RESUMO
A novel series of benzyl substituted thieno[2,3-d]pyrimidines were identified as potent A2A receptor antagonists. Several five- and six-membered heterocyclic replacements for the optimized methylfuran were explored. Select compounds effectively reverse catalepsy in mice when dosed orally.
Assuntos
Antagonistas do Receptor A2 de Adenosina/química , Pirimidinas/química , Receptor A2A de Adenosina/metabolismo , Antagonistas do Receptor A2 de Adenosina/farmacocinética , Antagonistas do Receptor A2 de Adenosina/uso terapêutico , Animais , Encéfalo/metabolismo , Catalepsia/tratamento farmacológico , Meia-Vida , Humanos , Cinética , Camundongos , Ligação Proteica , Pirimidinas/farmacocinética , Pirimidinas/uso terapêutico , Ratos , Receptor A2A de Adenosina/químicaRESUMO
2-Amino-4-phenyl-8-pyrrolidin-1-ylmethyl-indeno[1,2-d]pyrimidin-5-one (1) is a novel and potent selective dual A(2A)/A(1) adenosine receptor antagonist from the arylindenopyrimidine series that was determined to be genotoxic in both the Ames and Mouse Lymphoma L5178Y assays only following metabolic activation. Compound 1 was identified as a frame-shift mutagen in Salmonella typhimurium tester strain TA1537 as indicated by a significant dose-dependent increase in revertant colonies as compared to the vehicle control. The metabolic activation-dependent irreversible covalent binding of radioactivity to DNA, recovery of 1 and its enamine metabolite from acid hydrolysis of covalently modified DNA, and protection of covalent binding to DNA by both cyanide ion and methoxylamine suggest that the frame-shift mutation in TA1537 strain involved covalent binding instead of simple intercalation to DNA. Compound 1 was bioactivated to endocyclic iminium ion, aldehyde, epoxide, and α,ß-unsaturated keto reactive intermediates from the detection of cyano, oxime, and glutathione conjugates by data-dependent high resolution accurate mass measurements. Collision-induced dissociation of these conjugates provided evidence for bioactivation of the pyrrolidine ring of 1. The epoxide and α,ß-unsaturated keto reactive intermediates were unlikely to cause the genotoxicity of 1 because the formation of their glutathione adducts did not ameliorate the binding of compound related material to DNA. Instead, the endocyclic iminium ions and amino aldehydes were likely candidates responsible for genotoxicity based on, first, the protection afforded by both cyanide ion and methoxylamine, which reduced the potential to form covalent adducts with DNA, and, second, analogues of 1 designed with low probability to form these reactive intermediates were not genotoxic. It was concluded that 1 also had the potential to be mutagenic in humans based on observing the endocyclic iminium ion following incubation with a human liver S9 preparation and the commensurate detection of DNA adducts. An understanding of this genotoxicity mechanism supported an evidence-based approach to selectively modify the structure of 1 which resulted in analogues being synthesized that were devoid of a genotoxic liability. In addition, potency and selectivity against both adenosine A(2A) and A(1) receptors were maintained.
Assuntos
Antagonistas do Receptor A1 de Adenosina/toxicidade , Antagonistas do Receptor A2 de Adenosina/toxicidade , Iminas/química , Indenos/toxicidade , Pirimidinas/química , Pirimidinas/toxicidade , Pirrolidinas/toxicidade , Receptor A1 de Adenosina/química , Receptor A2A de Adenosina/química , Antagonistas do Receptor A1 de Adenosina/química , Antagonistas do Receptor A1 de Adenosina/metabolismo , Antagonistas do Receptor A2 de Adenosina/química , Antagonistas do Receptor A2 de Adenosina/metabolismo , Animais , Biotransformação , Cromatografia Líquida de Alta Pressão , DNA/química , DNA/metabolismo , Adutos de DNA/química , Adutos de DNA/metabolismo , Humanos , Indenos/química , Íons/química , Espectrometria de Massas , Camundongos , Testes de Mutagenicidade , Pirrolidinas/química , Pirrolidinas/metabolismo , Ratos , Receptor A1 de Adenosina/metabolismo , Receptor A2A de Adenosina/metabolismo , Salmonella typhimurium/efeitos dos fármacos , Salmonella typhimurium/genéticaRESUMO
Nicotinic agonists have been shown to improve cognition and mood, but this improvement is inconsistent and short-lived, possibly due to receptor desensitization. Positive Allosteric Modulators (PAMs) of the nicotinic alpha-7 nicotinic-acetyl-choline receptor (a7nAChR) are hypothesized to change the configuration of the nicotinic receptor and delay desensitization, potentially increasing the duration of the activation of the receptor, and improving clinical efficacy. This was a randomized controlled trial (RCT) adding JNJ-39393406 9 (a PAM of the a7nAChR) (n=35) or placebo (n=36) to treatment as usual for two weeks in 71 patients with unipolar depression. Mixed models for repeated measures analyses were performed Primary outcome measures were the Brief Assessment of Cognition in Schizophrenia (BACS) composite and the Montgomery-Asperg Depression Rating Scale (MADRS) scores. The drug was well tolerated, however mixed models for repeated measures comparing JNJ-39393406 to placebo showed no significant difference for MADRS total score (p=0.78), BACS composite score (p=0.34), or any of the secondary outcome measures. There was no significant difference in adverse events between the study groups (p=0.44). In conclusion, this study's findings do not support the hypothesis that a positive nicotinic receptor modulator can improve cognitive or depressive symptomatology in patients with unipolar depression.
