RESUMO
We report the discovery of a novel series of DGAT1 inhibitors in the benzimidazole class with a piperdinyl-oxy-cyclohexanecarboxylic acid moiety. This novel series possesses significantly improved selectivity against the A2A receptor, no ACAT1 off-target activity at 10 µM, and higher aqueous solubility and free fraction in plasma as compared to the previously reported pyridyl-oxy-cyclohexanecarboxylic acid series. In particular, 5B was shown to possess an excellent selectivity profile by screening it against a panel of more than 100 biological targets. Compound 5B significantly reduces lipid excursion in LTT in mouse and rat, demonstrates DGAT1 mediated reduction of food intake and body weight in mice, is negative in a 3-strain Ames test, and appears to distribute preferentially in the liver and the intestine in mice. We believe this lead series possesses significant potential to identify optimized compounds for clinical development.
RESUMO
Herein we report the design and synthesis of a series of novel bicyclic DGAT1 inhibitors with a carboxylic acid moiety. The optimization of the initial lead compound 7 based on in vitro and in vivo activity led to the discovery of potent indoline and quinoline classes of DGAT1 inhibitors. The structure-activity relationship studies of these novel series of bicyclic carboxylic acid derivatives as DGAT1 inhibitors are described.
Assuntos
Ácidos Carboxílicos/farmacologia , Diacilglicerol O-Aciltransferase/antagonistas & inibidores , Descoberta de Drogas , Inibidores Enzimáticos/farmacologia , Quinolonas/farmacologia , Animais , Ácidos Carboxílicos/síntese química , Ácidos Carboxílicos/química , Diacilglicerol O-Aciltransferase/metabolismo , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Camundongos , Modelos Moleculares , Estrutura Molecular , Quinolonas/síntese química , Quinolonas/química , Relação Estrutura-AtividadeRESUMO
The optimization of oxazole-based PDE4 inhibitor 1 has led to the identification of both oral (compound 16) and inhaled (compound 34) PDE4 inhibitors. Selectivity against PDE10/PDE11, off target screening, and in vivo activity in the rat are discussed.
Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/química , Oxazóis/química , Prolina/análogos & derivados , Quinolinas/síntese química , Administração Oral , Animais , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Avaliação Pré-Clínica de Medicamentos , Meia-Vida , Inalação , Oxazóis/síntese química , Oxazóis/farmacocinética , Inibidores da Fosfodiesterase 4/síntese química , Inibidores da Fosfodiesterase 4/química , Inibidores da Fosfodiesterase 4/farmacocinética , Prolina/síntese química , Prolina/química , Prolina/farmacocinética , Quinolinas/química , Quinolinas/farmacocinética , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
The structure-activity relationship studies of a novel series of carboxylic acid derivatives of pyridine-carboxamides as DGAT-1 inhibitors is described. The optimization of the initial lead compound 6 based on in vitro and in vivo activity led to the discovery of key compounds 10j and 17h.
Assuntos
Amidas/farmacologia , Diacilglicerol O-Aciltransferase/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Piridinas/farmacologia , Animais , Diacilglicerol O-Aciltransferase/metabolismo , Inibidores Enzimáticos/química , Humanos , Camundongos , Relação Estrutura-AtividadeRESUMO
We report the design and synthesis of a series of novel DGAT1 inhibitors in the benzimidazole class with a pyridyl-oxy-cyclohexanecarboxylic acid moiety. In particular, compound 11A is a potent DGAT1 inhibitor with excellent selectivity against ACAT1. Compound 11A significantly reduces triglyceride excursion in lipid tolerance tests (LTT) in both mice and dogs at low plasma exposure. An in vivo study in mice with des-fluoro analogue 10A indicates that this series of compounds appears to distribute in intestine preferentially over plasma. The propensity to target intestine over plasma could be advantageous in reducing potential side effects since lower circulating levels of drug are required for efficacy. However, in the preclinical species, compound 11A undergoes cis/trans epimerization in vivo, which could complicate further development due to the presence of an active metabolite.
RESUMO
A detailed structure-activity relationship study of a novel series of pyridazine-based small molecule glucan synthase inhibitors is described. The optimization of the PK profile of this series led to the discovery of compound 11g, which demonstrated in vivo potency ip in a lethal fungal infection model.
