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1.
ACS Med Chem Lett ; 10(3): 306-311, 2019 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-30891131

RESUMO

The four members of the Janus family of nonreceptor tyrosine kinases play a significant role in immune function. The JAK family kinase inhibitor, tofacitinib 1, has been approved in the United States for use in rheumatoid arthritis (RA) patients. A number of JAK inhibitors with a variety of JAK family selectivity profiles are currently in clinical trials. Our goal was to identify inhibitors that were functionally selective for JAK1 and JAK3. Compound 22 was prepared with the desired functional selectivity profile, but it suffered from poor absorption related to physical properties. Use of the phosphate prodrug 32 enabled progression to a murine collagen induced arthritis (CIA) model. The demonstration of a robust efficacy in the CIA model suggests that use of phosphate prodrugs may resolve issues with progressing this chemotype for the treatment of autoimmune diseases such as RA.

2.
Bioorg Med Chem Lett ; 28(23-24): 3721-3725, 2018 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-30348490

RESUMO

Endothelial lipase (EL) inhibitors have been shown to elevate HDL-C levels in pre-clinical murine models and have potential benefit in prevention and treatment of cardiovascular diseases. Modification of the 1-ethyl-3-hydroxy-1,5-dihydro-2H-pyrrol-2-one (DHP) lead, 1, led to the discovery of a series of potent tetrahydropyrimidinedione (THP) EL inhibitors. Synthesis and SAR studies including modification of the amide group, together with changes on the pyrimidinone core led to a series of arylcycloalkyl, indanyl, and tetralinyl substituted 5-amino or 5-hydroxypyrimidinedione-4-carboxamides. Several compounds were advanced to PK evaluation. Among them, compound 4a was one of the most potent with measurable ELHDL hSerum potency and compound 3g demonstrated the best overall pharmacokinetic parameters.


Assuntos
Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Lipase/antagonistas & inibidores , Pirimidinonas/química , Pirimidinonas/farmacologia , Animais , HDL-Colesterol/sangue , HDL-Colesterol/metabolismo , Inibidores Enzimáticos/sangue , Inibidores Enzimáticos/síntese química , Humanos , Lipase/sangue , Lipase/metabolismo , Camundongos , Modelos Moleculares , Pirimidinonas/sangue , Pirimidinonas/síntese química , Relação Estrutura-Atividade
3.
ACS Med Chem Lett ; 9(7): 673-678, 2018 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-30034599

RESUMO

Screening of a small set of nonselective lipase inhibitors against endothelial lipase (EL) identified a potent and reversible inhibitor, N-(3-(3,4-dichlorophenyl)propyl)-3-hydroxy-1-methyl-2-oxo-1,2-dihydropyridine-4-carboxamide (5; EL IC50 = 61 nM, ELHDL IC50 = 454 nM). Deck mining identified a related hit, N-(3-(3,4-dichlorophenyl)propyl)-4-hydroxy-1-methyl-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxamide (6a; EL IC50 = 41 nM, ELHDL IC50 = 1760 nM). Both compounds were selective against lipoprotein lipase (LPL) but nonselective versus hepatic lipase (HL). Optimization of compound 6a for EL inhibition using HDL as substrate led to N-(4-(3,4-dichlorophenyl)butan-2-yl)-1-ethyl-4-hydroxy-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxamide (7c; EL IC50 = 148 nM, ELHDL IC50 = 218 nM) having improved PK over compound 6a, providing a tool molecule to test for the ability to increase HDL-cholesterol (HDL-C) levels in vivo using a reversible EL inhibitor. Compound 7c did not increase HDL-C in vivo despite achieving plasma exposures targeted on the basis of enzyme activity and protein binding demonstrating the need to develop more physiologically relevant in vitro assays to guide compound progression for in vivo evaluation.

4.
Bioorg Med Chem Lett ; 28(4): 732-736, 2018 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-29398543

RESUMO

A novel series of o-phenylenediamine-based inhibitors of indoleamine 2,3-dioxygenase (IDO) has been identified. IDO is a heme-containing enzyme, overexpressed in the tumor microenvironment of many cancers, which can contribute to the suppression of the host immune system. Synthetic modifications to a previously described diarylether series resulted in an additional degree of molecular diversity which was exploited to afford compounds that demonstrated significant potency in the HeLa human cervical cancer IDO1 assay. .