Assuntos
Transtorno Depressivo Maior , Receptores Nicotínicos , Cognição , Transtorno Depressivo Maior/tratamento farmacológico , Método Duplo-Cego , Humanos , Nicotina/farmacologia , Piridinas , Resultado do Tratamento , TriazóisRESUMO
A novel series of arylindenopyrimidines were identified as A(2A) and A(1) receptor antagonists. The series was optimized for in vitro activity by substituting the 8- and 9-positions with methylene amine substituents. The compounds show excellent activity in mouse models of Parkinson's disease when dosed orally.
Assuntos
Antagonistas do Receptor A1 de Adenosina , Antagonistas do Receptor A2 de Adenosina , Aminas/química , Neurotransmissores/química , Pirimidinas/química , Aminas/síntese química , Aminas/uso terapêutico , Animais , Catalepsia/tratamento farmacológico , Modelos Animais de Doenças , Camundongos , Neurotransmissores/síntese química , Neurotransmissores/uso terapêutico , Pirimidinas/síntese química , Pirimidinas/uso terapêutico , Receptor A1 de Adenosina/metabolismo , Receptor A2A de Adenosina/metabolismo , Relação Estrutura-AtividadeRESUMO
Two reactive metabolites were identified in vivo for the dual A(2A)/A(1) receptor antagonist 1. Two strategies were implemented to successfully mitigate the metabolic liabilities associated with 1. Optimization of the arylindenopyrimidines led to a number of amide, ether, and amino analogs having comparable in vitro and in vivo activity.
Assuntos
Antagonistas do Receptor A1 de Adenosina , Antagonistas do Receptor A2 de Adenosina , Neurotransmissores/química , Pirimidinas/química , Animais , Catalepsia/tratamento farmacológico , Modelos Animais de Doenças , Camundongos , Neurotransmissores/síntese química , Neurotransmissores/uso terapêutico , Pirimidinas/síntese química , Pirimidinas/uso terapêutico , Receptor A1 de Adenosina/metabolismo , Receptor A2A de Adenosina/metabolismo , Relação Estrutura-AtividadeRESUMO
Preclinical research shows that compounds acting at α7 nicotinic receptors (nAChRs) can reduce nicotine self-administration, suggesting that a positive allosteric modulator (PAM) of α7 receptors, JNJ-39393406, may aid smoking cessation. Moreover, individuals with schizophrenia, who have very high rates of smoking, have reduced expression of α7 nAChRs and may particularly benefit from this compound. In two parallel studies using a within-subject cross-over design, 36 healthy smokers (Study 1) and 62 smokers with schizophrenia (Study 2), both groups high in quit interest, attempted to initiate quitting temporarily during each of two 3-week phases. Treatments were the α7 nicotinic receptor PAM JNJ-39393406 (100 mg b.i.d.) or placebo (double-blind, counter-balanced). In each phase, all smoked ad lib with no drug on week 1 or during dose run-up on week 2, and then tried to quit every day during week 3. Abstinence (confirmed by CO <5 p.p.m.) and smoking reduction (CO <8), as well as cigarettes/day (in Study 1), were assessed daily (Monday-Friday) each quit week and compared between conditions. Secondary outcomes included abstinence symptoms (withdrawal and craving) and cognitive test responding (N-back; continuous performance task). In both studies, compared with placebo, active JNJ-39393406 did not increase the number of abstinent days nor reduce total smoking exposure. We also found no significant improvements in craving, withdrawal, or cognitive function. With this dose and study duration, our findings do not support further testing of this α7 nAChR PAM compound for possible efficacy in smoking cessation, in smokers with or without schizophrenia.
