RESUMO
Glucokinase (GK) is a key regulator of glucose homeostasis, and its small-molecule activators represent a promising opportunity for the treatment of type 2 diabetes. Several GK activators have been advanced into clinical trials and have demonstrated promising efficacy; however, hypoglycemia represents a key risk for this mechanism. In an effort to mitigate this hypoglycemia risk while maintaining the efficacy of the GK mechanism, we have investigated a series of amino heteroaryl phosphonate benzamides as ''partial" GK activators. The structure-activity relationship studies starting from a "full GK activator" 11, which culminated in the discovery of the "partial GK activator" 31 (BMS-820132), are discussed. The synthesis and in vitro and in vivo preclinical pharmacology profiles of 31 and its pharmacokinetics (PK) are described. Based on its promising in vivo efficacy and preclinical ADME and safety profiles, 31 was advanced into human clinical trials.
Assuntos
Azetidinas , Diabetes Mellitus Tipo 2 , Hipoglicemia , Organofosfonatos , Azetidinas/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Glucoquinase , Humanos , Hipoglicemia/tratamento farmacológico , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Organofosfonatos/farmacologia , Organofosfonatos/uso terapêuticoRESUMO
Scaffold hopping and structure-based drug design were employed to identify substituted 4-aminoquinolines and 4-aminonaphthyridines as potent, small molecule inhibitors of tumor necrosis factor alpha (TNFα). Structure-activity relationships in both the quinoline and naphthyridine series leading to the identification of compound 42 with excellent potency and pharmacokinetic profile are discussed. X-ray co-crystal structure analysis and ultracentrifugation experiments clearly demonstrate that these inhibitors distort the TNFα trimer upon binding, leading to aberrant signaling when the trimer binds to TNF receptor 1 (TNFR1). Pharmacokinetic-pharmacodynamic activity of compound 42 in a TNF-induced IL-6 mouse model and in vivo activity in a collagen antibody-induced arthritis model, where it showed biologic-like in vivo efficacy, will be discussed.
Assuntos
Naftiridinas/farmacologia , Quinolinas/farmacologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Animais , Artrite Experimental/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Desenho de Fármacos , Feminino , Humanos , Camundongos Endogâmicos C57BL , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Naftiridinas/síntese química , Naftiridinas/farmacocinética , Naftiridinas/uso terapêutico , Estudo de Prova de Conceito , Quinolinas/síntese química , Quinolinas/farmacocinética , Quinolinas/uso terapêutico , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Employing a virtual screening approach, we identified the pyroglutamide moiety as a nonacid replacement for the cyclohexanecarboxylic acid group which, when coupled to our previously reported conformationally locked tricyclic core, provided potent and selective RORγt inverse agonists. Structure-activity relationship optimization of the pyroglutamide moiety led to the identification of compound 18 as a potent and selective RORγt inverse agonist, albeit with poor aqueous solubility. We took advantage of the tertiary carbinol group in 18 to synthesize a phosphate prodrug, which provided good solubility, excellent exposures in mouse PK studies, and significant efficacy in a mouse model of psoriasis.
RESUMO
Bruton's tyrosine kinase (BTK) has been shown to play a key role in the pathogenesis of autoimmunity. Therefore, the inhibition of the kinase activity of BTK with a small molecule inhibitor could offer a breakthrough in the clinical treatment of many autoimmune diseases. This Letter describes the discovery of BMS-986143 through systematic structure-activity relationship (SAR) development. This compound benefits from defined chirality derived from two rotationally stable atropisomeric axes, providing a potent and selective single atropisomer with desirable efficacy and tolerability profiles.
RESUMO
In order to rapidly develop C6 and C8 SAR of our reported tricyclic sulfone series of RORγt inverse agonists, a late-stage bromination was employed. Although not regioselective, the bromination protocol allowed us to explore new substitution patterns/vectors that otherwise would have to be incorporated at the very beginning of the synthesis. Based on the SAR obtained from this exercise, compound 15 bearing a C8 fluorine was developed as a very potent and selective RORγt inverse agonist. This analog's in vitro profile, pharmacokinetic (PK) data and efficacy in an IL-23 induced mouse acanthosis model will be discussed.
