RESUMO
Histone deacetylase (HDAC) inhibitors induce the hyperacetylation of nucleosomal histones in carcinoma cells resulting in the expression of repressed genes that cause growth arrest, terminal differentiation, and/or apoptosis. In vitro selectivity of several novel hydroxamate HDAC inhibitors including succinimide macrocyclic hydroxamates and the non-hydroxamate alpha-ketoamide inhibitors was investigated using isolated enzyme preparations and cellular assays. In vitro selectivity for the HDAC isozymes (HDAC1/2, 3, 4/3, and 6) was not observed for these HDAC inhibitors or the reference HDAC inhibitors, MS-275 and SAHA. In T24 and HCT116 cells these compounds caused the accumulation of acetylated histones H3 and H4; however, the succinimide macrocyclic hydroxamates and the alpha-ketoamides did not cause the accumulation of acetylated alpha-tubulin. These data suggest "selectivity" can be observed at the cellular level with HDAC inhibitors and that the nature of the zinc-chelating moiety is an important determinant of activity against tubulin deacetylase.
Assuntos
Amidas/farmacologia , Neoplasias da Mama/enzimologia , Fibrossarcoma/enzimologia , Inibidores de Histona Desacetilases , Histona Desacetilases/metabolismo , Ácidos Hidroxâmicos/farmacologia , Amidas/química , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos , Fibrossarcoma/patologia , Histona Desacetilases/química , Humanos , Ácidos Hidroxâmicos/químicaRESUMO
A novel series of biaryl ether reverse hydroxamate MMP inhibitors has been developed. These compounds are potent MMP-2 inhibitors with limited activity against MMP-1. Select members of this series exhibit excellent pharmacokinetic properties with long elimination half-lives (7 h) and high oral bioavailability (100%).
Assuntos
Ácidos Hidroxâmicos/síntese química , Inibidores de Metaloproteinases de Matriz , Administração Oral , Animais , Antineoplásicos/sangue , Antineoplásicos/síntese química , Antineoplásicos/farmacocinética , Disponibilidade Biológica , Inibidores Enzimáticos/sangue , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacocinética , Meia-Vida , Ácidos Hidroxâmicos/química , Concentração Inibidora 50 , Injeções Intravenosas , Macaca fascicularisRESUMO
Modification of the biphenyl portion of MMP inhibitor 2a gave analogue 2i which is greater than 1000-fold selective against MMP-2 versus MMP-1. The stereospecific synthesis of both enantiomers of 2i was achieved beginning with (S)- or (R)-benzyl glycidyl ether. The (S)-enantiomer, 11 (ABT-770), is orally bioavailable and efficacious in an in vivo model of tumor growth.
Assuntos
Compostos de Bifenilo/farmacocinética , Ácidos Hidroxâmicos/farmacocinética , Inibidores de Metaloproteinases de Matriz , Administração Oral , Animais , Antineoplásicos/sangue , Antineoplásicos/síntese química , Antineoplásicos/farmacocinética , Área Sob a Curva , Disponibilidade Biológica , Compostos de Bifenilo/sangue , Compostos de Bifenilo/síntese química , Divisão Celular/efeitos dos fármacos , Cães , Inibidores Enzimáticos/sangue , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacocinética , Meia-Vida , Haplorrinos , Ácidos Hidroxâmicos/sangue , Ácidos Hidroxâmicos/síntese química , Concentração Inibidora 50 , Injeções Intravenosas , Taxa de Depuração Metabólica , Neoplasias Experimentais/tratamento farmacológico , Ratos , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
Two series of compounds synthesized as specific matrix metalloproteinase (MMP) inhibitors have been evaluated for their inhibition of non-MMPs. In a series of substituted succinyl hydroxamic acids, some were found to be significant (IC50 < 1 microM) inhibitors of leucine (microsomal) aminopeptidase, neprilysin (3.4.24.11), and thermolysin. Macrocyclic compounds in which the alpha carbon of the succinyl hydroxamate is linked to the side chain of the P2' amino acid were found to be good inhibitors of aminopeptidase, but not of neprilysin or thermolysin. Compounds of neither series were found to be significant inhibitors of angiotensin converting enzyme or carboxypeptidase A.