Assuntos
Antifúngicos/química , Inibidores Enzimáticos/química , Glucosiltransferases/antagonistas & inibidores , Piridazinas/química , Sulfonamidas/química , Animais , Antifúngicos/farmacocinética , Antifúngicos/uso terapêutico , Candida/efeitos dos fármacos , Candidíase/tratamento farmacológico , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/uso terapêutico , Glucosiltransferases/metabolismo , Meia-Vida , Camundongos , Testes de Sensibilidade Microbiana , Piridazinas/farmacocinética , Piridazinas/uso terapêutico , Ratos , Relação Estrutura-Atividade , Sulfonamidas/farmacocinética , Sulfonamidas/uso terapêuticoRESUMO
The structure-activity relationship studies of a novel sulfonylurea series of piperazine pyridazine-based small molecule glucan synthase inhibitors is described. The optimization of PK profiles within the series led to the discovery of several compounds with improved pharmacokinetic profiles which demonstrated in vitro potency against clinically relevant strains. However, the advancement of compounds from this series into a non-lethal systemic fungal infection model failed to show in vivo efficacy.
Assuntos
Antifúngicos/química , Inibidores Enzimáticos/química , Glucosiltransferases/antagonistas & inibidores , Chumbo/química , Piperazinas/química , Piridazinas/química , Compostos de Sulfonilureia/química , Animais , Antifúngicos/farmacologia , Candida/efeitos dos fármacos , Linhagem Celular , Inibidores Enzimáticos/farmacologia , Humanos , Estrutura Molecular , Piperazina , Piridazinas/farmacologia , Ratos , Relação Estrutura-Atividade , Compostos de Sulfonilureia/farmacologiaRESUMO
Optimization of oxazole-based PDE4 inhibitors has led to the discovery of a series of quinolyl oxazoles, with 4-benzylcarboxamide and 5-α-aminoethyl groups which exhibit picomolar potency against PDE4. Selectivity profiles and in vivo biological activity are also reported.
Assuntos
Anti-Inflamatórios/síntese química , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/química , Oxazóis/síntese química , Inibidores da Fosfodiesterase 4/síntese química , Quinolinas/síntese química , Animais , Anti-Inflamatórios/farmacologia , Óxidos N-Cíclicos/química , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Descoberta de Drogas , Humanos , Modelos Moleculares , Oxazóis/farmacologia , Inibidores da Fosfodiesterase 4/farmacologia , Quinolinas/química , Quinolinas/farmacologia , Ratos , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/antagonistas & inibidoresRESUMO
The echinocandins are a class of semisynthetic natural products that target ß-1,3-glucan synthase (GS). Their proven clinical efficacy combined with minimal safety issues has made the echinocandins an important asset in the management of fungal infection in a variety of patient populations. However, the echinocandins are delivered only parenterally. A screen for antifungal bioactivities combined with mechanism-of-action studies identified a class of piperazinyl-pyridazinones that target GS. The compounds exhibited in vitro activity comparable, and in some cases superior, to that of the echinocandins. The compounds inhibit GS in vitro, and there was a strong correlation between enzyme inhibition and in vitro antifungal activity. In addition, like the echinocandins, the compounds caused a leakage of cytoplasmic contents from yeast and produced a morphological response in molds characteristic of GS inhibitors. Spontaneous mutants of Saccharomyces cerevisiae with reduced susceptibility to the piperazinyl-pyridazinones had substitutions in FKS1. The sites of these substitutions were distinct from those conferring resistance to echinocandins; likewise, echinocandin-resistant isolates remained susceptible to the test compounds. Finally, we present efficacy and pharmacokinetic data on an example of the piperazinyl-pyridazinone compounds that demonstrated efficacy in a murine model of Candida glabrata infection.
Assuntos
Antifúngicos/farmacologia , Glucosiltransferases/antagonistas & inibidores , Animais , Antifúngicos/química , Candida glabrata/efeitos dos fármacos , Candida glabrata/enzimologia , Candida glabrata/patogenicidade , Candidíase/tratamento farmacológico , Masculino , Camundongos , Estrutura Molecular , Piperazinas/química , Piperazinas/farmacologia , Piridazinas/química , Piridazinas/farmacologia , Saccharomyces cerevisiae/efeitos dos fármacos , Saccharomyces cerevisiae/enzimologiaRESUMO
A novel series of pyridazinone analogs has been developed as potent ß-1,3-glucan synthase inhibitors through structure-activity relationship study of the lead 5-[4-(benzylsulfonyl)piperazin-1-yl]-4-morpholino-2-phenyl-pyridazin-3(2H)-one (1). The effect of changes to the core structure is described in detail. Optimization of the sulfonamide moiety led to the identification of important compounds with much improved systematic exposure while retaining good antifungal activity against the fungal strains Candida glabrata and Candida albicans.
