RESUMO
The ability to restrict low molecular weight compounds to the gastrointestinal (GI) tract may enable an enhanced therapeutic index for molecular targets known to be associated with systemic toxicity. Using a triazolopyrazine CSF1R inhibitor scaffold, a broad range of prodrugs were synthesized and evaluated for enhanced delivery to the colon in mice. Subsequently, the preferred cyclodextrin prodrug moiety was appended to a number of CSF1R inhibitory active parent molecules, enabling GI-restricted delivery. Evaluation of a cyclodextrin prodrug in a dextran sodium sulfate (DSS)-induced mouse colitis model resulted in enhanced GI tissue levels of active parent. At a dose where no significant depletion of systemic monocytes were detected, the degree of pharmacodynamic effect-measured as reduction in macrophages in the colon-was inferior to that observed with a systemically available positive control. This suggests that a suitable therapeutic index cannot be achieved with CSF1R inhibition by using GI-restricted delivery in mice. However, these efforts provide a comprehensive frame-work in which to pursue additional gut-restricted delivery strategies for future GI targets.
Assuntos
Colite/imunologia , Ciclodextrinas/química , Pró-Fármacos/administração & dosagem , Pró-Fármacos/síntese química , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/antagonistas & inibidores , Animais , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colo/química , Sulfato de Dextrana/efeitos adversos , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Feminino , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Modelos Moleculares , Estrutura Molecular , Pró-Fármacos/química , Pró-Fármacos/farmacocinéticaRESUMO
Previous work investigating tricyclic pyrrolopyrazines as kinase cores led to the discovery that 1-cyclohexyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (12) had Jak inhibitory activity. Herein we describe our initial efforts to develop orally bioavailable analogs of 12 with improved selectivity of Jak1 over Jak2.
Assuntos
Janus Quinase 1/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Pirazinas/farmacologia , Triazóis/farmacologia , Animais , Linhagem Celular , Relação Dose-Resposta a Droga , Humanos , Janus Quinase 1/metabolismo , Masculino , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Pirazinas/síntese química , Pirazinas/química , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Triazóis/síntese química , Triazóis/químicaRESUMO
We previously demonstrated that selective inhibition of protein kinase Cθ (PKCθ) with triazinone 1 resulted in dose-dependent reduction of paw swelling in a mouse model of arthritis.1,2 However, a high concentration was required for efficacy, thus providing only a minimal safety window. Herein we describe a strategy to deliver safer compounds based on the hypothesis that optimization of potency in concert with good oral pharmacokinetic (PK) properties would enable in vivo efficacy at reduced exposures, resulting in an improved safety window. Ultimately, transformation of 1 yielded analogues that demonstrated excellent potency and PK properties and fully inhibited IL-2 production in an acute model. In spite of good exposure, twice-a-day treatment with 17l in the glucose-6-phosphate isomerase chronic in vivo mouse model of arthritis yielded only moderate efficacy. On the basis of the exposure achieved, we conclude that PKCθ inhibition alone is insufficient for complete efficacy in this rodent arthritis model.
Assuntos
Anti-Inflamatórios/farmacologia , Artrite Experimental/tratamento farmacológico , Isoenzimas/antagonistas & inibidores , Proteína Quinase C/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/metabolismo , Artrite Experimental/metabolismo , Cristalografia por Raios X , Modelos Animais de Doenças , Humanos , Interleucina-2/metabolismo , Isoenzimas/química , Isoenzimas/metabolismo , Masculino , Camundongos , Modelos Químicos , Modelos Moleculares , Estrutura Molecular , Ligação Proteica , Proteína Quinase C/química , Proteína Quinase C/metabolismo , Proteína Quinase C-theta , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/metabolismo , Estrutura Terciária de Proteína , Resultado do TratamentoRESUMO
Protein kinase Cθ (PKCθ) regulates a key step in the activation of T cells. On the basis of its mechanism of action, inhibition of this kinase is hypothesized to serve as an effective therapy for autoimmune diseases such as rheumatoid arthritis (RA), inflammatory bowel disease (IBD), and psoriasis. Herein, the discovery of a small molecule PKCθ inhibitor is described, starting from a fragment hit 1 and advancing to compound 41 through the use of structure-based drug design. Compound 41 demonstrates excellent in vitro activity, good oral pharmacokinetics, and efficacy in both an acute in vivo mechanistic model and a chronic in vivo disease model but suffers from tolerability issues upon chronic dosing.