Assuntos
Agonistas Nicotínicos/uso terapêutico , Piridinas/uso terapêutico , Esquizofrenia/complicações , Agentes de Cessação do Hábito de Fumar/uso terapêutico , Fumar/tratamento farmacológico , Triazóis/uso terapêutico , Receptor Nicotínico de Acetilcolina alfa7/agonistas , Adulto , Regulação Alostérica , Estudos Cross-Over , Método Duplo-Cego , Feminino , Humanos , Masculino , Esquizofrenia/metabolismo , Fumar/metabolismo , Abandono do Hábito de Fumar , Tabagismo/complicações , Tabagismo/tratamento farmacológico , Tabagismo/metabolismo , Resultado do Tratamento , Receptor Nicotínico de Acetilcolina alfa7/metabolismoRESUMO
Adenosine A2A antagonists are believed to have therapeutic potential in the treatment of Parkinson's disease (PD). We have characterized the dual adenosine A2A/A1 receptor antagonist JNJ-40255293 (2-amino-8-[2-(4-morpholinyl)ethoxy]-4-phenyl-5H-indeno[1,2-d]pyrimidin-5-one). JNJ-40255293 was a high-affinity (7.5 nM) antagonist at the human A2A receptor with 7-fold in vitro selectivity versus the human A1 receptor. A similar A2A:A1 selectivity was seen in vivo (ED50's of 0.21 and 2.1 mg/kg p.o. for occupancy of rat brain A2A and A1 receptors, respectively). The plasma EC50 for occupancy of rat brain A2A receptors was 13 ng/mL. In sleep-wake encephalographic (EEG) studies, JNJ-40255293 dose-dependently enhanced a consolidated waking associated with a subsequent delayed compensatory sleep (minimum effective dose: 0.63 mg/kg p.o.). As measured by microdialysis, JNJ-40255293 did not affect dopamine and noradrenaline release in the prefrontal cortex and the striatum. However, it was able to reverse effects (catalepsy, hypolocomotion, and conditioned avoidance impairment in rats; hypolocomotion in mice) produced by the dopamine D2 antagonist haloperidol. The compound also potentiated the agitation induced by the dopamine agonist apomorphine. JNJ-40255293 also reversed hypolocomotion produced by the dopamine-depleting agent reserpine and potentiated the effects of l-dihydroxyphenylalanine (L-DOPA) in rats with unilateral 6-hydroxydopamine-induced lesions of the nigro-striatal pathway, an animal model of Parkinson's disease. Extrapolating from the rat receptor occupancy dose-response curve, the occupancy required to produce these various effects in rats was generally in the range of 60-90%. The findings support the continued research and development of A2A antagonists as potential treatments for PD.
Assuntos
Antiparkinsonianos/farmacologia , Indenos/farmacologia , Pirimidinas/farmacologia , Antagonistas do Receptor A1 de Adenosina/química , Antagonistas do Receptor A1 de Adenosina/farmacocinética , Antagonistas do Receptor A1 de Adenosina/farmacologia , Antagonistas do Receptor A2 de Adenosina/química , Antagonistas do Receptor A2 de Adenosina/farmacocinética , Antagonistas do Receptor A2 de Adenosina/farmacologia , Animais , Antiparkinsonianos/química , Antiparkinsonianos/farmacocinética , Encéfalo/efeitos dos fármacos , Encéfalo/fisiopatologia , Células CHO , Cricetulus , Dopamina/metabolismo , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Indenos/química , Indenos/farmacocinética , Masculino , Camundongos , Atividade Motora/efeitos dos fármacos , Norepinefrina/metabolismo , Transtornos Parkinsonianos/tratamento farmacológico , Transtornos Parkinsonianos/fisiopatologia , Pirimidinas/química , Pirimidinas/farmacocinética , Ratos Sprague-Dawley , Ratos Wistar , Receptor A1 de Adenosina/metabolismo , Receptor A2A de Adenosina/metabolismo , Proteínas Recombinantes/metabolismoRESUMO
The design and characterization of two, dual adenosine A(2A)/A(1) receptor antagonists in several animal models of Parkinson's disease is described. Compound 1 was previously reported as a potential treatment for Parkinson's disease. Further characterization of 1 revealed that it was metabolized to reactive intermediates that caused the genotoxicity of 1 in the Ames and mouse lymphoma L51784 assays. The identification of the metabolites enabled the preparation of two optimized compounds 13 and 14 that were devoid of the metabolic liabilities associated with 1. Compounds 13 and 14 are potent dual A(2A)/A(1) receptor antagonists that have excellent activity, after oral administration, across a number of animal models of Parkinson's disease including mouse and rat models of haloperidol-induced catalepsy, mouse and rat models of reserpine-induced akinesia, and the rat 6-hydroxydopamine (6-OHDA) lesion model of drug-induced rotation.