Assuntos
Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Glucosiltransferases/antagonistas & inibidores , Piridazinas/síntese química , Piridazinas/farmacologia , Antifúngicos/síntese química , Antifúngicos/química , Antifúngicos/farmacologia , Candida albicans/efeitos dos fármacos , Candida glabrata/efeitos dos fármacos , Inibidores Enzimáticos/química , Estrutura Molecular , Piridazinas/química , Relação Estrutura-AtividadeRESUMO
A structure-activity relationship study of the lead 5-[4-(benzylsulfonyl)piperazin-1-yl]-4-morpholino-2-phenyl-pyridazin-3(2H)-one 1 has resulted in the identification of 2-(3,5-difluorophenyl)-4-(3-fluorocyclopentyloxy)-5-[4-(isopropylsulfonyl)piperazin-1-yl]-pyridazin-3(2H)-one 11c as a ß-1,3-glucan synthase inhibitor. Compound 11c exhibited significant efficacy in an in vivo mouse model of Candida glabrata infection.
Assuntos
Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Glucosiltransferases/antagonistas & inibidores , Piridazinas/química , Piridazinas/farmacologia , Inibidores Enzimáticos/síntese química , Piridazinas/síntese química , Relação Estrutura-AtividadeRESUMO
A structure-activity relationship study of the lead piperazinylcarbonylpiperidine compound 3 resulted in the identification of 4-benzimidazolyl-piperidinylcarbonyl-piperidine 6h as a histamine-3 (H(3)) receptor antagonist. Additional optimization of 6h led to the identification of compounds 11i-k with K(i) Assuntos
Antagonistas dos Receptores Histamínicos H3/síntese química
, Antagonistas dos Receptores Histamínicos H3/farmacologia
, Piperidinas/síntese química
, Piperidinas/farmacologia
, Relação Estrutura-Atividade
RESUMO
The syntheses and structure-activity relationships of the tartrate-based TACE inhibitors are discussed. The optimization of both the prime and non-prime sites led to compounds with picomolar activity. Several analogs demonstrated good rat pharmacokinetics.
Assuntos
Proteínas ADAM/antagonistas & inibidores , Inibidores de Proteases/química , Tartaratos/química , Proteínas ADAM/metabolismo , Proteína ADAM17 , Animais , Sítios de Ligação , Simulação por Computador , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacocinética , Ratos , Relação Estrutura-Atividade , Tartaratos/síntese química , Tartaratos/farmacocinéticaRESUMO
A strategy to overcome the side effect liabilities of oral PDE4 inhibitors has been to deliver the drugs by inhalation. In this report, we identify 1-[[5-(1(S)-aminoethly)-2-[8-methoxy-2-(triflurormethyl)-5-quinolinyl]-4-oxazolyl] carbonyl]-4(R)-[(cyclopropylcarbonyl)amino]-L-proline, ethyl ester xinafoate salt, (COMPOUND 1) as a potent and selective inhibitor of PDE4 with biological and pharmacokinetic properties suitable for delivery by the inhaled route. COMPOUND 1 potently inhibits human PDE4 (IC(50)=70pM) with little or no activity against other PDEs. It is highly potent against PDE4B and PDE4D which are important isoforms of PDE4 controlling inflammation and airway functions. In an allergen-challenged Brown Norway rat model of asthma, COMPOUND 1 inhibited the late phase influx of inflammatory cells and reductions in lung function following its administration by the intratracheal or nose-only routes of administration. Important differences were seen between intratracheal COMPOUND 1 and our previously published results with the oral PDE4 inhibitor roflumilast (Celly et al., 2005), as COMPOUND 1 rapidly (within 1h) reversed the decline in lung function when it was given therapeutically to rats already challenged with antigen. COMPOUND 1 was weakly active by the oral route which is a finding consistent with results showing this compound has poor oral bioavailability in animals. Positive interactions between COMPOUND 1 and albuterol, and COMPOUND 1 and mometasone furoate were seen on the improvement in lung functions in allergen-challenged rats. These results identify COMPOUND 1 as a potent and selective inhibitor of PDE4 with properties suitable for delivery by inhalation.
Assuntos
Antialérgicos/administração & dosagem , Antialérgicos/farmacologia , Asma/tratamento farmacológico , Inibidores da Fosfodiesterase 4/administração & dosagem , Inibidores da Fosfodiesterase 4/farmacologia , Prolina/análogos & derivados , Quinolinas/farmacologia , Administração por Inalação , Aerossóis , Animais , Antialérgicos/sangue , Antialérgicos/farmacocinética , Anti-Inflamatórios/uso terapêutico , Asma/imunologia , Asma/fisiopatologia , Disponibilidade Biológica , Líquido da Lavagem Broncoalveolar/citologia , Broncodilatadores/uso terapêutico , Nucleotídeo Cíclico Fosfodiesterase do Tipo 3/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Sinergismo Farmacológico , Meia-Vida , Humanos , Leucócitos/efeitos dos fármacos , Leucócitos/enzimologia , Leucócitos/metabolismo , Inibidores da Fosfodiesterase 4/sangue , Inibidores da Fosfodiesterase 4/farmacocinética , Pós , Prolina/farmacologia , Ratos , Ratos Endogâmicos BN , Fator de Necrose Tumoral alfa/metabolismoRESUMO
A novel series of TNF-alpha convertase (TACE) inhibitors which are non-hydroxamate have been discovered. These compounds are bis-amides of L-tartaric acid (tartrate) and coordinate to the active site zinc in a tridentate manner. They are selective for TACE over other MMP's. We report the first X-ray crystal structure for a tartrate-based TACE inhibitor.
