RESUMO
In an effort to discover oral inverse agonists of RORγt to treat inflammatory diseases, a new 2,6-difluorobenzyl ether series of cyclopentyl sulfones were found to be surprisingly more potent than the corresponding alcohol derivatives. When combined with a more optimized phenyl ((R)-3-phenylpyrrolidin-3-yl)sulfone template, the 2,6-difluorobenzyl ethers yielded a set of very potent RORγt inverse agonists (e.g., compound 26, RORγt Gal4 EC50 11 nM) that are highly selective against PXR, LXRα and LXRß. After optimizing for stability in human and mouse liver microsomes, compounds 29 and 38 were evaluated in vivo and found to have good oral bioavailability (56% and 101%, respectively) in mice. X-ray co-crystal structure of compound 27 in RORγt revealed that the bulky benzyl ether group causes helix 11 of the protein to partially uncoil to create a new, enlarged binding site, which nicely accommodates the benzyl ether moiety, leading to net potency gain.
Assuntos
Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/antagonistas & inibidores , Pirrolidinas/farmacologia , Sulfonas/farmacologia , Animais , Cristalografia por Raios X , Descoberta de Drogas , Agonismo Inverso de Drogas , Estabilidade de Medicamentos , Células Hep G2 , Humanos , Camundongos , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Pirrolidinas/síntese química , Pirrolidinas/metabolismo , Relação Estrutura-Atividade , Sulfonas/síntese química , Sulfonas/metabolismoRESUMO
A novel series of cis-3,4-diphenylpyrrolidines were designed as RORγt inverse agonists based on the binding conformation of previously reported bicyclic sulfonamide 1. Preliminary synthesis and structure-activity relationship (SAR) study established (3S,4S)-3-methyl-3-(4-fluorophenyl)-4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxyprop-2-yl)phenyl)pyrrolidine as the most effective scaffold. Subsequent SAR optimization led to identification of a piperidinyl carboxamide 31, which was potent against RORγt (EC50 of 61 nM in an inverse agonist assay), selective relative to RORα, RORß, LXRα and LXRß, and stable in human and mouse liver microsomes. Furthermore, compound 31 exhibited considerably lower PXR Ymax (46%) and emerged as a promising lead. The binding mode of the diphenylpyrrolidine series was established with an X-ray co-crystal structure of 10A/RORγt.
Assuntos
Desenho de Fármacos , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Pirrolidinas/química , Animais , Sítios de Ligação , Cristalografia por Raios X , Agonismo Inverso de Drogas , Humanos , Camundongos , Microssomos Hepáticos/metabolismo , Simulação de Dinâmica Molecular , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/agonistas , Receptor de Pregnano X/agonistas , Receptor de Pregnano X/metabolismo , Pirrolidinas/síntese química , Pirrolidinas/metabolismo , Relação Estrutura-AtividadeRESUMO
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 , Receptor gama de Ácido RetinoicoRESUMO
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/agonistasRESUMO
This Letter describes synthesis, SAR, and biological activity of (2-oxo-1,4-benzodiazepin-3-yl)-succinamides as inhibitors of γ-secretase mediated signaling of Notch receptors. Optimization of this series led to the identification of BMS-871 (compound 30) which displayed robust in vivo efficacy in Notch-dependent leukemia and solid tumor xenograft models.
Assuntos
Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Benzodiazepinonas/administração & dosagem , Benzodiazepinonas/farmacologia , Receptores Notch/antagonistas & inibidores , Administração Oral , Animais , Antineoplásicos/química , Benzodiazepinonas/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Camundongos , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Receptores Notch/metabolismo , Relação Estrutura-AtividadeRESUMO
Pyrrolo[2,1-f][1,2,4]triazine based inhibitors of p38α have been prepared exploring functional group modifications at the C6 position. Incorporation of aryl and heteroaryl ketones at this position led to potent inhibitors with efficacy in in vivo models of acute and chronic inflammation.
Assuntos
Anti-Inflamatórios/química , Proteína Quinase 14 Ativada por Mitógeno/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Pirróis/química , Triazinas/química , Administração Oral , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Artrite/tratamento farmacológico , Sítios de Ligação , Cristalografia por Raios X , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Feminino , Camundongos , Proteína Quinase 14 Ativada por Mitógeno/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Estrutura Terciária de Proteína , Ratos , Relação Estrutura-Atividade , Triazinas/farmacologia , Triazinas/uso terapêuticoRESUMO
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-AtividadeRESUMO
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/biossínteseRESUMO
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 â¼ 5 days).