Assuntos
Inibidores de Metaloproteinases de Matriz , Metaloendopeptidases/antagonistas & inibidores , Inibidores da Enzima Conversora de Angiotensina , Animais , Proteínas de Bactérias , Carboxipeptidases/antagonistas & inibidores , Carboxipeptidases A , Bovinos , Ácidos Hidroxâmicos/síntese química , Ácidos Hidroxâmicos/metabolismo , Concentração Inibidora 50 , Leucil Aminopeptidase/antagonistas & inibidores , Neprilisina/antagonistas & inibidores , Inibidores de Proteases/síntese química , Inibidores de Proteases/química , Inibidores de Proteases/metabolismo , Coelhos , Ratos , Suínos , Termolisina/antagonistas & inibidores , Zinco/metabolismoRESUMO
Excess MMP proteolytic activity has been associated with a wide variety of pathological conditions such as arthritis, cancer and heart failure. The potential utility of MMP inhibitors as therapeutic interventions in these diverse and important disease states has led to an intense effort toward the development of such inhibitors. The first generation of compounds were peptide-like broad spectrum inhibitors, active against a broad range of MMPs. However, the induction of musculoskeletal side effects seen in clinical trials with these agents has emphasized the need for a better understanding of the role that each of the MMPs plays in normal tissue turnover and disease progression. Advances in our ability to engineer and synthesize selective inhibitors as well as the discovery of small molecule, non-peptidic inhibitors has spurred an intense effort to identify potent and bioavailable second generation compounds. There are now several such compounds targeted against various subsets of the MMPs in clinical development. This review will focus on the design and structure activity relationships of these second generation compounds.
Assuntos
Inibidores Enzimáticos/uso terapêutico , Inibidores de Metaloproteinases de Matriz , Metaloproteínas/fisiologia , Peptídeos/farmacologia , Succinatos/farmacologia , Ensaios Clínicos como Assunto , Humanos , Relação Estrutura-AtividadeRESUMO
Platelet-activating factor (PAF) may be an important mediator of allergic rhinitis. In the present study we evaluated the effectiveness of a recently described PAF antagonist (ABT-491) in rat and guinea pig models of allergic rhinitis. PAF, when perfused through the nasal passages of anesthetized Brown Norway rats, provoked an acute increase, measured as dye leakage, in nasal vascular permeability evident within 15 min after exposure to PAF. ABT-491, given orally 1 hr before PAF challenge, inhibited the response in a dose-related manner (ED50 = 0.3 mg/kg). Intranasal perfusion with ovalbumin in rats sensitized to the antigen 18 to 21 days before challenge also induced an increase in vascular permeability. The antigen-induced leakage was inhibited a maximum of 74% (P < or = .001) by pretreatment with ABT-491 (3 mg/kg p.o.). An antihistamine (mepyramine, 10 mg/kg i.p.), a serotonin antagonist (methysergide) and a 5-lipoxygenase inhibitor (A-79175) also exhibited efficacy in this model (56%, 87% and 65% inhibition, respectively). Nearly complete inhibition (93%, P < or = .001) of the response was achieved by coadministration of ABT-491 and methysergide. In guinea pigs intranasal administration of PAF resulted in increased airway resistance that was inhibited in a dose-dependent manner by oral administration of ABT-491 (ED50 = 1 mg/kg). Antigen-induced nasal airway resistance, triggered by exposure of sensitized animals to aerosolized ovalbumin, was also inhibited by ABT-491 (maximum inhibition 64%, P < or = .05, 10 mg/kg p.o.). The effectiveness of the antagonist was increased to 80% protection by coadministration with either an antihistamine or a 5-lipoxygenase inhibitor, agents which were separately insignificant in blocking the response to antigen. These results suggest a therapeutic utility for ABT-491, perhaps in combination with other anti-inflammatory agents, in the treatment of allergic rhinitis.