Assuntos
Proteínas ADAM/antagonistas & inibidores , Proteínas ADAM/metabolismo , Descoberta de Drogas , Inibidores de Proteases/química , Tartaratos/química , Fator de Necrose Tumoral alfa/metabolismo , Proteína ADAM17 , Sítios de Ligação , Técnicas de Química Combinatória , Cristalografia por Raios X , Descoberta de Drogas/métodos , Humanos , Inibidores de Proteases/metabolismo , Inibidores de Proteases/farmacologia , Tartaratos/metabolismo , Tartaratos/farmacologiaRESUMO
Fungi can cause life threatening diseases, particularly in patients with weakened immune systems. While treatment options are available for these individuals, dose limiting toxicity and the appearance of drug resistant organisms are growing problems. Therefore, the identification, development, and registration of new, safe, and efficacious agents are needed. Herein, we review recent developments in the field of antifungal drug discovery. We focus on recently launched drugs (triazoles and echinocandins), agents in clinical development, and compounds in discovery.
Assuntos
Antifúngicos/química , Antifúngicos/uso terapêutico , Micoses/tratamento farmacológico , Antifúngicos/farmacologia , Desenho de Fármacos , Fungos/efeitos dos fármacos , Humanos , Estrutura MolecularRESUMO
Substituted quinolyl oxazoles were discovered as a novel and highly potent series of phosphodiesterase 4 (PDE4) inhibitors. Structure-activity relationship studies revealed that the oxazole core, with 4-carboxamide and 5-aminomethyl groups, is a novel PDE4 inhibitory pharmacophore. Selectivity profiles and in vivo biological activity are also reported.
Assuntos
Oxazóis/farmacologia , Inibidores de Fosfodiesterase/farmacologia , Animais , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/efeitos dos fármacos , Modelos Moleculares , Oxazóis/química , Inibidores de Fosfodiesterase/química , RatosRESUMO
A novel series of histamine H3 receptor antagonists based on the 4-[(1H-imidazol-4-yl)methyl]piperidine template displaying low CYP2D6 and CYP3A4 inhibitory profiles has been identified. Structural features responsible for the reduction of P450 activity, a typical liability of 4-substituted imidazoles, have been established.
Assuntos
Inibidores das Enzimas do Citocromo P-450 , Inibidores Enzimáticos/farmacologia , Antagonistas dos Receptores Histamínicos/farmacologia , Imidazóis/farmacologia , Piperidinas/farmacologia , Receptores Histamínicos H3/efeitos dos fármacos , Animais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Cobaias , Haplorrinos , Antagonistas dos Receptores Histamínicos/síntese química , Antagonistas dos Receptores Histamínicos/química , Humanos , Imidazóis/síntese química , Imidazóis/química , Estrutura Molecular , Piperidinas/síntese química , Piperidinas/química , Ratos , Relação Estrutura-Atividade , Distribuição TecidualRESUMO
Structure-activity relationship study of bipiperidine amide 1 has identified the reverse bipiperidine amide 4a as a CC chemokine-3 (CCR3) receptor antagonist. Optimization of the structure-activity relationship of compound 4a has resulted in the identification of a CCR3 antagonist 4i as well as a CCR3 agonist 13.
Assuntos
Amidas/síntese química , Amidas/farmacologia , Piperidinas/síntese química , Piperidinas/farmacologia , Receptores de Quimiocinas/agonistas , Receptores de Quimiocinas/antagonistas & inibidores , Quimiocina CCL11 , Quimiocinas CC/metabolismo , Fatores Quimiotáticos de Eosinófilos/metabolismo , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Humanos , Ligação Proteica , Receptores CCR3 , Receptores de HIV/agonistas , Receptores de HIV/antagonistas & inibidores , Relação Estrutura-AtividadeRESUMO
Bipiperidine amide 1 has been identified as a CC chemokine receptor 3 (CCR3) antagonist. Optimization of its structure-activity relationship has resulted in the identification of cis (R,R)-4-[(3,4-dichlorophenyl)methyl]-3-hydroxymethyl-1'(6-quinolinylcarbonyl)-1,4'-bipiperidine 14n, which exhibits potent receptor affinity and inhibition of both calcium flux and eosinophil chemotaxis.