Assuntos
Inibidores Enzimáticos/farmacologia , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Fenilenodiaminas/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Células HeLa , Humanos , Microssomos Hepáticos/metabolismo , Fenilenodiaminas/síntese química , Fenilenodiaminas/química , Fenilenodiaminas/metabolismo , Relação Estrutura-Atividade
5.
J Med Chem ; 61(3): 681-694, 2018 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-29316397

RESUMO

G protein-coupled receptor 40 (GPR40) has become an attractive target for the treatment of diabetes since it was shown clinically to promote glucose-stimulated insulin secretion. Herein, we report our efforts to develop highly selective and potent GPR40 agonists with a dual mechanism of action, promoting both glucose-dependent insulin and incretin secretion. Employing strategies to increase polarity and the ratio of sp3/sp2 character of the chemotype, we identified BMS-986118 (compound 4), which showed potent and selective GPR40 agonist activity in vitro. In vivo, compound 4 demonstrated insulinotropic efficacy and GLP-1 secretory effects resulting in improved glucose control in acute animal models.


Assuntos
Descoberta de Drogas , Pirazóis/farmacologia , Pirazóis/farmacocinética , Receptores Acoplados a Proteínas-G/agonistas , Administração Oral , Animais , Disponibilidade Biológica , Humanos , Masculino , Camundongos , Modelos Moleculares , Conformação Molecular , Pirazóis/administração & dosagem , Pirazóis/química , Pirrolidinas/química
6.
Bioorg Med Chem Lett ; 28(2): 85-93, 2018 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-29233651

RESUMO

We disclose the optimization of a high throughput screening hit to yield benzothiazine and tetrahydroquinoline sulfonamides as potent RORγt inverse agonists. However, a majority of these compounds showed potent activity against pregnane X receptor (PXR) and modest activity against liver X receptor α (LXRα). Structure-based drug design (SBDD) led to the identification of benzothiazine and tetrahydroquinoline sulfonamide analogs which completely dialed out LXRα activity and were less potent at PXR. Pharmacodynamic (PD) data for compound 35 in an IL-23 induced IL-17 mouse model is discussed along with the implications of a high Ymax in the PXR assay for long term preclinical pharmacokinetic (PK) studies.


Assuntos
Compostos Bicíclicos com Pontes/farmacologia , Desenho de Fármacos , Propanóis/farmacologia , Receptores do Ácido Retinoico/agonistas , Receptores de Esteroides/agonistas , Sulfonamidas/farmacologia , Animais , Compostos Bicíclicos com Pontes/síntese química , Compostos Bicíclicos com Pontes/química , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Humanos , Receptores X do Fígado/agonistas , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Modelos Moleculares , Estrutura Molecular , Receptor de Pregnano X , Propanóis/síntese química , Propanóis/química , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química
7.
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
8.
Bioorg Med Chem Lett ; 24(24): 5721-5726, 2014 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-25453808

RESUMO

A new class of Janus kinase (JAK) inhibitors was discovered using a rationally designed pyrrolo[1,2-b]pyridazine-3-carboxamide scaffold. Preliminary studies identified (R)-(2,2-dimethylcyclopentyl)amine as a preferred C4 substituent on the pyrrolopyridazine core (3b). Incorporation of amino group to 3-position of the cyclopentane ring resulted in a series of JAK3 inhibitors (4g-4j) that potently inhibited IFNγ production in an IL2-induced whole blood assay and displayed high functional selectivity for JAK3-JAK1 pathway relative to JAK2. Further modifications led to the discovery of an orally bioavailable (2-fluoro-2-methylcyclopentyl)amino analogue 5g which is a nanomolar inhibitor of both JAK3 and TYK2, functionally selective for the JAK3-JAK1 pathway versus JAK2, and active in a human whole blood assay.


Assuntos
Descoberta de Drogas , Janus Quinase 1/antagonistas & inibidores , Janus Quinase 2/antagonistas & inibidores , Janus Quinase 3/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Piridazinas/química , Pirróis/química , Administração Oral , Animais , Ensaio de Imunoadsorção Enzimática , Humanos , Interferon gama/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Modelos Moleculares , Estrutura Molecular , Conformação Proteica/efeitos dos fármacos , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/farmacocinética , Relação Estrutura-Atividade , Distribuição Tecidual
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