Assuntos
Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Melanose/tratamento farmacológico , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/antagonistas & inibidores , Sulfonas/uso terapêutico , Animais , Cristalografia por Raios X , Agonismo Inverso de Drogas , Feminino , Compostos Heterocíclicos com 3 Anéis/síntese química , Compostos Heterocíclicos com 3 Anéis/farmacocinética , Interleucina-18 , Masculino , Melanose/induzido quimicamente , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Estrutura Molecular , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Ligação Proteica , Relação Estrutura-Atividade , Sulfonas/síntese química , Sulfonas/farmacocinéticaRESUMO
RORγt is the master regulator of the IL-23/IL-17 axis, a pathway that is clinically validated for the treatment of various immunological disorders. Over the last few years, our group has reported different chemotypes that potently act as inverse agonists of RORγt. One of them, the tricyclic pyrrolidine chemotype, has demonstrated biologic-like preclinical efficacy and has led to our clinical candidate BMS-986251. In this letter, we discuss the invention of an annulation reaction which enabled the synthesis of a tricyclic exocyclic amide chemotype and the identification of compounds with RORγt inverse agonist activity. Preliminary structure activity relationships are disclosed.
Assuntos
Amidas/química , Hidrocarbonetos Cíclicos/química , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/antagonistas & inibidores , Sulfonas/química , Amidas/síntese química , Amidas/metabolismo , Animais , Ciclização , Agonismo Inverso de Drogas , Humanos , Hidrocarbonetos Cíclicos/síntese química , Hidrocarbonetos Cíclicos/metabolismo , Camundongos , Microssomos Hepáticos/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Relação Estrutura-Atividade , Sulfonas/síntese química , Sulfonas/metabolismoRESUMO
We describe an efficient synthetic route to differentially protected diester, 1-(tert-butyl) 4-methyl (1R,2S,4R)-2-methylcyclohexane-1,4-dicarboxylate (+)-1, via palladium-catalyzed methoxycarbonylation of an enol triflate derived from a Hagemann's ester derivative followed by a stereoselective Crabtree hydrogenation. Diester 1 is a novel chiral synthon useful in drug discovery and was instrumental in the generation of useful SAR during a RORγt inverse agonist program. In addition, we describe a second-generation synthesis of the clinical candidate BMS-986251, using diester 1 as a critical component.
Assuntos
Ácidos Carboxílicos , Ésteres , Cicloexanos , EstereoisomerismoRESUMO
Novel tricyclic analogues were designed, synthesized, and evaluated as RORγt inverse agonists. Several of these compounds were potent in an IL-17 human whole blood assay and exhibited excellent oral bioavailability in mouse pharmacokinetic studies. This led to the identification of compound 5, which displayed dose-dependent inhibition of IL-17F production in a mouse IL-2/IL-23 stimulated pharmacodynamic model. In addition, compound 5 was studied in mouse acanthosis and imiquimod-induced models of skin inflammation, where it demonstrated robust efficacy comparable to a positive control. As a result of this excellent overall profile, compound 5 (BMS-986251) was selected as a clinically viable developmental candidate.
RESUMO
RORγt is an important nuclear receptor that regulates the production of several pro-inflammatory cytokines such as IL-17 and IL-22. As a result, RORγt has been identified as a potential target for the treatment of various immunological disorders such as psoriasis, psoriatic arthritis, and inflammatory bowel diseases. Structure and computer-assisted drug design led to the identification of a novel series of tricyclic RORγt inverse agonists with significantly improved in vitro activity in the reporter (Gal4) and human whole blood assays compared to our previous chemotype. Through careful structure activity relationship, several potent and selective RORγt inverse agonists have been identified. Pharmacokinetic studies allowed the identification of the lead molecule 32 with a low peak-to-trough ratio. This molecule showed excellent activity in an IL-2/IL-23-induced mouse pharmacodynamic study and demonstrated biologic-like efficacy in an IL-23-induced preclinical model of psoriasis.
