechanism of action for this class of antagonists.


Assuntos
Asma/tratamento farmacológico , Furanos/uso terapêutico , Purinas/uso terapêutico , Canal de Cátion TRPA1/antagonistas & inibidores , Animais , Asma/induzido quimicamente , Asma/complicações , Células CHO , Cricetulus , Furanos/síntese química , Furanos/metabolismo , Cobaias , Humanos , Inflamação/tratamento farmacológico , Inflamação/etiologia , Ligantes , Masculino , Estrutura Molecular , Ovalbumina , Oxidiazóis/síntese química , Oxidiazóis/metabolismo , Oxidiazóis/uso terapêutico , Ligação Proteica , Purinas/síntese química , Purinas/metabolismo , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Canal de Cátion TRPA1/metabolismo
2.
Proc Natl Acad Sci U S A ; 116(51): 26008-26019, 2019 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-31796582

RESUMO

The transient receptor potential ankyrin 1 (TRPA1) channel functions as an irritant sensor and is a therapeutic target for treating pain, itch, and respiratory diseases. As a ligand-gated channel, TRPA1 can be activated by electrophilic compounds such as allyl isothiocyanate (AITC) through covalent modification or activated by noncovalent agonists through ligand binding. However, how covalent modification leads to channel opening and, importantly, how noncovalent binding activates TRPA1 are not well-understood. Here we report a class of piperidine carboxamides (PIPCs) as potent, noncovalent agonists of human TRPA1. Based on their species-specific effects on human and rat channels, we identified residues critical for channel activation; we then generated binding modes for TRPA1-PIPC interactions using structural modeling, molecular docking, and mutational analysis. We show that PIPCs bind to a hydrophobic site located at the interface of the pore helix 1 (PH1) and S5 and S6 transmembrane segments. Interestingly, this binding site overlaps with that of known allosteric modulators, such as A-967079 and propofol. Similar binding sites, involving π-helix rearrangements on S6, have been recently reported for other TRP channels, suggesting an evolutionarily conserved mechanism. Finally, we show that for PIPC analogs, predictions from computational modeling are consistent with experimental structure-activity studies, thereby suggesting strategies for rational drug design.


Assuntos
Simulação de Acoplamento Molecular , Piperidinas/farmacologia , Canal de Cátion TRPA1/química , Canal de Cátion TRPA1/efeitos dos fármacos , Animais , Sítios de Ligação , Canais de Cálcio/química , Canais de Cálcio/metabolismo , Desenho de Fármacos , Humanos , Isotiocianatos , Ligantes , Modelos Estruturais , Mutagênese , Oximas/farmacologia , Propofol/farmacologia , Domínios Proteicos , Ratos , Especificidade da Espécie , Canal de Cátion TRPA1/metabolismo
3.
Bioorg Med Chem Lett ; 24(24): 5769-5776, 2014 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-25453817

RESUMO

The identification of a new series of RORc inverse agonists is described. Comprehensive structure-activity relationship studies of this reversed sulfonamide series identified potent RORc inverse agonists in biochemical and cellular assays which were also selective against a panel of nuclear receptors. Our work has contributed a compound that may serve as a useful in vitro tool to delineate the complex biological pathways involved in signalling through RORc. An X-ray co-crystal structure of an analogue with RORc has also provided useful insights into the binding interactions of the new series.


Assuntos
Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/agonistas , Sulfonamidas/química , Sítios de Ligação , Sobrevivência Celular/efeitos dos fármacos , Cristalografia por Raios X , Citocinas/biossíntese , Agonismo Inverso de Drogas , Células HEK293 , Humanos , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/efeitos dos fármacos , Simulação de Dinâmica Molecular , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/antagonistas & inibidores , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Ligação Proteica , Estrutura Terciária de Proteína , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/toxicidade
4.
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
5.
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
6.
J Med Chem ; 55(13): 6176-93, 2012 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-22698084

RESUMO

Herein we report the discovery of the C-2 methyl substituted imidazopyrrolopyridine series and its optimization to provide potent and orally bioavailable JAK1 inhibitors with selectivity over JAK2. The C-2 methyl substituted inhibitor 4 exhibited not only improved JAK1 potency relative to unsubstituted compound 3 but also notable JAK1 vs JAK2 selectivity (20-fold and >33-fold in biochemical and cell-based assays, respectively). Features of the X-ray structures of 4 in complex with both JAK1 and JAK2 are delineated. Efforts to improve the in vitro and in vivo ADME properties of 4 while maintaining JAK1 selectivity are described, culminating in the discovery of a highly optimized and balanced inhibitor (20). Details of the biological characterization of 20 are disclosed including JAK1 vs JAK2 selectivity levels, preclinical in vivo PK profiles, performance in an in vivo JAK1-mediated PK/PD model, and attributes of an X-ray structure in complex with JAK1.


Assuntos
Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Compostos Heterocíclicos com 3 Anéis/química , Janus Quinase 1/antagonistas & inibidores , Janus Quinase 2/antagonistas & inibidores , Animais , Bioensaio , Disponibilidade Biológica , Linhagem Celular , Cristalografia por Raios X , Cães , Hepatócitos/citologia , Compostos Heterocíclicos com 3 Anéis/farmacocinética , Humanos , Janus Quinase 1/química , Janus Quinase 2/química , Camundongos , Modelos Moleculares , Ratos , Relação Estrutura-Atividade
7.
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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