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1.
J Med Chem ; 64(3): 1454-1480, 2021 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-33492963

RESUMO

Sphingosine-1-phosphate (S1P) binds to a family of sphingosine-1-phosphate G-protein-coupled receptors (S1P1-5). The interaction of S1P with these S1P receptors has a fundamental role in many physiological processes in the vascular and immune systems. Agonist-induced functional antagonism of S1P1 has been shown to result in lymphopenia. As a result, agonists of this type hold promise as therapeutics for autoimmune disorders. The previously disclosed differentiated S1P1 modulator BMS-986104 (1) exhibited improved preclinical cardiovascular and pulmonary safety profiles as compared to earlier full agonists of S1P1; however, it demonstrated a long pharmacokinetic half-life (T1/2 18 days) in the clinic and limited formation of the desired active phosphate metabolite. Optimization of this series through incorporation of olefins, ethers, thioethers, and glycols into the alkyl side chain afforded an opportunity to reduce the projected human T1/2 and improve the formation of the active phosphate metabolite while maintaining efficacy as well as the improved safety profile. These efforts led to the discovery of 12 and 24, each of which are highly potent, biased agonists of S1P1. These compounds not only exhibited shorter in vivo T1/2 in multiple species but are also projected to have significantly shorter T1/2 values in humans when compared to our first clinical candidate. In models of arthritis, treatment with 12 and 24 demonstrated robust efficacy.


Assuntos
Compostos Bicíclicos com Pontes/síntese química , Compostos Bicíclicos com Pontes/farmacologia , Pró-Proteína Convertases/efeitos dos fármacos , Serina Endopeptidases/efeitos dos fármacos , Animais , Artrite Experimental/tratamento farmacológico , Doenças Autoimunes/tratamento farmacológico , Biotransformação , Compostos Bicíclicos com Pontes/efeitos adversos , Líquido da Lavagem Broncoalveolar , Quimiotaxia de Leucócito/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Meia-Vida , Humanos , Pneumopatias/induzido quimicamente , Pneumopatias/patologia , Masculino , Miócitos Cardíacos/efeitos dos fármacos , Fosforilação , Ratos , Ratos Endogâmicos Lew , Relação Estrutura-Atividade
2.
ACS Med Chem Lett ; 11(9): 1751-1758, 2020 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-32944143

RESUMO

The toll-like receptor (TLR) family is an evolutionarily conserved component of the innate immune system, responsible for the early detection of foreign or endogenous threat signals. In the context of autoimmunity, the unintended recognition of self-motifs as foreign promotes initiation or propagation of disease. Overactivation of TLR7 and TLR9 have been implicated as factors contributing to autoimmune disorders such as psoriasis, arthritis, and lupus. In our search for small molecule antagonists of TLR7/9, 7f was identified as possessing excellent on-target potency for human TLR7/9 as well as for TLR8, with selectivity against other representative TLR family members. Good pharmacokinetic properties and a relatively balanced potency against TLR7 and TLR9 in mouse systems (systems which lack functional TLR8) made this an excellent in vivo tool compound, and efficacy from oral dosing in preclinical models of autoimmune disease was demonstrated.

3.
ACS Med Chem Lett ; 11(9): 1766-1772, 2020 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-32944145

RESUMO

Efforts aimed at increasing the in vivo potency and reducing the elimination half-life of 1 and 2 led to the identification of aryl ether and thioether-derived bicyclic S1P1 differentiated modulators 3-6. The effects of analogs 3-6 on lymphocyte reduction in the rat (desired pharmacology) along with pulmonary- and cardiovascular-related effects (undesired pharmacology) are described. Optimization of the overall properties in the aryl ether series yielded 3d, and the predicted margin of safety against the cardiovascular effects of 3d would be large enough for human studies. Importantly, compared to 1 and 2, compound 3d had a better profile in both potency (ED50 < 0.05 mg/kg) and predicted human half-life (t 1/2 ∼ 5 days).

4.
J Med Chem ; 62(5): 2265-2285, 2019 03 14.
Artigo em Inglês | MEDLINE | ID: mdl-30785748

RESUMO

Recently, our research group reported the identification of BMS-986104 (2) as a differentiated S1P1 receptor modulator. In comparison to fingolimod (1), a full agonist of S1P1 currently marketed for the treatment of relapse remitting multiple sclerosis (RRMS), 2 offers several potential advantages having demonstrated improved safety multiples in preclinical evaluations against undesired pulmonary and cardiovascular effects. In clinical trials, 2 was found to exhibit a pharmacokinetic half-life ( T1/2) longer than that of 1, as well as a reduced formation of the phosphate metabolite that is required for activity against S1P1. Herein, we describe our efforts to discover highly potent, partial agonists of S1P1 with a shorter T1/2 and increased in vivo phosphate metabolite formation. These efforts culminated in the discovery of BMS-986166 (14a), which was advanced to human clinical evaluation. The pharmacokinetic/pharmacodynamic (PK/PD) relationship as well as pulmonary and cardiovascular safety assessments are discussed. Furthermore, efficacy of 14a in multiple preclinical models of autoimmune diseases are presented.