Assuntos
Desenho de Fármacos , Agonismo Inverso de Drogas , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/agonistas , Pirrolidinas/farmacologia , Animais , Humanos , Células Jurkat , Camundongos , Modelos Moleculares , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/química , Conformação Proteica , Pirrolidinas/química , Pirrolidinas/farmacocinética , Relação Estrutura-Atividade , Distribuição TecidualRESUMO
Bruton's tyrosine kinase (BTK), a non-receptor tyrosine kinase, is a member of the Tec family of kinases and is essential for B cell receptor (BCR) mediated signaling. BTK also plays a critical role in the downstream signaling pathways for the Fcγ receptor in monocytes, the Fcε receptor in granulocytes, and the RANK receptor in osteoclasts. As a result, pharmacological inhibition of BTK is anticipated to provide an effective strategy for the clinical treatment of autoimmune diseases such as rheumatoid arthritis and lupus. This article will outline the evolution of our strategy to identify a covalent, irreversible inhibitor of BTK that has the intrinsic potency, selectivity, and pharmacokinetic properties necessary to provide a rapid rate of inactivation systemically following a very low dose. With excellent in vivo efficacy and a very desirable tolerability profile, 5a (branebrutinib, BMS-986195) has advanced into clinical studies.
Assuntos
Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Descoberta de Drogas , Indóis/farmacologia , Piperidinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Animais , Artrite Reumatoide/tratamento farmacológico , Relação Dose-Resposta a Droga , Humanos , Indóis/farmacocinética , Indóis/uso terapêutico , Concentração Inibidora 50 , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Macaca fascicularis , Camundongos , Piperidinas/farmacocinética , Piperidinas/uso terapêutico , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/uso terapêuticoRESUMO
Bruton's tyrosine kinase (BTK) plays an essential role in multiple cell types responsible for numerous autoimmune diseases, thus inhibition of BTK is anticipated to provide an effective strategy for the clinical treatment of autoimmune diseases. Preparative-scale super/subcritical fluid chromatography (SFC) separation methods for four groups of highly potent and selective BTK inhibitor atropisomers were successfully developed. Depending on the rotation barrier around the chiral axis, the compounds were prepared as a single stereochemically stable atropisomer or as an atropisomeric mixture. Among the four, compound 2 with one rotationally stable atropisomeric center (carbazole/quinazolinedione based) was resolved as a mixture of two atropisomers, while compound 3 (carbazole-chlorine/quinazolinedione based) and 4 (tetrahydrocarbazole-fluorine/quinazolinedione based) with two rotationally stable atropisomeric centers were resolved into a single stable atropisomer. This article discusses the challenges and strategies in preparing large quantities of these atropisomeric active pharmaceutical ingredients (APIs) in support of the BTK program discovery efforts.
Assuntos
Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Cromatografia com Fluido Supercrítico/métodos , Descoberta de Drogas/métodos , Inibidores de Proteínas Quinases/análise , Inibidores de Proteínas Quinases/isolamento & purificação , Descoberta de Drogas/instrumentação , Humanos , EstereoisomerismoRESUMO
Incorporation of a suitably-placed electrophilic group transformed a series of reversible BTK inhibitors based on carbazole-1-carboxamide and tetrahydrocarbazole-1-carboxamide into potent, irreversible inhibitors. Removal of one ring from the core of these compounds provided a potent irreversible series of 2,3-dimethylindole-7-carboxamides having excellent potency and improved selectivity, with the additional advantages of reduced lipophilicity and molecular weight.