Assuntos
Antagonistas do Receptor A1 de Adenosina/síntese química , Antagonistas do Receptor A2 de Adenosina/síntese química , Indenos/síntese química , Transtornos Parkinsonianos/tratamento farmacológico , Pirimidinas/síntese química , Receptor A2A de Adenosina/metabolismo , Antagonistas do Receptor A1 de Adenosina/farmacocinética , Antagonistas do Receptor A1 de Adenosina/farmacologia , Antagonistas do Receptor A2 de Adenosina/farmacocinética , Antagonistas do Receptor A2 de Adenosina/farmacologia , Administração Oral , Animais , Desenho de Fármacos , Feminino , Indenos/farmacocinética , Indenos/farmacologia , Macaca fascicularis , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Transtornos Parkinsonianos/induzido quimicamente , Pirimidinas/farmacocinética , Pirimidinas/farmacologia , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
This study examined the relation between misperception of healthy weight and obesity, as well as moderators of this relation, in a sample of middle-aged black men. Survey data from 404 mostly immigrant, black males living in greater New York City were collected as part of a larger randomized controlled trial. Data included measures of health status, BMI, perceived healthy weight, and misperception of healthy weight. Misperception of healthy weight was more frequent among obese men (90.2%) than nonobese men (48.7%) (P < 0.001). Mean level of misperception was also significantly higher in obese men than nonobese men (P < 0.001). Health status moderated the relation between misperception of healthy weight and obesity: obese men who felt healthy or who had fewer comorbid conditions had greater misperception of healthy weight than obese men who felt unhealthy or had relatively more comorbid conditions (P < 0.01). Our findings demonstrate that misperception of healthy weight discriminates between obese and nonobese black men, and the magnitude of this relation is exacerbated in obese men who are relatively healthy. Future studies should determine the prevalence of misperception of healthy weight in more diverse populations and identify potential mediators of the relation between misperception of healthy weight and obesity.
Assuntos
População Negra/psicologia , População Negra/estatística & dados numéricos , Imagem Corporal , Peso Corporal , Obesidade/etnologia , Obesidade/psicologia , Idoso , Atitude Frente a Saúde , Índice de Massa Corporal , Região do Caribe/etnologia , Comorbidade , Emigrantes e Imigrantes/psicologia , Emigrantes e Imigrantes/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Cidade de Nova Iorque/epidemiologia , Prevalência , Fatores de Risco , População Urbana/estatística & dados numéricosRESUMO
The in vivo characterization of a dual adenosine A(2A)/A(1) receptor antagonist in several animal models of Parkinson's disease is described. Discovery and scale-up syntheses of compound 1 are described in detail, highlighting optimization steps that increased the overall yield of 1 from 10.0% to 30.5%. Compound 1 is a potent A(2A)/A(1) receptor antagonist in vitro (A(2A) K(i) = 4.1 nM; A(1) K(i) = 17.0 nM) that has excellent activity, after oral administration, across a number of animal models of Parkinson's disease including mouse and rat models of haloperidol-induced catalepsy, mouse model of reserpine-induced akinesia, rat 6-hydroxydopamine (6-OHDA) lesion model of drug-induced rotation, and MPTP-treated non-human primate model.
Assuntos
Antagonistas do Receptor A1 de Adenosina/síntese química , Antagonistas do Receptor A2 de Adenosina/síntese química , Antiparkinsonianos/síntese química , Indenos/síntese química , Doença de Parkinson/metabolismo , Pirimidinas/síntese química , Receptor A2A de Adenosina/fisiologia , Antagonistas do Receptor A1 de Adenosina/farmacocinética , Antagonistas do Receptor A1 de Adenosina/farmacologia , Antagonistas do Receptor A2 de Adenosina/farmacocinética , Antagonistas do Receptor A2 de Adenosina/farmacologia , Administração Oral , Animais , Antiparkinsonianos/farmacocinética , Antiparkinsonianos/farmacologia , Callithrix , Modelos Animais de Doenças , Feminino , Indenos/farmacocinética , Indenos/farmacologia , Macaca fascicularis , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Pirimidinas/farmacocinética , Pirimidinas/farmacologia , Ratos , Ratos Sprague-DawleyRESUMO
A series of novel 5,5-diphenylimidazolones was synthesized and evaluated for activity against the human neuropeptide Y5 receptor. The 3-pyridyl analog 46 demonstrated an IC(50) of 8.3 nM with a favorable pharmacokinetic profile in rats, but was ineffective in reducing food intake.