RESUMO
Explorations in the pyrimidinetrione series of MMP-13 inhibitors led to the discovery of a series of spiro-fused compounds that are potent and selective inhibitors of MMP-13. While other spiro-fused motifs are hydrolytically unstable, presumably due to electronic destabilization of the pyrimidinetrione ring, the spiropyrrolidine series does not share this liability. Greater than 100-fold selectivity versus other MMP family members was achieved by incorporation of an extended aryl-heteroaryl P1'group. When dosed as the sodium salt, these compounds displayed excellent oral absorption and pharmacokinetic properties. Despite the selectivity, a representative of this series produced fibroplasia in a 14 day rat study.
Assuntos
Inibidores de Metaloproteinases de Matriz , Inibidores de Proteases/química , Pirimidinas/química , Pirrolidinas/química , Compostos de Espiro/química , Animais , Estabilidade Enzimática/efeitos dos fármacos , Metaloproteinase 13 da Matriz/metabolismo , Inibidores de Proteases/farmacologia , Pirimidinas/farmacologia , Pirrolidinas/farmacologia , Ratos , Compostos de Espiro/farmacologia , Relação Estrutura-AtividadeRESUMO
In osteoarthritis (OA), cartilage degradation is accompanied by subchondral bone changes. The pathogenesis and physiology of bone changes in OA are still unclear. The changes in subchondral bone architecture and cartilage damage were compared in differently induced experimental models of OA. Experimental OA was induced bilaterally by anterior cruciate ligament transection (ACLT) or by cartilage trauma (Groove model); bilateral sham surgery served as control. Lysylpyridinoline (LP, bone resorption) and C-telopeptide of type II collagen (CTX-II, cartilage breakdown) were measured over time. At 20 weeks after surgery, the subchondral cortical plate and trabecular bone of the tibia were analyzed by micro-computed tomography (microCT) and cartilage degeneration was analyzed histologically and biochemically. In both models, cartilage degeneration and cortical subchondral plate thinning were present. CTX-II levels were elevated over time in both models. Subchondral trabecular bone changes were observed only in the ACLT model, not in the Groove model. Correspondingly, LP levels were elevated over time in the ACLT model and not in the Groove model. Interestingly, the trabecular bone changes in the ACLT model were extended to the metaphyseal area. The early decrease in plate thickness, present in both models, as was cartilage damage, suggests that plate thinning is a phenomenon that is intrinsic to the process of OA independent of the cause/induction of OA. On the other hand, trabecular changes in subchondral and metaphyseal bone are not part of a common pathway of OA development and may be induced biomechanically in the destabilized and less loaded ACLT joint.
Assuntos
Osso e Ossos/patologia , Osteoartrite/patologia , Aminoácidos/metabolismo , Animais , Ligamento Cruzado Anterior/cirurgia , Cartilagem/lesões , Cartilagem/metabolismo , Colágeno Tipo I/metabolismo , Modelos Animais de Doenças , Cães , Feminino , Lâmina de Crescimento/patologia , Peptídeos/metabolismo , Fraturas Salter-Harris , Tíbia/patologia , Microtomografia por Raio-XRESUMO
Insulin-like growth factor binding protein 5 (IGFBP-5) has been proposed to promote cartilage anabolism through insulin-like growth factor (IGF-1) signaling. A proteolytic activity towards IGFBP-5 has been detected in synovial fluids from human osteoarthritic (OA) joints. The purpose of this study was to determine if protease activity towards IGFBP-5 is present in the rat medial meniscal tear (MMT) model of OA and whether inhibition of this activity would alter disease progression. Sprague-Dawley rats were subject to MMT surgery. Synovial fluid lavages were assessed for the presence of IGFBP-5 proteolytic activity. Treatment animals received intra-articular injections of vehicle or protease inhibitor peptide PB-145. Cartilage lesions were monitored by India ink staining followed by macroscopic measurement of lesion width and depth. The MMT surgery induced a proteolytic activity towards IGFPB-5 that was detectable in joint fluid. This activity was stimulated by calcium and was sensitive to serine protease inhibitors as well as peptide PB-145. Significantly, intra-articular administration of PB-145 after surgery protected cartilage from lesion development. PB-145 treatment also resulted in an increase in cartilage turnover as evidenced by increases in serum levels of procollagen type II C-propeptide (CPII) as well as synovial fluid lavage levels of collagen type II neoepitope (TIINE). IGFBP-5 metabolism is disrupted in the rat MMT model of OA, potentially contributing to cartilage degradation. Inhibition of IGFBP-5 proteolysis protected cartilage from lesion development and enhanced cartilage turnover. These data are consistent with IGFBP-5 playing a positive role in anabolic IGF signaling in cartilage.
