RESUMO
A series of novel benzimidazole derivatives has been designed via a scaffold morphing approach based on known calcilytics chemotypes. Subsequent lead optimisation led to the discovery of penta-substituted benzimidazoles that exhibit attractive in vitro and in vivo calcium-sensing receptor (CaSR) inhibitory profiles. In addition, synthesis and structure-activity relationship data are provided.
Assuntos
Benzimidazóis/farmacologia , Receptores de Detecção de Cálcio/antagonistas & inibidores , Benzimidazóis/química , Benzimidazóis/farmacocinética , Modelos Moleculares , Relação Estrutura-AtividadeRESUMO
A series of novel benzoxazole derivatives has been designed and shown to exhibit attractive JAK2 inhibitory profiles in biochemical and cellular assays, capable of delivering compounds with favorable PK properties in rats. Synthesis and structure-activity relationship data are also provided.
Assuntos
Benzoxazóis/química , Janus Quinase 2/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Administração Oral , Animais , Benzoxazóis/síntese química , Benzoxazóis/farmacocinética , Janus Quinase 2/metabolismo , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacocinética , Ratos , Relação Estrutura-AtividadeRESUMO
Starting from the purine lead structure 1, a new series of cathepsin K inhibitors based on a pyrimidine scaffold have been explored. Investigations of P3 and P2 substituents based on molecular modeling suggestions resulted in potent cathepsin K inhibitors with an improved selectivity profile over other cathepsins.
Assuntos
Catepsinas/antagonistas & inibidores , Catepsinas/química , Cisteína Endopeptidases/química , Modelos Moleculares , Nitrilas/síntese química , Inibidores de Proteases/síntese química , Pirimidinas/síntese química , Animais , Sítios de Ligação , Catepsina K , Cristalografia por Raios X , Nitrilas/química , Nitrilas/farmacocinética , Inibidores de Proteases/química , Inibidores de Proteases/farmacocinética , Pirimidinas/química , Pirimidinas/farmacocinética , Ratos , Relação Estrutura-AtividadeRESUMO
Detailed knowledge of the relationship between plant diversity and productivity is critical for advancing our understanding of ecosystem functioning and for achieving success in habitat restoration efforts. However, effects and interactions of diversity, succession and biotic invasions on productivity remain elusive. We studied newly established communities in relation to preexisting homogeneous vegetation invaded by exotic plants in the northern Great Plains, USA, at four study sites for 3 years. We observed variant diversity-productivity relationships for the seeded communities (generally positive monotonic at three sites and non-monotonic at the other site) but no relationships for the resident community or the seeded and resident communities combined at all sites and all years. Community richness was enhanced by seeding additional species but productivity was not. The optimal diversity (as indicated by maximum productivity) changed among sites and as the community developed. The findings shed new light on ecosystem functioning of biodiversity under different conditions and have important implications for restoration.
Assuntos
Biodiversidade , Ecossistema , Plantas/classificação , Biomassa , Recuperação e Remediação Ambiental/métodos , North Dakota , Sementes/crescimento & desenvolvimentoRESUMO
We disclose herein the discovery of estrogen receptor alpha (ERalpha) selective estrogen receptor modulators (SERMs) of the tetrahydroisoquinoline series that incorporate novel conformationally restricted side chains as replacement of the aminoethoxy residue typical of SERMs. Molecular modeling studies used in conjunction with the X-ray crystal structure of the ERalpha ligand binding domain (LBD) with raloxifene (7) suggested a diazadecaline moiety as a viable mimic of the SERM side chain. On the basis of this knowledge, the piperidinylethoxy moiety of our lead compound 60 was replaced by a diazadecaline subunit, providing the novel tetrahydroisoquinoline 29. In addition to exhibiting a binding affinity to ERalpha and antagonistic properties in the estrogen response element and MCF-7 assays similar to those of the parent compound 60, ligand 29 showed a reduced agonist behavior in the MCF-7 assay in the absence of 17beta-estradiol. These data point toward the fact that 29 may have a potential for breast cancer prevention/treatment in vivo, a feature which is particularly attractive in the quest for safe alternatives to hormone replacement therapy. In a pharmacokinetic experiment carried out in rats, 29 displayed an interesting profile, with a bioavailability of 49%. We also disclose the X-ray crystal structure of 29 in complex with ERalpha-LBD, which reveals the preferred configurations of 29 at the two chiral centers and the details of its interactions with the receptor. Finally, our structure-activity relationship studies show that other analogues bearing constrained side chains retain potency and antagonist activity and that a 3-OH substituted phenyl D-ring increases the selectivity of a set of piperazinyl-containing ligands in favor of ERalpha over ERbeta.