Assuntos
Ensaios Clínicos como Assunto , Naftalenos/farmacologia , Receptores de Esfingosina-1-Fosfato/agonistas , Tetra-Hidronaftalenos/farmacologia , Animais , Líquido da Lavagem Broncoalveolar , Relação Dose-Resposta a Droga , Meia-Vida , Humanos , Naftalenos/química , Naftalenos/farmacocinética , Ratos , Ratos Endogâmicos Lew , Tetra-Hidronaftalenos/química , Tetra-Hidronaftalenos/farmacocinética
5.
J Med Chem ; 60(13): 5267-5289, 2017 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-28291340

RESUMO

The sphingoid base derived class of lipids (sphingolipids) is a family of interconverting molecules that play key roles in numerous structural and signaling processes. The biosynthetic pathway of the sphingolipids affords many opportunities for therapeutic intervention: targeting the ligands directly, targeting the various proteins involved in the interconversion of the ligands, or targeting the receptors that respond to the ligands. The focus of this article is on the most advanced of the sphingosine-related therapeutics, agonists of sphingosine-1-phosphate receptor 1 (S1P1). The diverse structural classes of S1P1 agonists will be discussed and the status of compounds of clinical relevance will be detailed. An examination of how potential safety concerns are being navigated with compounds currently under clinical evaluation is followed by a discussion of the novel methods being explored to identify next-generation S1P1 agonists with improved safety profiles. Finally, therapeutic opportunities for sphingosine-related targets outside of S1P1 are touched upon.


Assuntos
Cloridrato de Fingolimode/farmacologia , Lisofosfolipídeos/metabolismo , Receptores de Lisoesfingolipídeo/agonistas , Esfingosina/análogos & derivados , Relação Dose-Resposta a Droga , Cloridrato de Fingolimode/química , Humanos , Ligantes , Estrutura Molecular , Receptores de Lisoesfingolipídeo/metabolismo , Esfingosina/metabolismo , Relação Estrutura-Atividade
6.
Medchemcomm ; 8(4): 725-729, 2017 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30108791

RESUMO

Recently, our research group reported the identification of prodrug amino-alcohol 2 as a potent and efficacious S1P1 receptor modulator. This molecule is differentiated preclinically over the marketed drug fingolimod (Gilenya 1), whose active phosphate metabolite is an S1P1 full agonist, in terms of pulmonary and cardiovascular safety. S1P1 partial agonist 2, however, has a long half-life in rodents and was projected to have a long half-life in humans. The purpose of this communication is to disclose highly potent partial agonists of S1P1 with shorter half-lives relative to the clinical compound 2. PK/PD relationships as well as their preclinical pulmonary and cardiovascular safety assessment are discussed.

7.
J Med Chem ; 59(24): 11138-11147, 2016 12 22.
Artigo em Inglês | MEDLINE | ID: mdl-28002964

RESUMO

We describe a highly efficient route for the synthesis of 4a (BMS-986104). A key step in the synthesis is the asymmetric hydroboration of trisubstituted alkene 6. Particularly given the known difficulties involved in this type of transformation (6 → 7), the current methodology provides an efficient approach to prepare this class of compounds. In addition, we disclose the efficacy of 4a in a mouse EAE model, which is comparable to 4c (FTY720). Mechanistically, 4a exhibited excellent remyelinating effects on lysophosphatidylcholine (LPC) induced demyelination in a three-dimensional brain cell culture assay.


Assuntos
Encefalomielite Autoimune Experimental/tratamento farmacológico , Naftalenos/farmacologia , Receptores de Lisoesfingolipídeo/agonistas , Animais , Células Cultivadas , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Células HEK293 , Humanos , Linfócitos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Estrutura Molecular , Naftalenos/síntese química , Naftalenos/química , Relação Estrutura-Atividade
8.
J Med Chem ; 59(21): 9837-9854, 2016 11 10.
Artigo em Inglês | MEDLINE | ID: mdl-27726358

RESUMO

Fingolimod (1) is the first approved oral therapy for the treatment of relapsing remitting multiple sclerosis. While the phosphorylated metabolite of fingolimod was found to be a nonselective S1P receptor agonist, agonism specifically of S1P1 is responsible for the peripheral blood lymphopenia believed to be key to its efficacy. Identification of modulators that maintain activity on S1P1 while sparing activity on other S1P receptors could offer equivalent efficacy with reduced liabilities. We disclose in this paper a ligand-based drug design approach that led to the discovery of a series of potent tricyclic agonists of S1P1 with selectivity over S1P3 and were efficacious in a pharmacodynamic model of suppression of circulating lymphocytes. Compound 10 had the desired pharmacokinetic (PK) and pharmacodynamic (PD) profile and demonstrated maximal efficacy when administered orally in a rat adjuvant arthritis model.