RESUMO
A new phenyl (3-phenylpyrrolidin-3-yl)sulfone series of RORγt inverse agonists was discovered utilizing the binding conformation of previously reported bicyclic sulfonamide 1. Through a combination of structure-based design and structure-activity relationship studies, a polar set of amides at N1-position of the pyrrolidine ring and perfluoroisopropyl group at para-position of the 3-phenyl group were identified as critical structural elements to achieve high selectivity against PXR, LXRα, and LXRß. Further optimization led to the discovery of (1R,4r)-4-((R)-3-((4-fluorophenyl)sulfonyl)-3-(4-(perfluoropropan-2-yl)phenyl)pyrrolidine-1-carbonyl)cyclohexane-1-carboxylic acid (26), which displayed excellent selectivity, desirable liability and pharmacokinetic properties in vitro, and a good pharmacokinetic profile in mouse. Oral administration of 26 demonstrated dose-dependent inhibition of IL-17 production in a mouse IL-2/IL-23-induced pharmacodynamic model and biologic-like efficacy in an IL-23-induced mouse acanthosis model.
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/farmacocinéticaRESUMO
A novel structural class of p38 mitogen-activated protein (MAP) kinase inhibitors consisting of substituted 4-(phenylamino)-pyrrolo[2,1- f][1,2,4]triazines has been discovered. An initial subdeck screen revealed that the oxindole-pyrrolo[2,1- f][1,2,4]triazine lead 2a displayed potent enzyme inhibition (IC 50 60 nM) and was active in a cell-based TNFalpha biosynthesis inhibition assay (IC 50 210 nM). Replacement of the C4 oxindole with 2-methyl-5- N-methoxybenzamide aniline 9 gave a compound with superior p38 kinase inhibition (IC 50 10 nM) and moderately improved functional inhibition in THP-1 cells. Further replacement of the C6 ester of the pyrrolo[2,1- f][1,2,4]triazine with amides afforded compounds with increased potency, excellent oral bioavailability, and robust efficacy in a murine model of acute inflammation (murine LPS-TNFalpha). In rodent disease models of chronic inflammation, multiple compounds demonstrated significant inhibition of disease progression leading to the advancement of 2 compounds 11b and 11j into further preclinical and toxicological studies.
Assuntos
Anti-Inflamatórios não Esteroides/síntese química , Proteína Quinase 14 Ativada por Mitógeno/antagonistas & inibidores , Pirróis/síntese química , Triazinas/síntese química , Administração Oral , Animais , Anti-Inflamatórios não Esteroides/farmacocinética , Anti-Inflamatórios não Esteroides/farmacologia , Artrite Experimental/tratamento farmacológico , Sítios de Ligação , Cristalografia por Raios X , Desenho de Fármacos , Feminino , Humanos , Técnicas In Vitro , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Microssomos Hepáticos/metabolismo , Proteína Quinase 14 Ativada por Mitógeno/química , Modelos Moleculares , Pirróis/farmacocinética , Pirróis/farmacologia , Ratos , Ratos Endogâmicos Lew , Relação Estrutura-Atividade , Triazinas/farmacocinética , Triazinas/farmacologia , Fator de Necrose Tumoral alfa/biossíntese , Fator de Necrose Tumoral alfa/sangueRESUMO
A novel series of compounds based on the pyrrolo[2,1-f][1,2,4]triazine ring system have been identified as potent p38 alpha MAP kinase inhibitors. The synthesis, structure-activity relationships (SAR), and in vivo activity of selected analogs from this class of inhibitors are reported. Additional studies based on X-ray co-crystallography have revealed that one of the potent inhibitors from this series binds to the DFG-out conformation of the p38 alpha enzyme.