Assuntos
Receptor alfa de Estrogênio/efeitos dos fármacos , Isoquinolinas/síntese química , Moduladores Seletivos de Receptor Estrogênico/síntese química , Tetra-Hidroisoquinolinas/síntese química , Animais , Disponibilidade Biológica , Linhagem Celular Tumoral , Cristalografia por Raios X , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Concentração Inibidora 50 , Isoquinolinas/química , Isoquinolinas/farmacologia , Ligantes , Modelos Moleculares , Piperazinas/síntese química , Piperazinas/química , Piperazinas/farmacologia , Piperidinas/síntese química , Piperidinas/química , Piperidinas/farmacologia , Ensaio Radioligante , Ratos , Moduladores Seletivos de Receptor Estrogênico/química , Moduladores Seletivos de Receptor Estrogênico/farmacologia , Relação Estrutura-Atividade , Tetra-Hidroisoquinolinas/química , Tetra-Hidroisoquinolinas/farmacologiaRESUMO
As part of a program aimed at the development of selective estrogen receptor modulators (SERMs), tetrahydroisoquinoline derivative 27 was discovered by high throughput screening. Successive replacements of the p-F substituent of 27 by an aminoethoxy side chain and of the 1-H of the tetrahydroisoquinoline core by a 1-Me group provided analogues 19 and 20. These compounds showed potencies in a cell-based reporter gene assay (ERE assay) varying between 0.6 and 20 nM and displayed antagonist behaviors in the MCF-7 human breast adenocarcinoma cell line with IC(50)s in the range of 2-36 nM. The effect of N-phenyl substituents on the activity and pharmacokinetic properties of tetrahydroisoquinoline analogues was explored. As a result of this investigation, two potent derivatives bearing a p-F N-aryl group, 19c and 20c, were discovered as candidates suitable for further profiling. To gain insight into the ligand-receptor interaction, the X-ray crystallographic structure of the 1-H tetrahydroisoquinoline derivative (R)-18a in complex with ERalpha-ligand binding domain (LBD)(301)(-)(553)/C-->S triple mutant was solved to 2.28 A. An overlay of this X-ray crystal structure with that reported for the complex of ERalpha-LBD(301)(-)(553)/carboxymethylated C and raloxifene (5) shows that both compounds bind to the same cleft of the receptor and display comparable binding modes, with differences being observed in the conformation of their "D-ring" phenyl groups.