Assuntos
Desenho de Fármacos , Cloridrato de Fingolimode/farmacologia , Compostos Heterocíclicos com 3 Anéis/farmacologia , Receptores de Lisoesfingolipídeo/agonistas , Animais , Artrite Experimental/tratamento farmacológico , Artrite Experimental/imunologia , Cães , Relação Dose-Resposta a Droga , Cloridrato de Fingolimode/administração & dosagem , Cloridrato de Fingolimode/química , Adjuvante de Freund/administração & dosagem , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Compostos Heterocíclicos com 3 Anéis/química , Ligantes , Linfócitos/efeitos dos fármacos , Macaca fascicularis , Masculino , Camundongos , Estrutura Molecular , Mycobacterium/efeitos dos fármacos , Ratos , Ratos Endogâmicos Lew , Relação Estrutura-Atividade , Distribuição Tecidual
9.
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
10.
Bioorg Med Chem Lett ; 26(10): 2470-2474, 2016 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-27055941

RESUMO

The synthesis and structure-activity relationship (SAR) of a series of pyridyl-isoxazole based agonists of S1P1 are discussed. Compound 5b provided potent in vitro activity with selectivity, had an acceptable pharmacokinetic profile, and demonstrated efficacy in a dose dependent manner when administered orally in a rodent model of arthritis.


Assuntos
Artrite Experimental/tratamento farmacológico , Lisofosfolipídeos/agonistas , Esfingosina/análogos & derivados , Relação Estrutura-Atividade , Administração Oral , Animais , Técnicas de Química Sintética , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos/métodos , Humanos , Isoxazóis/química , Isoxazóis/farmacologia , Contagem de Linfócitos , Masculino , Ratos Endogâmicos Lew , Receptores de Lisoesfingolipídeo/agonistas , Esfingosina/agonistas
11.
ACS Med Chem Lett ; 7(3): 283-8, 2016 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-26985316

RESUMO

Clinical validation of S1P receptor modulation therapy was achieved with the approval of fingolimod (Gilenya, 1) as the first oral therapy for relapsing remitting multiple sclerosis. However, 1 causes a dose-dependent reduction in the heart rate (bradycardia), which occurs within hours after first dose. We disclose the identification of clinical compound BMS-986104 (3d), a novel S1P1 receptor modulator, which demonstrates ligand-biased signaling and differentiates from 1 in terms of cardiovascular and pulmonary safety based on preclinical pharmacology while showing equivalent efficacy in a T-cell transfer colitis model.

12.
J Med Chem ; 59(6): 2820-40, 2016 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-26924461

RESUMO

Sphingosine 1-phosphate (S1P) is the endogenous ligand for the sphingosine 1-phosphate receptors (S1P1-5) and evokes a variety of cellular responses through their stimulation. The interaction of S1P with the S1P receptors plays a fundamental physiological role in a number of processes including vascular development and stabilization, lymphocyte migration, and proliferation. Agonism of S1P1, in particular, has been shown to play a significant role in lymphocyte trafficking from the thymus and secondary lymphoid organs, resulting in immunosuppression. This article will detail the discovery and SAR of a potent and selective series of isoxazole based full agonists of S1P1. Isoxazole 6d demonstrated impressive efficacy when administered orally in a rat model of arthritis and in a mouse experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis.


Assuntos
Isoxazóis/síntese química , Isoxazóis/farmacologia , Lisofosfolipídeos/agonistas , Esfingosina/análogos & derivados , Animais , Artrite Experimental/tratamento farmacológico , Células CHO , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Cricetinae , Cricetulus , Descoberta de Drogas , Encefalomielite Autoimune Experimental/tratamento farmacológico , Humanos , Imunossupressores/síntese química , Imunossupressores/farmacologia , Sistema Linfático/citologia , Sistema Linfático/efeitos dos fármacos , Linfócitos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Ratos , Ratos Endogâmicos Lew , Esfingosina/agonistas , Relação Estrutura-Atividade , Timo/citologia , Timo/efeitos dos fármacos
13.
Bioorg Med Chem Lett ; 24(9): 2206-11, 2014 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-24685542

RESUMO

Investigation of various heterocyclic core isosteres of imidazopyrazines 1 & 2 yielded purine derivatives 3 & 8 as potent and selective BTK inhibitors. Subsequent SAR studies of the purine series led to the discovery of 20 as a leading compound. Compound 20 is very selective when screened against a panel of 400 kinases and is a potent inhibitor in cellular assays of human B cell function including B-Cell proliferation and CD86 cell surface expression and exhibited in vivo efficacy in a mouse PCA model. Its X-ray co-crystal structure with BTK shows that the high selectivity is gained from filling a BTK specific lipophilic pocket. However, physical and ADME properties leading to low oral exposure hindered further development.