RESUMO
As exemplified by the lead compound 2, octahydrophenanthrene-2,7-diol analogues exhibit the profile of a pathway-selective or "dissociated" agonist of the glucocorticoid receptor (GR), retaining the potent activity that glucocorticoids have for transrepression (as measured by inhibition of IL-1 induced MMP-13 expression) but showing an attenuated capacity for transactivation (as measured in an MMTV luciferase reporter assay). With the guidance of a homology model of the GR ligand binding domain, structural modifications to 2 were carried out that were successful in replacing the allyl and propynyl side chains with groups likely to be more chemically stable and less likely to produce toxic metabolites. Key to success was the introduction of an additional hydroxyl group onto the tricyclic carbon framework of the series.
Assuntos
Descoberta de Drogas , Fenantrenos/farmacologia , Receptores de Glucocorticoides/agonistas , Cromatografia Líquida de Alta Pressão , Cristalografia por Raios X , Espectrometria de Massas , Modelos Moleculares , Fenantrenos/químicaRESUMO
Using SAR from two related series of pyrimidinetrione-based inhibitors, compounds with potent MMP-13 inhibition and >100-fold selectivity against other MMPs have been identified. Despite high molecular weights, clogPs, and polar surface areas, the compounds are generally well absorbed and have excellent pharmacokinetic (PK) properties when dosed as sodium salts. In a rat fibrosis model, a compound from the series displayed no fibrosis at exposures many fold greater than its MMP-13 IC50.
Assuntos
Inibidores de Metaloproteinases de Matriz , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacologia , Pirimidinonas/química , Animais , Fibrose/tratamento farmacológico , Fibrose/patologia , Ácidos Hidroxâmicos/química , Concentração Inibidora 50 , Peso Molecular , Ratos , Sais/química , Sódio/química , Relação Estrutura-AtividadeRESUMO
A series of pipecolic hydroxamate inhibitors of MMP-13 and aggrecanase was discovered based on screening known inhibitors of TNF-alpha converting enzyme (TACE). Potency versus aggrecanase was optimized by modification of the benzyloxyarylsulfonamide group. Incorporation of geminal alkyl substitution at the 3-position of the piperidine ring improved metabolic stability, presumably by increasing steric hindrance around the metabolically labile hydroxamic acid. This modification also resulted in dramatic improvement of aggrecanase activity with a slight reduction in selectivity versus MMP-1. Synthesis, structure activity relationships, and strategies to reduce metabolic clearance are described.
Assuntos
Endopeptidases/efeitos dos fármacos , Ácidos Hidroxâmicos/farmacologia , Inibidores de Metaloproteinases de Matriz , Inibidores de Proteases/farmacologia , Ácidos Hidroxâmicos/química , Metaloproteinase 13 da Matriz , Inibidores de Proteases/químicaRESUMO
A series of 3-hydroxy-3-methylpipecolic hydroxamate inhibitors of MMP-13 and aggrecanase was designed based on the observation of increased aggrecanase activity with substitution at the 3-position of the piperidine ring. Potency versus aggrecanase was optimized by modification of the benzyloxyarylsulfonamide group that binds in the S1' pocket. These compounds also possess markedly improved bioavailability and lower metabolic clearance compared to analogous 3,3-dimethyl-5-hydroxypipecolic hydroxamates. These improvements are attributed to lowered lipophilicity proximal to the metabolically labile hydroxamic acid. Synthesis, structure activity relationships, and in vivo efficacy data are described.