Assuntos
Moduladores de Receptor Estrogênico/síntese química , Isoquinolinas/síntese química , Receptores de Estrogênio/efeitos dos fármacos , Administração Oral , Animais , Sítios de Ligação , Disponibilidade Biológica , Divisão Celular/efeitos dos fármacos , Cristalografia por Raios X , Estradiol/farmacologia , Moduladores de Receptor Estrogênico/química , Moduladores de Receptor Estrogênico/farmacologia , Receptor alfa de Estrogênio , Receptor beta de Estrogênio , Feminino , Células HeLa , Humanos , Isoquinolinas/química , Isoquinolinas/farmacologia , Ligantes , Modelos Moleculares , Ensaio Radioligante , Cloridrato de Raloxifeno/química , Cloridrato de Raloxifeno/farmacologia , Ratos , Estereoisomerismo , Relação Estrutura-Atividade , Transcrição Gênica , Células Tumorais CultivadasRESUMO
Cathepsin K is a cysteine proteinase, primarily expressed in osteoclasts, which has a strong collagenolytic activity and plays an essential role involved in bone matrix degradation. Its inhibition could provide a novel approach to the treatment and prevention of osteoporosis. One structural class of lead compounds in our cathepsin K inhibitors program is based on an arylaminoethyl amide scaffold, which has potential metabolic weak points that might be stabilized by appropriate chemical modification(s). For the identification of potential metabolic "soft spots" and the rational design of improved derivatives, early biotransformation of a potent arylaminoethyl amide cathepsin K inhibitor (NVP-AAV490-NX) was investigated in plasma, urine and liver homogenates of rats after intravenous bolus administration of 10 mg/kg. The detection and identification of metabolites was achieved by high-resolution mass spectrometry (time-of-flight MS) and multi-dimensional mass spectrometry (ion trap MS). Both mass spectrometers were combined with reversed-phase capillary high-performance liquid chromatography columns. It was demonstrated that both mass analyzers complement each other and that, even in the sub-nanogram range, the resulting set of MS data can be successfully used to elucidate most of the metabolic changes unambiguously, solely by mass spectrometric techniques. The proposed metabolite structures were additionally corroborated by exact mass measurement of the protonated molecular ions to confirm the predicted elemental composition, by determination of the number of the exchangeable hydrogen atoms replacing water against deuterium oxide as mobile phase and, in one case, by an MS(3) product ion experiment in order to elucidate the site of conjugation.
Assuntos
Catepsinas/antagonistas & inibidores , Cromatografia Líquida de Alta Pressão/métodos , Inibidores Enzimáticos/análise , Espectrometria de Massas/métodos , Animais , Catepsina K , Feminino , Ratos , Ratos Sprague-DawleyRESUMO
Parathyroid hormone (PTH), when injected daily as either the intact hormone PTH(1-84) or the active fragment PTH(1-34) (teriparatide), is an efficacious bone anabolic treatment option for osteoporosis patients. Injections lead to rapid and transient spikes in hormone exposure levels, a profile which is a prerequisite to effectively form bone. Oral antagonists of the calcium-sensing receptor (calcilytics) stimulate PTH secretion and represent thus an alternative approach to elevate hormone levels transiently. We report here on ATF936, a novel calcilytic, which triggered rapid, transient spikes in endogenous PTH levels when given orally in single doses of 10 and 30mg/kg to growing rats, and of 1mg/kg to dogs. Eight weeks daily oral application of 30mg/kg of ATF936 to aged female rats induced in the proximal tibia metaphysis increases in bone mineral density, cancellous bone volume and cortical and trabecular thickness as evaluated by computed tomography. In healthy humans, single oral doses of ATF936 produced peak PTH levels in plasma after a median time of 1h and levels returned to normal at 24-h post-dose. The average maximum PTH concentration increase from baseline was 1.9, 3.6, and 6.0-fold at doses of 40, 70, and 140mg. ATF936 was well tolerated. The sharp, transient increase in PTH levels produced by the oral calcilytic ATF936 was comparable to the PTH profile observed after subcutaneous administration of teriparatide. In conclusion, ATF936 might hold potential as an oral bone-forming osteoporosis therapy.
Assuntos
Anabolizantes/farmacologia , Densidade Óssea/efeitos dos fármacos , Hormônio Paratireóideo/metabolismo , Hormônio Paratireóideo/farmacologia , Quinazolinonas/farmacologia , Receptores de Detecção de Cálcio/antagonistas & inibidores , Adulto , Anabolizantes/farmacocinética , Animais , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/metabolismo , Cálcio/metabolismo , Cães , Feminino , Humanos , Masculino , Estrutura Molecular , Quinazolinonas/farmacocinética , Ratos , Ratos WistarRESUMO
Parathyroid hormone (PTH) is an effective bone anabolic agent. However, only when administered by daily sc injections exposure of short duration is achieved, a prerequisite for an anabolic response. Instead of applying exogenous PTH, mobilization of endogenous stores of the hormone can be envisaged. The secretion of PTH stored in the parathyroid glands is mediated by a calcium sensing receptor (CaSR) a GPCR localized at the cell surface. Antagonists of CaSR (calcilytics) mimic a state of hypocalcaemia and stimulate PTH release to the bloodstream. Screening of the internal compound collection for inhibition of CaSR signaling function afforded 2a. In vitro potency could be improved >1000 fold by optimization of its chemical structure. The binding mode of our compounds was predicted based on molecular modeling and confirmed by testing with mutated receptors. While the compounds readily induced PTH release after iv application a special formulation was needed for oral activity. The required profile was achieved by using microemulsions. Excellent PK/PD correlation was found in rats and dogs. High levels of PTH were reached in plasma within minutes which reverted to baseline in about 1-2 h in both species.