Assuntos
Isoenzimas/antagonistas & inibidores , Isoenzimas/química , Proteína Quinase C/antagonistas & inibidores , Proteína Quinase C/química , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Administração Oral , Animais , Área Sob a Curva , Artrite Experimental/tratamento farmacológico , Disponibilidade Biológica , Células Cultivadas , Cromatografia Líquida , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Desenho de Fármacos , Descoberta de Drogas , Feminino , Humanos , Isoenzimas/metabolismo , Espectrometria de Massas , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos DBA , Modelos Moleculares , Estrutura Molecular , Ligação Proteica , Proteína Quinase C/metabolismo , Proteína Quinase C-theta , Inibidores de Proteínas Quinases/farmacocinética , Estrutura Terciária de Proteína , Ratos , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacocinética , Bibliotecas de Moléculas Pequenas/farmacologia , Linfócitos T/efeitos dos fármacosRESUMO
We report the SAR around a series of 2,4-diaminopyrimidine-5-carboxamide inhibitors of Sky kinase. 2-Aminophenethyl analogs demonstrate excellent potency but moderate kinase selectivity, while 2-aminobenzyl analogs that fill the Ala571 subpocket exhibit good inhibition activity and excellent kinase selectivity.
Assuntos
Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/química , Pirimidinas/farmacologia , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Amidas/química , Amidas/farmacologia , Animais , Humanos , Camundongos , Relação Estrutura-Atividade , Especificidade por SubstratoRESUMO
Optimization of the ADME properties of a series of 2,4-diaminopyrimidine-5-carboxamide inhibitors of Sky kinase resulted in the identification of highly selective compounds with properties suitable for use as in vitro and in vivo tools to probe the effects of Sky inhibition.
Assuntos
Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/química , Pirimidinas/farmacologia , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Amidas/química , Amidas/farmacologia , Animais , Humanos , Camundongos , Receptores Proteína Tirosina Quinases/química , Relação Estrutura-Atividade , Especificidade por SubstratoRESUMO
Mining of an in-house collection of angiotensin II type 1 receptor antagonists to identify compounds with activity at the peroxisome proliferator-activated receptor-γ (PPARγ) revealed a new series of imidazo[4,5-b]pyridines 2 possessing activity at these two receptors. Early availability of the crystal structure of the lead compound 2a bound to the ligand binding domain of human PPARγ confirmed the mode of interaction of this scaffold to the nuclear receptor and assisted in the optimization of PPARγ activity. Among the new compounds, (S)-3-(5-(2-(1H-tetrazol-5-yl)phenyl)-2,3-dihydro-1H-inden-1-yl)-2-ethyl-5-isobutyl-7-methyl-3H-imidazo[4,5-b]pyridine (2l) was identified as a potent angiotensin II type I receptor blocker (IC(50) = 1.6 nM) with partial PPARγ agonism (EC(50) = 212 nM, 31% max) and oral bioavailability in rat. The dual pharmacology of 2l was demonstrated in animal models of hypertension (SHR) and insulin resistance (ZDF rat). In the SHR, 2l was highly efficacious in lowering blood pressure, while robust lowering of glucose and triglycerides was observed in the male ZDF rat.
Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/síntese química , Anti-Hipertensivos/síntese química , Hipoglicemiantes/síntese química , Imidazóis/síntese química , PPAR gama/agonistas , Piridinas/síntese química , Administração Oral , Bloqueadores do Receptor Tipo 1 de Angiotensina II/química , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Animais , Anti-Hipertensivos/química , Anti-Hipertensivos/farmacologia , Disponibilidade Biológica , Glicemia/análise , Cristalografia por Raios X , Agonismo Parcial de Drogas , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Imidazóis/química , Imidazóis/farmacologia , Resistência à Insulina , Masculino , Modelos Moleculares , Piridinas/química , Piridinas/farmacologia , Ensaio Radioligante , Ratos , Ratos Endogâmicos SHR , Estereoisomerismo , Relação Estrutura-Atividade , Ativação Transcricional , Triglicerídeos/sangueAssuntos
Química Farmacêutica , Informática , Algoritmos , Desenho de Fármacos , Humanos , Relação Estrutura-AtividadeRESUMO
Aiming to improve upon previously disclosed Factor Xa inhibitors, a series of 4,4-disubstituted pyrrolidine-1,2-dicarboxamides were explored with the intent of increasing the projected human half-life versus 5 (projected human t(1/2)=6 h). A stereospecific route to compounds containing a 4-aryl-4-hydroxypyrrolidine scaffold was developed, resulting in several compounds that demonstrated an increase in the half-life as well as an increase in the in vitro potency compared to 5. Reported herein is the discovery of 26, containing a (2R,4S)-4-hydroxy-4-(2,4-difluorophenyl)-pyrrolidine scaffold, which is a selective, orally bioavailable, efficacious Factor Xa inhibitor that appears suitable for a once-daily dosing (projected human t(1/2)=23 h).