Assuntos
Proteína Quinase 14 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 14 Ativada por Mitógeno/metabolismo , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Pirróis/química , Triazinas/síntese química , Triazinas/farmacologia , Amidas/química , Animais , Cristalografia por Raios X , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade , Triazinas/química , Fator de Necrose Tumoral alfa/biossínteseRESUMO
The synthesis and structure-activity relationships (SAR) of p38 alpha MAP kinase inhibitors based on a pyrazolo-pyrimidine scaffold are described. These studies led to the identification of compound 2x as a potent and selective inhibitor of p38 alpha MAP kinase with excellent cellular potency toward the inhibition of TNFalpha production. Compound 2x was highly efficacious in vivo in inhibiting TNFalpha production in an acute murine model of TNFalpha production. X-ray co-crystallography of a pyrazolo-pyrimidine analog 2b bound to unphosphorylated p38 alpha is also disclosed.
Assuntos
Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/química , Pirimidinas/síntese química , Pirimidinas/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Cristalografia por Raios X , Humanos , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/química , Pirimidinas/química , Relação Estrutura-Atividade , Proteínas Quinases p38 Ativadas por Mitógeno/químicaRESUMO
A novel structural class of p38alpha MAP kinase inhibitors has been identified via iterative SAR studies of a focused deck screen hit. Optimization of the lead series generated 6e, BMS-640994, a potent and selective p38alpha inhibitor that is orally efficacious in rodent models of acute and chronic inflammation.
Assuntos
Proteína Quinase 14 Ativada por Mitógeno/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Tiazóis/farmacologia , Animais , Artrite/tratamento farmacológico , Células CACO-2 , Permeabilidade da Membrana Celular/efeitos dos fármacos , Células Cultivadas , Cristalografia por Raios X , Inibidores das Enzimas do Citocromo P-450 , Sistema Enzimático do Citocromo P-450/metabolismo , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Humanos , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Microssomos Hepáticos/efeitos dos fármacos , Proteína Quinase 14 Ativada por Mitógeno/metabolismo , Estrutura Molecular , Monócitos/citologia , Monócitos/efeitos dos fármacos , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacocinética , Ratos , Ratos Endogâmicos Lew , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/farmacocinética , Fator de Necrose Tumoral alfa/metabolismoRESUMO
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.
RESUMO
2-aminothiazole (1) was discovered as a novel Src family kinase inhibitor template through screening of our internal compound collection. Optimization through successive structure-activity relationship iterations identified analogs 2 (Dasatinib, BMS-354825) and 12m as pan-Src inhibitors with nanomolar to subnanomolar potencies in biochemical and cellular assays. Molecular modeling was used to construct a putative binding model for Lck inhibition by this class of compounds. The framework of key hydrogen-bond interactions proposed by this model was in agreement with the subsequent, published crystal structure of 2 bound to structurally similar Abl kinase. The oral efficacy of this class of inhibitors was demonstrated with 12m in inhibiting the proinflammatory cytokine IL-2 ex vivo in mice (ED50 approximately 5 mg/kg) and in reducing TNF levels in an acute murine model of inflammation (90% inhibition in LPS-induced TNFalpha production when dosed orally at 60 mg/kg, 2 h prior to LPS administration). The oral efficacy of 12m was further demonstrated in a chronic model of adjuvant arthritis in rats with established disease when administered orally at 0.3 and 3 mg/kg twice daily. Dasatinib (2) is currently in clinical trials for the treatment of chronic myelogenous leukemia.
Assuntos
Anti-Inflamatórios não Esteroides/síntese química , Pirimidinas/síntese química , Tiazóis/síntese química , Quinases da Família src/antagonistas & inibidores , Administração Oral , Animais , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Artrite Experimental/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Doença Crônica , Dasatinibe , Feminino , Humanos , Técnicas In Vitro , Inflamação/sangue , Inflamação/induzido quimicamente , Interleucina-2/antagonistas & inibidores , Lipopolissacarídeos , Proteína Tirosina Quinase p56(lck) Linfócito-Específica/antagonistas & inibidores , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Modelos Moleculares , Ligação Proteica , Pirimidinas/química , Pirimidinas/farmacologia , Ratos , Ratos Endogâmicos Lew , Relação Estrutura-Atividade , Linfócitos T/citologia , Linfócitos T/efeitos dos fármacos , Tiazóis/química , Tiazóis/farmacologia , Fator de Necrose Tumoral alfa/metabolismoRESUMO
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-AtividadeRESUMO
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.
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.