Assuntos
Conservadores da Densidade Óssea/síntese química , Hormônio Paratireóideo/metabolismo , Quinazolinonas/síntese química , Receptores de Detecção de Cálcio/metabolismo , Administração Oral , Animais , Conservadores da Densidade Óssea/administração & dosagem , Conservadores da Densidade Óssea/química , Conservadores da Densidade Óssea/farmacocinética , Cães , Concentração Inibidora 50 , Masculino , Quinazolinonas/administração & dosagem , Quinazolinonas/química , Quinazolinonas/farmacocinética , Ratos , Ratos Wistar , Receptores de Detecção de Cálcio/antagonistas & inibidores , Receptores de Detecção de Cálcio/genética , Relação Estrutura-AtividadeRESUMO
The structural features contributing to the different pharmacokinetic properties of the TACE/MMP inhibitors TNF484 and Trocade were analyzed using an in vivo cassette-dosing approach in rats. This enabled us to identify a new lead compound with excellent pharmacokinetic properties, but weaker activity on the biological targets. Directed structural modifications maintained oral bioavailability and restored biological activity, leading to a novel compound almost equipotent to TNF484 in vivo, but with a more than tenfold higher oral bioavailability.
Assuntos
Proteínas ADAM/antagonistas & inibidores , Ácidos Hidroxâmicos/farmacologia , Inibidores de Metaloproteinases de Matriz , Inibidores de Proteases/farmacologia , Proteína ADAM17 , Administração Oral , Animais , Disponibilidade Biológica , Relação Dose-Resposta a Droga , Ácidos Hidroxâmicos/administração & dosagem , Ácidos Hidroxâmicos/farmacocinética , Inibidores de Proteases/administração & dosagem , Inibidores de Proteases/farmacocinética , RatosRESUMO
A series of dipeptidyl nitriles as inhibitors of cathepsin K have been explored starting from lead structure 1 (Cbz-Leu-NH-CH2-CN, IC50 = 39 nM). Attachment of non-natural amino acid side chains in P1 and modification of the P3 subunit led to inhibitors with higher potency and improved pharmacokinetic properties.
Assuntos
Catepsinas/antagonistas & inibidores , Dipeptídeos/farmacologia , Inibidores Enzimáticos/farmacologia , Nitrilas/farmacologia , Animais , Catepsina K , Catepsinas/metabolismo , Dipeptídeos/síntese química , Dipeptídeos/química , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Técnicas In Vitro , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/enzimologia , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Nitrilas/síntese química , Nitrilas/química , Ratos , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
The design, synthesis, and the biological evaluation of 2-benzamido-pyrimidines as novel IKK inhibitors are described. By optimization of the lead compound 3, compounds 16 and 24 are identified as good inhibitors of IKK2 with IC(50) values of 40 and 25 nM, respectively. Compound 16 also demonstrated significant in vivo activity in an acute model of cytokine release.
Assuntos
Química Farmacêutica/métodos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Quinase I-kappa B/antagonistas & inibidores , Pirimidinas/síntese química , Citocinas/metabolismo , Relação Dose-Resposta a Droga , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Células HeLa , Humanos , Concentração Inibidora 50 , Modelos Químicos , Pirimidinas/química , Pirimidinas/farmacologia , Relação Estrutura-AtividadeRESUMO
A test library with three novel p38alpha inhibitory scaffolds and a narrow set of substituents was prepared. Appropriate combination of substituent and scaffold generated potent p38alpha inhibitors, for example, pyrazolo[3,4-b]pyridine 9, pyrazolo[3,4-d]pyrimidine 18a and pyrazolo[3,4-b]pyrazine 23b with potent in vivo activity upon oral administration in animal models of rheumatoid arthritis.