Assuntos
Pirrolidinas/farmacologia , Administração Oral , Cristalografia por Raios X , Meia-Vida , Humanos , Pirrolidinas/administração & dosagem , Pirrolidinas/farmacocinéticaRESUMO
Herein, we report the discovery of novel, proline-based factor Xa inhibitors containing a neutral P1 chlorophenyl pharmacophore. Through the additional incorporation of 1-(4-amino-3-fluoro-phenyl)-1H-pyridin-2-one 22, as a P4 pharmacophore, we discovered compound 7 (PD 0348292). This compound is a selective, orally bioavailable, efficacious FXa inhibitor that is currently in phase II clinical trials for the treatment and prevention of thrombotic disorders.
Assuntos
Antitrombina III/síntese química , Antitrombina III/farmacologia , Piridonas/síntese química , Piridonas/farmacologia , Pirrolidinas/síntese química , Pirrolidinas/farmacologia , Animais , Anticoagulantes/síntese química , Anticoagulantes/farmacocinética , Anticoagulantes/farmacologia , Antitrombina III/farmacocinética , Cristalografia por Raios X , Cães , Humanos , Masculino , Piridonas/farmacocinética , Pirrolidinas/farmacocinética , Coelhos , Ratos , Relação Estrutura-AtividadeRESUMO
We report the design and synthesis of a series of 6-(2,4-diaminopyrimidinyl)-1,4-benzoxazin-3-ones as orally bioavailable small molecule inhibitors of renin. Compounds with a 2-methyl-2-aryl substitution pattern exhibit potent renin inhibition and good permeability, solubility, and metabolic stability. Oral bioavailability was found to be dependent on metabolic clearance and cellular permeability, and was optimized through modulation of the sidechain that binds in the S3(sp) subsite.
Assuntos
Benzoxazinas/química , Benzoxazinas/farmacologia , Desenho de Fármacos , Piridinas/química , Renina/antagonistas & inibidores , Aminação , Animais , Benzoxazinas/síntese química , Benzoxazinas/metabolismo , Cristalografia por Raios X , Masculino , Modelos Moleculares , Estrutura Molecular , Ratos , Ratos Sprague-Dawley , Renina/química , Renina/metabolismo , Relação Estrutura-AtividadeRESUMO
A novel series of pyrrolidine-1,2-dicarboxamides was discovered as factor Xa inhibitors using structure-based drug design. This series consisted of a neutral 4-chlorophenylurea P1, a biphenylsulfonamide P4 and a D-proline scaffold (1, IC(50) = 18 nM). Optimization of the initial hit resulted in an orally bioavailable, subnanomolar inhibitor of factor Xa (13, IC(50) = 0.38 nM), which was shown to be efficacious in a canine electrolytic model of thrombosis with minimal bleeding.
Assuntos
Antitrombina III/química , Química Farmacêutica/métodos , Ácido Pirrolidonocarboxílico/farmacologia , Administração Oral , Animais , Antitrombina III/farmacologia , Cristalização , Cães , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Modelos Químicos , Modelos Moleculares , Ligação Proteica , Ácido Pirrolidonocarboxílico/química , Relação Estrutura-Atividade , Fatores de TempoRESUMO
Novel 2,4-diaminopyrimidine-based small molecule renin inhibitors are disclosed. Through high throughput screening, parallel synthesis, X-ray crystallography, and structure based drug design, we have developed the first non-chiral, non-peptidic, small molecular template to possess moderate potency against renin. The designed compounds consist of a novel 6-ethyl-5-(1,2,3,4-tetrahydroquinolin-7-yl)pyrimidine-2,4-diamine ring system that exhibit moderate potency (IC(50): 91-650 nM) against renin while remaining 'Rule-of-five' compliant.
Assuntos
Química Farmacêutica/métodos , Pirimidinas/química , Renina/antagonistas & inibidores , Animais , Cristalografia por Raios X , Desenho de Fármacos , Concentração Inibidora 50 , Modelos Químicos , Modelos Moleculares , Conformação Molecular , Pirimidinas/síntese química , Pirimidinas/farmacologia , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
Herein, we report on the identification of three potent glycine and related amino acid-based series of FXa inhibitors containing a neutral P1 chlorophenyl pharmacophore. A X-ray crystal structure has shown that constrained glycine derivatives with optimized N-substitution can greatly increase hydrophobic interactions in the FXa active site. Also, the substitution of a pyridone ring for a phenylsulfone ring in the P4 sidechain resulted in an inhibitor with enhanced oral bioavailability.
