RESUMO
A series of 4,4-disubstituted cyclohexylamine NK(1) antagonists containing a lactam ring is described. The compounds are brain penetrant and activity is demonstrated in a ferret emesis model.
Assuntos
Antieméticos/síntese química , Antieméticos/farmacologia , Lactamas/química , Lactamas/farmacologia , Taquicininas/antagonistas & inibidores , Amidas/química , Animais , Antieméticos/química , Gerbillinae , Humanos , Concentração Inibidora 50 , Lactamas/síntese química , Metilação , Estrutura Molecular , Receptores da Neurocinina-1/metabolismo , Relação Estrutura-Atividade , Taquicininas/metabolismoRESUMO
Substituted 4-amino cyclohexylglycine analogues were evaluated for DP-IV inhibitory properties. Bis-sulfonamide 15e was an extremely potent 2.6 nM inhibitor of the enzyme with excellent selectivity over all counterscreens. 2,4-difluorobenzenesulfonamide 15b and 1-naphthyl amide 16b, however, combined an acceptable in vitro profile with good pharmacokinetic properties in the rat, and 15b was orally efficacious at 3 mpk in an OGTT in lean mice.
Assuntos
Dipeptidil Peptidase 4/metabolismo , Glicina/análogos & derivados , Glicina/metabolismo , Canais de Potássio de Abertura Dependente da Tensão da Membrana , Inibidores de Proteases/metabolismo , Animais , Proteínas de Transporte de Cátions/metabolismo , Canais de Potássio Éter-A-Go-Go , Hipoglicemiantes/química , Hipoglicemiantes/metabolismo , Hipoglicemiantes/farmacocinética , Camundongos , Canais de Potássio/metabolismo , Inibidores de Proteases/química , Inibidores de Proteases/farmacocinética , Ligação Proteica/efeitos dos fármacos , Ligação Proteica/fisiologia , RatosRESUMO
Extensive screening of compound libraries was undertaken to identify compounds with high affinity for the rat NK(1) receptor based on inhibition of [(125)I]-substance P binding. RP67580, SR140333, NKP-608 and GR205171 were selected as compounds of interest, with cloned rat NK(1) receptor binding K(i) values of 0.15-1.9 nM. Despite their high binding affinity, NKP-608 and GR205171 exhibited only a moderate functional antagonism of substance P-induced inositol-1-phosphate accumulation and acidification rate at 1 microM using cloned or native rat NK(1) receptors in vitro. The ability of the compounds to penetrate the CNS was determined by inhibition of NK(1) agonist-induced behaviours in gerbils and rats. GR205171 and NKP-608 potently inhibited GR73632-induced foot drumming in gerbils (ID(50) 0.04 and 0.2 mg/kg i.v., respectively). In contrast, RP67580 and SR140333 were poorly brain penetrant in gerbils (no inhibition at 10 mg/kg i.v.) and were not examined further in vivo. In rats, only high doses of GR205171 (10 or 30 mg/kg s.c.) inhibited NK(1) agonist-induced sniffing and hypertension, whilst NKP-608 (1 or 10 mg/kg i.p.) was without effect. GR205171 (3-30 mg/kg s.c.) caused only partial inhibition of separation-induced vocalisations in rat pups, a response that is known to be NK(1) receptor mediated in other species. These observations demonstrate the shortcomings of currently available NK(1) receptor antagonists for rat psychopharmacology assays.
Assuntos
Indóis/farmacologia , Antagonistas dos Receptores de Neurocinina-1 , Piperidinas/farmacologia , Quinolinas/farmacologia , Quinuclidinas/farmacologia , Tetrazóis/farmacologia , Animais , Células CHO , Cricetinae , Relação Dose-Resposta a Droga , Feminino , Gerbillinae , Humanos , Indóis/metabolismo , Isoindóis , Masculino , Piperidinas/metabolismo , Quinolinas/metabolismo , Quinuclidinas/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores da Neurocinina-1/metabolismo , Tetrazóis/metabolismo , Células Tumorais CultivadasRESUMO
The results of investigations in these laboratories of 2-aryl-4-(piperidin-1-yl)butanamines and 1,3,4-trisubstituted pyrrolidines as human CCR5 antagonists have recently been disclosed. To facilitate further development of these antagonists, we have developed a pharmacophore model based on the structure-activity relationships (SAR) and a human CCR5 receptor docking model using the crystal structure of rhodopsin as a template [Palczewski, K., et al. (2000) Science 289, 739-745]. Guided by the receptor docking model, we have mapped the compounds' site of interaction with CCR5 using site-directed mutagenesis experiments. Our results are consistent with a binding site for the two series that is located within a cavity near the extracellular surface formed by transmembrane helices 2, 3, 6, and 7. This site is overlapping yet distinct from that reported for another antiviral agent which binds to CCR5 [Dragic, T., et al. (2000) Proc. Natl. Acad. Sci. U.S.A. 97, 5639-5644].
Assuntos
Butanos/química , Antagonistas dos Receptores CCR5 , Modelos Moleculares , Mutagênese Sítio-Dirigida , Piperidinas/química , Pirrolidinas/química , Receptores CCR5/química , Alanina/genética , Amidas/química , Sequência de Aminoácidos , Substituição de Aminoácidos/genética , Animais , Sítios de Ligação/genética , Ligação Competitiva/genética , Células CHO , Bovinos , Cricetinae , Humanos , Dados de Sequência Molecular , Estrutura Secundária de Proteína/genética , Compostos de Amônio Quaternário/química , Receptores CCR5/biossíntese , Receptores CCR5/genética , Rodopsina/química , Homologia de Sequência de Aminoácidos , Relação Estrutura-AtividadeRESUMO
A series of G6-amino derivatives of a lipophilic vancomycin analogue was prepared. Antibacterial activity of the analogues was inversely proportional to the degree of substitution of the G6-nitrogen. The fully substituted (quaternary) analogues were essentially inactive against vanA phenotype VREF strains but retained substantial activity against other bacteria, a profile reminiscent of teicoplanin.