Assuntos
Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Carbazóis/farmacologia , Indóis/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Tirosina Quinase da Agamaglobulinemia/metabolismo , Carbazóis/síntese química , Carbazóis/química , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Humanos , Indóis/síntese química , Indóis/química , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Relação Estrutura-AtividadeRESUMO
Bruton's tyrosine kinase (BTK) regulates critical signal transduction pathways involved in the pathobiology of rheumatoid arthritis (RA) and other autoimmune disorders. BMS-986142 is a potent and highly selective reversible small molecule inhibitor of BTK currently being investigated in clinical trials for the treatment of both RA and primary Sjögren's syndrome. In the present report, we detail the in vitro and in vivo pharmacology of BMS-986142 and show this agent provides potent and selective inhibition of BTK (IC50 = 0.5 nM), blocks antigen receptor-dependent signaling and functional endpoints (cytokine production, co-stimulatory molecule expression, and proliferation) in human B cells (IC50 ≤ 5 nM), inhibits Fcγ receptor-dependent cytokine production from peripheral blood mononuclear cells, and blocks RANK-L-induced osteoclastogenesis. Through the benefits of impacting these important drivers of autoimmunity, BMS-986142 demonstrated robust efficacy in murine models of rheumatoid arthritis (RA), including collagen-induced arthritis (CIA) and collagen antibody-induced arthritis (CAIA). In both models, robust efficacy was observed without continuous, complete inhibition of BTK. When a suboptimal dose of BMS-986142 was combined with other agents representing the current standard of care for RA (e.g., methotrexate, the TNFα antagonist etanercept, or the murine form of CTLA4-Ig) in the CIA model, improved efficacy compared to either agent alone was observed. The results suggest BMS-986142 represents a potential therapeutic for clinical investigation in RA, as monotherapy or co-administered with agents with complementary mechanisms of action.
Assuntos
Artrite Experimental/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Tirosina Quinases/antagonistas & inibidores , Tirosina Quinase da Agamaglobulinemia , Animais , Formação de Anticorpos/efeitos dos fármacos , Artrite Experimental/imunologia , Artrite Experimental/patologia , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Linfócitos B/patologia , Feminino , Humanos , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/patologia , Camundongos Endogâmicos BALB C , Osteoclastos/efeitos dos fármacos , Osteoclastos/imunologia , Osteoclastos/patologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/imunologia , Ligante RANK/imunologiaRESUMO
Selective PI3Kδ inhibitors have recently been hypothesized to be appropriate immunosuppressive agents for the treatment of immunological disorders such as rheumatoid arthritis. However, few reports have highlighted molecules that are highly selective for PI3Kδ over the other PI3K isoforms. In this letter, isoform and kinome selective PI3Kδ inhibitors are presented. The Structural Activity Relationship leading to such molecules is outlined.
Assuntos
Inibidores de Fosfoinositídeo-3 Quinase , Inibidores de Proteínas Quinases/farmacologia , Animais , Relação Dose-Resposta a Droga , Humanos , Camundongos , Modelos Moleculares , Estrutura Molecular , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Relação Estrutura-AtividadeRESUMO
As demonstrated in preclinical animal models, the disruption of PI3Kδ expression or its activity leads to a decrease in inflammatory and immune responses. Therefore, inhibition of PI3Kδ may provide an alternative treatment for autoimmune diseases, such as RA, SLE, and respiratory ailments. Herein, we disclose the identification of 7-(3-(piperazin-1-yl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine derivatives as highly potent, selective and orally bioavailable PI3Kδ inhibitors. The lead compound demonstrated efficacy in an in vivo mouse KLH model.
Assuntos
Aminas/química , Inibidores de Fosfoinositídeo-3 Quinase , Inibidores de Proteínas Quinases/química , Aminas/metabolismo , Aminas/uso terapêutico , Animais , Doenças Autoimunes/tratamento farmacológico , Sítios de Ligação , Classe I de Fosfatidilinositol 3-Quinases , Cristalografia por Raios X , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Humanos , Camundongos , Microssomos Hepáticos/metabolismo , Simulação de Acoplamento Molecular , Fosfatidilinositol 3-Quinases/metabolismo , Piperazina , Piperazinas/química , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/metabolismo , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/uso terapêutico , Relação Estrutura-Atividade , Triazinas/químicaRESUMO
Bruton's tyrosine kinase (BTK), a nonreceptor tyrosine kinase, is a member of the Tec family of kinases. BTK plays an essential role in B cell receptor (BCR)-mediated signaling as well as Fcγ receptor signaling in monocytes and Fcε receptor signaling in mast cells and basophils, all of which have been implicated in the pathophysiology of autoimmune disease. As a result, inhibition of BTK is anticipated to provide an effective strategy for the clinical treatment of autoimmune diseases such as lupus and rheumatoid arthritis. This article details the structure-activity relationships (SAR) leading to a novel series of highly potent and selective carbazole and tetrahydrocarbazole based, reversible inhibitors of BTK. Of particular interest is that two atropisomeric centers were rotationally locked to provide a single, stable atropisomer, resulting in enhanced potency and selectivity as well as a reduction in safety liabilities. With significantly enhanced potency and selectivity, excellent in vivo properties and efficacy, and a very desirable tolerability and safety profile, 14f (BMS-986142) was advanced into clinical studies.