Assuntos
Artrite Experimental/tratamento farmacológico , Proteína Quinase 14 Ativada por Mitógeno/antagonistas & inibidores , Pirazinas/administração & dosagem , Pirazóis/administração & dosagem , Piridinas/administração & dosagem , Pirimidinas/administração & dosagem , Administração Oral , Animais , Modelos Animais de Doenças , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Camundongos , Estrutura Molecular , Pirazinas/síntese química , Pirazinas/química , Pirazóis/síntese química , Pirazóis/química , Piridinas/síntese química , Piridinas/química , Pirimidinas/síntese química , Pirimidinas/química , Ratos , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Cinnamides as novel CCR1 antagonist chemotypes are described with high affinity to human and rodent receptors. A1B1 and A4B7 showed oral activity in the mouse collagen induced arthritis.
Assuntos
Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/uso terapêutico , Artrite Experimental/tratamento farmacológico , Receptores de Quimiocinas/antagonistas & inibidores , Administração Oral , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Humanos , Camundongos , Ratos , Receptores CCR1 , Relação Estrutura-AtividadeRESUMO
A library of trisubstituted oxazoles, thiazoles, imidazoles (1,2,4- and 2,4,5-substituted) and imidazo[1,2-b]pyridines was prepared and evaluated in vitro as p38alpha inhibitors and in vivo in several models of rheumatoid arthritis. Four structures--32, 37, 45 and 59--were identified as potent inhibitors of p38alpha with high efficacy in the LPS induced TNFalpha release model in the mouse, the adjuvant induced arthritis and the collagen induced arthritis in the rat with ED50s between 1.0 and 9.5 mg/kg p.o.
Assuntos
Antirreumáticos/síntese química , Piridinas/síntese química , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Animais , Antirreumáticos/farmacologia , Antirreumáticos/uso terapêutico , Artrite Experimental/induzido quimicamente , Artrite Experimental/tratamento farmacológico , Colágeno , Modelos Animais de Doenças , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Imidazóis/química , Lipopolissacarídeos/farmacologia , Camundongos , Oxazóis/química , Piridinas/farmacologia , Piridinas/uso terapêutico , Ratos , Relação Estrutura-Atividade , Tiazóis/química , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Benzoylpyridines and benzophenones were synthesized and evaluated in vitro as p38alpha inhibitors and in vivo in several models of rheumatoid arthritis. Oral activity was found to depend upon substitution: 1,1-dimethylpropynylamine substituted benzophenone 10b (IC50: 14 nM) and pyridinoyl substituted benzimidazole 17b (IC50: 21 nM) showed highest efficacy and selectivity with ED50s of 9.5 and 8.6 mg/kg p.o. in CIA.
Assuntos
Benzofenonas/síntese química , Inibidores Enzimáticos/síntese química , Boca/metabolismo , Piridinas/síntese química , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Animais , Artrite Experimental/induzido quimicamente , Artrite Experimental/tratamento farmacológico , Benzofenonas/farmacologia , Benzofenonas/uso terapêutico , Modelos Animais de Doenças , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Concentração Inibidora 50 , Piridinas/farmacologia , Piridinas/uso terapêutico , Ratos , Relação Estrutura-AtividadeRESUMO
2,6-Diamino-3,5-difluoropyridinyl substituted pyridinylimidazoles, -pyrroles, -oxazoles, -thiazoles and -triazoles have been identified as novel p38alpha inhibitors. Pyridinylimidazole 11 potently inhibited LPS-induced TNFalpha in mice, showed good efficacy in the established rat adjuvant (ED(50): 10 mg/kg po b.i.d.) and collagen induced arthritis (ED(50): 5 mg/kg po b.i.d.) with disease modifying properties based on histological analysis of the joints.