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1.
J Med Chem ; 51(10): 2944-53, 2008 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-18433114

RESUMO

Research on the therapeutic applications of the histamine H3 receptor (H3R) has traditionally focused on antagonists/inverse agonists. In contrast, H3R agonists have received less attention despite their potential use in several disease areas. The lower availability of H3R agonists not only hampers their full therapeutic exploration, it also prevents an unequivocal understanding of the structural requirements for H3R activation. In the light of these important issues, we present our findings on 4-benzyl-1H-imidazole-based H3R agonists. Starting from two high throughput screen hits (10 and 11), the benzyl side chain was altered with lipophilic groups using combinatorial and classical chemical approaches (compounds 12-31). Alkyne- or oxazolino-substituents gave excellent affinities and agonist activities up to the single digit nM range. Our findings further substantiate the growing notion that basic ligand sidechains are not necessary for H 3R activation and reveal the oxazolino group as a hitherto unexplored functional group in H3R research.


Assuntos
Agonistas dos Receptores Histamínicos/síntese química , Imidazóis/síntese química , Oxazóis/síntese química , Receptores Histamínicos H3/metabolismo , Animais , Células CHO , Técnicas de Química Combinatória , Cricetinae , Cricetulus , Sistema Enzimático do Citocromo P-450/metabolismo , Desenho de Fármacos , Cobaias , Agonistas dos Receptores Histamínicos/química , Agonistas dos Receptores Histamínicos/farmacologia , Humanos , Imidazóis/química , Imidazóis/farmacologia , Técnicas In Vitro , Intestinos/efeitos dos fármacos , Intestinos/fisiologia , Modelos Moleculares , Contração Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Músculo Liso/fisiologia , Oxazóis/química , Oxazóis/farmacologia , Ligação Proteica , Ensaio Radioligante , Relação Estrutura-Atividade
2.
J Med Chem ; 47(3): 530-49, 2004 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-14736235

RESUMO

(S)-alpha-ethyl-2-oxopyrrolidine acetamide 2 (levetiracetam, Keppra, UCB S.A.), a structural analogue of piracetam, has recently been approved as an add-on treatment of refractory partial onset seizures in adults. This drug appears to combine significant efficacy and high tolerability due to a unique mechanism of action. The latter relates to a brain-specific binding site for 2 (LBS for levetiracetam binding site) that probably plays a major role in its antiepileptic properties. Using this novel molecular target, we initiated a drug-discovery program searching for ligands with significant affinity to LBS with the aim to characterize their therapeutic potential in epilepsy and other central nervous system diseases. We systematically investigated the various positions of the pyrrolidone acetamide scaffold. We found that (i) the carboxamide moiety on 2 is essential for affinity; (ii) among 100 different side chains, the preferred substitution alpha to the carboxamide is an ethyl group with the (S)-configuration; (iii) the 2-oxopyrrolidine ring is preferred over piperidine analogues or acyclic compounds; (iv) substitution of positions 3 or 5 of the lactam ring decreases the LBS affinity; and (v) 4-substitution of the lactam ring by small hydrophobic groups improves the in vitro and in vivo potency. Six interesting candidates substituted in the 4-position have been shown to be more potent antiseizure agents in vivo than 2. Further pharmacological studies from our group led to the selection of (2S)-2-[(4R)-2-oxo-4-propylpyrrolidin-1-yl]butanamide 83alpha (ucb 34714) as the most interesting candidate. It is approximately 10 times more potent than 2 as an antiseizure agent in audiogenic seizure-prone mice. A clinical phase I program has been successfully concluded and 83alpha will commence several phase II trials during 2003.


Assuntos
Amidas/síntese química , Anticonvulsivantes/síntese química , Butiratos/síntese química , Piracetam/análogos & derivados , Pirrolidinonas/síntese química , Estimulação Acústica , Amidas/farmacocinética , Amidas/farmacologia , Animais , Anticonvulsivantes/farmacocinética , Anticonvulsivantes/farmacologia , Sítios de Ligação , Butiratos/farmacocinética , Butiratos/farmacologia , Células CACO-2 , Córtex Cerebral/metabolismo , Cristalografia por Raios X , Feminino , Humanos , Técnicas In Vitro , Levetiracetam , Masculino , Camundongos , Camundongos Endogâmicos DBA , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Conformação Molecular , Piracetam/metabolismo , Pirrolidinonas/farmacocinética , Pirrolidinonas/farmacologia , Ratos , Ratos Sprague-Dawley , Convulsões/tratamento farmacológico , Convulsões/etiologia , Relação Estrutura-Atividade
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