Assuntos
Inibidores do Fator Xa , Fator Xa/química , Glicina/análogos & derivados , Glicina/química , Inibidores de Serina Proteinase/química , Cristalografia por Raios X , Humanos , Estrutura Molecular , Conformação ProteicaRESUMO
A systematic investigation of the S3 sub-pocket activity requirements was conducted. It was observed that linear and sterically small side chain substituents are preferred in the S3 sub-pocket for optimal renin inhibition. Polar groups in the S3-sub-pocket were not well tolerated and caused a reduction in renin inhibitory activity. Further, compounds with clog P's < or = 3 demonstrated a dramatic reduction in CYP3A4 inhibitory activity.
Assuntos
Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Piperazinas/química , Piperazinas/farmacologia , Renina/antagonistas & inibidores , Cristalografia por Raios X , Citocromo P-450 CYP3A , Sistema Enzimático do Citocromo P-450/efeitos dos fármacos , Inibidores Enzimáticos/síntese química , Humanos , Modelos Moleculares , Estrutura Molecular , Piperazinas/síntese química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
The activated factor VII/tissue factor complex (FVIIa/TF) is known to play a key role in the formation of blood clots. Inhibition of this complex may lead to new antithrombotic drugs. A fluoropyridine-based series of FVIIa/TF inhibitors was discovered which utilized a diisopropylamino group for binding in the S2 and S3 binding pockets of the active site of the enzyme complex. In this series, an enhancement in binding affinity was observed by substitution at the 5-position of the hydroxybenzoic acid sidechain. An X-ray crystal structure indicates that amides at this position may increase inhibitor binding affinity through interactions with the S1'/S2' pocket.
Assuntos
Inibidores Enzimáticos/farmacologia , Fator VIIa/antagonistas & inibidores , Piridinas/farmacologia , Tromboplastina/antagonistas & inibidores , Cristalografia por Raios X , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Modelos Moleculares , Estrutura Molecular , Piridinas/síntese química , Piridinas/química , Relação Estrutura-AtividadeRESUMO
Inhibition of renin enzymatic activity by a series of ketopiperazine-based compounds containing a C6 benzyloxymethyl substituent correlated with a +(pi+sigma) effect. A 3-pyridinyloxymethyl substituent was also found to be equipotent as higher molecular weight analogs, and exhibited decreased CYP3A4 inhibition levels and improved pharmacokinetic properties.
Assuntos
Piperazinas/síntese química , Renina/antagonistas & inibidores , Anti-Hipertensivos/síntese química , Anti-Hipertensivos/farmacocinética , Células CACO-2 , Permeabilidade da Membrana Celular , Citocromo P-450 CYP3A , Inibidores das Enzimas do Citocromo P-450 , Éter , Humanos , Concentração Inibidora 50 , Piperazina , Piperazinas/farmacocinética , Piperazinas/farmacologia , Solubilidade , Relação Estrutura-AtividadeRESUMO
The activated Factor VII/tissue factor complex (FVIIa/TF) plays a key role in the formation of blood clots. Inhibition of this complex may lead to new antithrombotic drugs. An X-ray crystal structure of a fluoropyridine-based FVIIa/TF inhibitor bound in the active site of the enzyme complex suggested that incorporation of substitution at the 5-position of the hydroxybenzoic acid side chain could lead to the formation of more potent inhibitors through interactions with the S1'/S2' pocket.
Assuntos
Inibidores Enzimáticos/síntese química , Fator VIIa/química , Fibrinolíticos/síntese química , Piridinas/síntese química , Tromboplastina/química , Sítios de Ligação , Cristalografia por Raios X , Inibidores Enzimáticos/química , Fator VIIa/antagonistas & inibidores , Inibidores do Fator Xa , Fibrinolíticos/química , Fibrinolíticos/farmacologia , Humanos , Concentração Inibidora 50 , Ligação Proteica , Tempo de Protrombina , Piridinas/química , Relação Estrutura-Atividade , Tromboplastina/antagonistas & inibidoresRESUMO
We have found that both enantiomeric configurations of the 6-alkoxymethyl-1-aryl-2-piperazinone scaffold display equipotent renin inhibition activity and similar SAR patterns. This enantiomeric flexibility is in contrast to a previously reported 3-alkoxymethyl-4-arylpiperidine scaffold.
Assuntos
Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Piperazinas/síntese química , Piperazinas/farmacologia , Renina/antagonistas & inibidores , Sítios de Ligação , Inibidores Enzimáticos/química , Indicadores e Reagentes , Conformação Molecular , Estrutura Molecular , Piperazinas/química , Conformação Proteica , Renina/química , EstereoisomerismoRESUMO
Ketopiperazine 2 was designed from a previously published analog. Compound 2 was shown to be a novel, potent inhibitor of renin that, when administered orally, lowered blood pressure in a hypertensive double transgenic (human renin and angiotensinogen) mouse model. Compound 2 was further optimized to sub-nanomolar potency by designing an analog that addressed the S3 sub-pocket of the renin enzyme (16).