RESUMO
OBJECTIVES: Prescription stimulants are vulnerable to oral and parenteral abuse. Intravenous forms of abuse may be most detrimental due to an enhanced risk of dependence, overdose, and infectious diseases. Our objective was to discover an orally active prodrug of a stimulant that would not be easily converted to its parent when injected, thus hindering intravenous abuse. METHODS: Following an initial analysis of stimulant structures, the fencamfamine isomer [(-)-FCF; (N-ethyl-3-phenylbicyclo[2.2.1]heptan-2-amine)] was chosen as a parent drug due to its favorable biochemical properties. Subsequently, PRX-P4-003 {(-)-N-(Octadecanoyloxymethoxycarbonyl)-N-ethyl-3-phenylbicyclo[2.2.1]heptan-2-amine} qualified for further development. Experimental testing of PRX-P4-003 included radioligand binding assays, stability studies, and rodent pharmacokinetic and locomotor assays. RESULTS: Prodrug PRX-P4-003 is a pharmacologically inactive, hydrophobic compound, whereas its parent (-)-FCF is a dopamine reuptake inhibitor with weaker effects on norepinephrine reuptake (Kiâ¯=â¯0.07 and 0.80⯵M, respectively). PRX-P4-003 is metabolized to (-)-FCF in simulated intestinal fluid (with pancreatin) but not in simulated gastric fluid (with pepsin). Finally, PRX-P4-003 shows a significant oral but no intravenous increase in locomotion, correlating with its pharmacokinetics by these different routes of administration. CONCLUSIONS: PRX-P4-003 is a novel prodrug stimulant enzymatically activated in the gut. Our data suggest a pancreatic, lipase-based mechanism of activation and as only 1% of this enzyme is found in the systemic circulation, PRX-P4-003 is unlikely to be bioactive if injected intravenously. Enzymatic release of (-)-FCF is needed prior to its systemic absorption, which may discourage oral abuse (e.g., by chewing). PRX-P4-003 is being developed for apathy in Alzheimer's disease and binge eating disorder.
Assuntos
Comportamento Aditivo/enzimologia , Trato Gastrointestinal/enzimologia , Doença Iatrogênica/prevenção & controle , Pró-Fármacos/metabolismo , Transtornos Relacionados ao Uso de Substâncias/enzimologia , Animais , Comportamento Aditivo/tratamento farmacológico , Comportamento Aditivo/prevenção & controle , Estimulantes do Sistema Nervoso Central/administração & dosagem , Estimulantes do Sistema Nervoso Central/metabolismo , Cristalografia por Raios X , Ativação Enzimática/efeitos dos fármacos , Ativação Enzimática/fisiologia , Trato Gastrointestinal/efeitos dos fármacos , Locomoção/efeitos dos fármacos , Locomoção/fisiologia , Masculino , Pró-Fármacos/administração & dosagem , Pró-Fármacos/química , Ratos , Ratos Sprague-Dawley , Fatores de Risco , Transtornos Relacionados ao Uso de Substâncias/tratamento farmacológico , Transtornos Relacionados ao Uso de Substâncias/prevenção & controleRESUMO
A series of novel pyrrolocarbazole lactams was identified as potent PARP-1 inhibitors in vitro and in a PC12 cellular NAD(+) depletion assay. The SAR trends of substituents at the 3-position, as well as the effect of blocking the indole or lactam NH-groups of the template by methylation or formylation, are discussed in relation to molecular modeling studies.
Assuntos
Carbazóis/química , Carbazóis/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Lactamas/química , Lactamas/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases , Pirróis/química , Pirróis/farmacologia , Animais , Carbazóis/síntese química , Permeabilidade da Membrana Celular/efeitos dos fármacos , Inibidores Enzimáticos/química , Imidas/química , Concentração Inibidora 50 , Lactamas/síntese química , Modelos Moleculares , Células PC12 , Poli(ADP-Ribose) Polimerases/química , Poli(ADP-Ribose) Polimerases/metabolismo , Estrutura Terciária de Proteína , Pirróis/síntese química , Ratos , Relação Estrutura-AtividadeRESUMO
A series of novel pyrrolocarbazoles was synthesized as potential PARP-1 inhibitors. Pyrrolocarbazole 1 was identified as a potent PARP-1 inhibitor (IC50 = 36 nM) from our internal database. Synthesis of analogs around this template with the aid of modeling studies led to the identification of the truncated imide 14. Compound 14 (IC50 = 40 nM), with deleted B-ring, was found to be an equipotent PARP-1 inhibitor.
Assuntos
Carbazóis/síntese química , Carbazóis/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases , Carbazóis/química , Cristalografia por Raios X , Inibidores Enzimáticos/química , Humanos , Modelos Moleculares , Estrutura Molecular , Poli(ADP-Ribose) Polimerase-1 , Relação Estrutura-AtividadeRESUMO
A series of potent 1,2-benzothiazine 1,1-dioxide alpha-ketoamide inhibitors of calpain I is described.