Assuntos
Hipersensibilidade/tratamento farmacológico , Imidazóis/farmacologia , Indóis/farmacologia , Fator de Ativação de Plaquetas/antagonistas & inibidores , Rinite/tratamento farmacológico , Resistência das Vias Respiratórias/efeitos dos fármacos , Animais , Permeabilidade Capilar/efeitos dos fármacos , Cobaias , Masculino , Fator de Ativação de Plaquetas/fisiologia , Ratos , Ratos Endogâmicos BNRESUMO
Studies conducted with the goal of discovering a second-generation platelet-activating factor (PAF) antagonist have identified a novel class of potent and orally active antagonists which have high aqueous solubility and long duration of action in animal models. The compounds arose from the combination of the lipophilic indole portion of Abbott's first-generation PAF antagonist ABT-299 (2) with the methylimidazopyridine heterocycle moiety of British Biotechnology's BB-882 (1) and possess the positive attributes of both of these clinical candidates. Structure-activity relationship (SAR) studies indicated that modification of the indole and benzoyl spacer of lead compound 7b gave analogues that were more potent, longer-lived, and bioavailable and resulted in the identification of 1-(N, N-dimethylcarbamoyl)-4-ethynyl-3-[3-fluoro-4-[(1H-2-methylimidazo[4,5-c] pyrid-1-yl)methyl]benzoyl]indole hydrochloride (ABT-491, 22 m.HCl) which has been evaluated extensively and is currently in clinical development.
Assuntos
Imidazóis/síntese química , Fator de Ativação de Plaquetas/antagonistas & inibidores , Inibidores da Agregação Plaquetária/síntese química , Glicoproteínas da Membrana de Plaquetas/metabolismo , Piridinas/síntese química , Receptores de Superfície Celular , Receptores Acoplados a Proteínas G , Animais , Disponibilidade Biológica , Plaquetas/efeitos dos fármacos , Plaquetas/fisiologia , Permeabilidade Capilar/efeitos dos fármacos , Cães , Feminino , Cobaias , Humanos , Imidazóis/química , Imidazóis/farmacologia , Macaca fascicularis , Masculino , Estrutura Molecular , Fator de Ativação de Plaquetas/farmacologia , Inibidores da Agregação Plaquetária/química , Inibidores da Agregação Plaquetária/farmacocinética , Inibidores da Agregação Plaquetária/farmacologia , Piridinas/química , Piridinas/farmacocinética , Piridinas/farmacologia , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
A series of P1 C alpha gem-disubstituted succinamide hydroxamate matrix metalloproteinase inhibitors were prepared stereoselectively and evaluated in vitro for their ability to inhibit MMP-1, MMP-2, and MMP-3. It was found that while methyl/allyl substitution as in 2 and 18 provided compounds that were broad spectrum inhibitors and nearly equipotent with parent inhibitor 1, a larger group such as bis-allyl as in 13 or gem-cyclopentyl as in 14 significantly reduced enzyme inhibition.
Assuntos
Ácidos Hidroxâmicos/farmacologia , Metaloendopeptidases/antagonistas & inibidores , Inibidores de Proteases/farmacologia , Animais , Ácidos Hidroxâmicos/química , Ácidos Hidroxâmicos/farmacocinética , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteases/química , Inibidores de Proteases/farmacocinética , RatosRESUMO
A series of succinate-derived hydroxamic acids incorporating a macrocyclic ring were designed, synthesized, and evaluated as inhibitors of matrix metalloproteinases. The inhibitors were designed based on the published X-ray crystal structure of batimastat (1) complexed with human neutrophil collagenase (MMP-8). The synthesized compounds were shown to inhibit selected MMPs in vitro with low nanomolar potency.