Assuntos
Carbazóis/química , Carbazóis/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Tirosina Quinase da Agamaglobulinemia , Animais , Carbazóis/farmacocinética , Cristalografia por Raios X , Feminino , Humanos , Isomerismo , Macaca fascicularis , Camundongos , Camundongos Endogâmicos BALB C , Modelos Moleculares , Inibidores de Proteínas Quinases/farmacocinética , Proteínas Tirosina Quinases/metabolismo , Quinazolinas/química , Quinazolinas/farmacocinética , Quinazolinas/farmacologia , Relação Estrutura-AtividadeRESUMO
Bruton's tyrosine kinase (BTK) belongs to the TEC family of nonreceptor tyrosine kinases and plays a critical role in multiple cell types responsible for numerous autoimmune diseases. This article will detail the structure-activity relationships (SARs) leading to a novel second generation series of potent and selective reversible carbazole inhibitors of BTK. With an excellent pharmacokinetic profile as well as demonstrated in vivo activity and an acceptable safety profile, 7-(2-hydroxypropan-2-yl)-4-[2-methyl-3-(4-oxo-3,4-dihydroquinazolin-3-yl)phenyl]-9H-carbazole-1-carboxamide 6 (BMS-935177) was selected to advance into clinical development.
Assuntos
Antirreumáticos/química , Carbazóis/química , Proteínas Tirosina Quinases/antagonistas & inibidores , Quinazolinonas/química , Administração Oral , Tirosina Quinase da Agamaglobulinemia , Animais , Antirreumáticos/síntese química , Antirreumáticos/farmacocinética , Antirreumáticos/farmacologia , Artrite Experimental/tratamento farmacológico , Artrite Experimental/patologia , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/patologia , Disponibilidade Biológica , Carbazóis/síntese química , Carbazóis/farmacocinética , Carbazóis/farmacologia , Linhagem Celular , Cristalografia por Raios X , Cães , Humanos , Macaca fascicularis , Camundongos , Microssomos Hepáticos/metabolismo , Permeabilidade , Proteínas Tirosina Quinases/química , Quinazolinonas/síntese química , Quinazolinonas/farmacocinética , Quinazolinonas/farmacologia , Relação Estrutura-AtividadeRESUMO
BMS-711939 (3) is a potent and selective peroxisome proliferator-activated receptor (PPAR) α agonist, with an EC50 of 4 nM for human PPARα and >1000-fold selectivity vs human PPARγ (EC50 = 4.5 µM) and PPARδ (EC50 > 100 µM) in PPAR-GAL4 transactivation assays. Compound 3 also demonstrated excellent in vivo efficacy and safety profiles in preclinical studies and thus was chosen for further preclinical evaluation. The synthesis, structure-activity relationship (SAR) studies, and in vivo pharmacology of 3 in preclinical animal models as well as its ADME profile are described.
RESUMO
Four series of disubstituted carbazole-1-carboxamides were designed and synthesised as inhibitors of Bruton's tyrosine kinase (BTK). 4,7- and 4,6-disubstituted carbazole-1-carboxamides were potent and selective inhibitors of BTK, while 3,7- and 3,6-disubstituted carbazole-1-carboxamides were potent and selective inhibitors of Janus kinase 2 (JAK2).
Assuntos
Amidas/farmacologia , Carbazóis/farmacologia , Desenho de Fármacos , Janus Quinase 2/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Amidas/síntese química , Amidas/química , Carbazóis/química , Relação Dose-Resposta a Droga , Humanos , Janus Quinase 2/metabolismo , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Proteínas Tirosina Quinases/metabolismo , Relação Estrutura-AtividadeRESUMO
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.