Assuntos
Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Purinas/química , Purinas/farmacologia , Tirosina Quinase da Agamaglobulinemia , Animais , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/enzimologia , Linfócitos B/efeitos dos fármacos , Cristalografia por Raios X , Humanos , Camundongos , Modelos Moleculares , Anafilaxia Cutânea Passiva/efeitos dos fármacos , Proteínas Tirosina Quinases/metabolismo , Ratos
14.
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
15.
Bioorg Med Chem Lett ; 21(23): 7006-12, 2011 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-22018461

RESUMO

The synthesis, structure-activity relationships (SAR), and biological results of pyridyl-substituted azaindole based tricyclic inhibitors of IKK2 are described. Compound 4m demonstrated potent in vitro potency, acceptable pharmacokinetic and physicochemical properties, and efficacy when dosed orally in a mouse model of inflammatory bowel disease.


Assuntos
Acetamidas/química , Descoberta de Drogas , Inibidores Enzimáticos/química , Compostos Heterocíclicos com 3 Anéis/química , Quinase I-kappa B/antagonistas & inibidores , Acetamidas/síntese química , Acetamidas/farmacologia , Administração Oral , Animais , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Compostos Heterocíclicos com 3 Anéis/síntese química , Compostos Heterocíclicos com 3 Anéis/farmacologia , Humanos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Concentração Inibidora 50 , Camundongos , Estrutura Molecular , Ratos , Relação Estrutura-Atividade
16.
Bioorg Med Chem Lett ; 21(15): 4633-7, 2011 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-21705217
18.
Bioorg Med Chem Lett ; 20(23): 6886-9, 2010 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-21035336

RESUMO

The synthesis and structure-activity relationships (SAR) of p38α MAP kinase inhibitors based on a 5-amino-pyrazole scaffold are described. These studies led to the identification of compound 2j as a potent and selective inhibitor of p38α MAP kinase with excellent cellular potency toward the inhibition of TNFα production. Compound 2j was highly efficacious in vivo in inhibiting TNFα production in an acute murine model of TNFα production. X-ray co-crystallography of a 5-amino-pyrazole analog 2f bound to unphosphorylated p38α is also disclosed.


Assuntos
Proteína Quinase 14 Ativada por Mitógeno/química , Inibidores de Proteínas Quinases/síntese química , Pirazóis/farmacologia , Animais , Cristalografia por Raios X , Camundongos , Proteína Quinase 14 Ativada por Mitógeno/antagonistas & inibidores , Ligação Proteica , Conformação Proteica , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/síntese química , Pirazóis/química , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/biossíntese
19.
J Med Chem ; 53(18): 6629-39, 2010 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-20804198

RESUMO

The discovery and characterization of 7k (BMS-582949), a highly selective p38α MAP kinase inhibitor that is currently in phase II clinical trials for the treatment of rheumatoid arthritis, is described. A key to the discovery was the rational substitution of N-cyclopropyl for N-methoxy in 1a, a previously reported clinical candidate p38α inhibitor. Unlike alkyl and other cycloalkyls, the sp(2) character of the cyclopropyl group can confer improved H-bonding characteristics to the directly substituted amide NH. Inhibitor 7k is slightly less active than 1a in the p38α enzymatic assay but displays a superior pharmacokinetic profile and, as such, was more effective in both the acute murine model of inflammation and pseudoestablished rat AA model. The binding mode of 7k with p38α was confirmed by X-ray crystallographic analysis.


Assuntos
Anti-Inflamatórios não Esteroides/síntese química , Proteína Quinase 14 Ativada por Mitógeno/antagonistas & inibidores , Pirróis/síntese química , Triazinas/síntese química , Animais , Anti-Inflamatórios não Esteroides/farmacocinética , Anti-Inflamatórios não Esteroides/farmacologia , Artrite Experimental/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Disponibilidade Biológica , Células CACO-2 , Cristalografia por Raios X , Feminino , Humanos , Ligação de Hidrogênio , Técnicas In Vitro , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Microssomos Hepáticos/metabolismo , Proteína Quinase 14 Ativada por Mitógeno/química , Modelos Moleculares , Conformação Molecular , Ligação Proteica , Pirróis/farmacocinética , Pirróis/farmacologia , Ratos , Ratos Endogâmicos Lew , Ratos Sprague-Dawley , Estereoisomerismo , Relação Estrutura-Atividade , Triazinas/farmacocinética , Triazinas/farmacologia , Fator de Necrose Tumoral alfa/biossíntese
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