Assuntos
Endopeptidases/efeitos dos fármacos , Ácidos Hidroxâmicos/síntese química , Ácidos Hidroxâmicos/farmacocinética , Inibidores de Metaloproteinases de Matriz , Ácidos Pipecólicos/síntese química , Ácidos Pipecólicos/farmacocinética , Administração Oral , Animais , Colagenases/metabolismo , Desenho de Fármacos , Endopeptidases/metabolismo , Humanos , Ácidos Hidroxâmicos/química , Metaloproteinase 13 da Matriz , Estrutura Molecular , Ácidos Pipecólicos/química , Inibidores de Proteases/síntese química , Inibidores de Proteases/química , Inibidores de Proteases/farmacocinética , Relação Estrutura-AtividadeRESUMO
Through the use of computational modeling, a series of pyrimidinetrione-based inhibitors of MMP-13 was designed based on a lead inhibitor identified through file screening. Incorporation of a biaryl ether moiety at the C-5 position of the pyrimidinetrione ring resulted in a dramatic enhancement of MMP-13 potency. Protein crystallography revealed that this moiety binds in the S(1)(') pocket of the enzyme. Optimization of the C-4 substituent of the terminal aromatic ring led to incorporation of selectivity versus MMP-14 (MT-1 MMP). Structure activity relationships of the biaryl ether substituent are presented as is pharmacokinetic data for a compound that meets our in vitro potency and selectivity goals.
Assuntos
Inibidores Enzimáticos/síntese química , Inibidores de Metaloproteinases de Matriz , Pirimidinas/química , Sítios de Ligação , Colagenases/química , Cristalografia por Raios X , Inibidores Enzimáticos/farmacologia , Metaloproteinase 13 da Matriz , Relação Estrutura-AtividadeRESUMO
Phosphinic acid-based inhibitors of MMP-13 have been investigated with the aim of identifying potent inhibitors with high selectivity versus MMP-1. Independent variation of the substituents on a P(1)' phenethyl group and a P(2) benzyl group improved potencies in both cases around 3-fold over the unsubstituted parent. Combining improved P(1)' and P(2) groups into a single molecule gave an inhibitor with a 4.5 nM IC(50) against MMP-13 and which is 270-fold selective over MMP-1.
Assuntos
Metaloproteinase 1 da Matriz/efeitos dos fármacos , Metaloproteinase 3 da Matriz/efeitos dos fármacos , Inibidores de Metaloproteinases de Matriz , Ácidos Fosfínicos/química , Ácidos Fosfínicos/farmacologia , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacologia , Colagenases/química , Indicadores e Reagentes , Isomerismo , Metaloproteinase 1 da Matriz/química , Metaloproteinase 13 da Matriz , Metaloproteinase 3 da Matriz/química , Relação Estrutura-Atividade , Especificidade por SubstratoRESUMO
N-Hydroxy-3-hydroxy-4-arylsulfonyltetrahydropyranyl-3-carboxamides were designed as novel inhibitors of MMP-13 and aggrecanase based on known endocyclic hydroxamate inhibitors of matrix metalloproteinases. These compounds offer favorable physicochemical properties and low metabolic clearance. Synthesis and structure-activity relationships are reported.
Assuntos
Endopeptidases/metabolismo , Ácidos Hidroxâmicos/síntese química , Inibidores de Metaloproteinases de Matriz , Inibidores de Proteases/síntese química , Piranos/síntese química , Animais , Colagenases/química , Endopeptidases/química , Ácidos Hidroxâmicos/química , Ácidos Hidroxâmicos/farmacocinética , Metaloproteinase 1 da Matriz/química , Metaloproteinase 13 da Matriz , Inibidores de Proteases/química , Inibidores de Proteases/farmacocinética , Piranos/química , Piranos/farmacocinética , Ratos , Relação Estrutura-AtividadeRESUMO
The SAR of a series of sterically hindered sulfonamide hydroxamic acids with relatively large P1' groups is described. The compounds typically spare MMP-1 while being potent inhibitors of MMP-13. The metabolically more stable compounds in the series contain either a monocyclic or bicyclic pyran ring adjacent to the hydroxamate group. Despite the sparing of MMP-1, pre-clinical and clinical studies revealed that fibrosis in rats and MSS in humans is still produced.