RESUMO
A rational structure-activity relationship study around compound (1) is reported. The lead optimisation programme led to the identification of sulfonamide (25), a molecule combining dopamine D2/D3 receptor antagonism with serotonin 5-HT2A, 5-HT2C, 5-HT6 receptor antagonism for an effective treatment of schizophrenia. Compound (25) was shown to possess the required in vivo activity with no EPS liability.
Assuntos
Antipsicóticos/síntese química , Antipsicóticos/farmacologia , Alquilação , Sistema Enzimático do Citocromo P-450/química , Sistema Enzimático do Citocromo P-450/metabolismo , Antagonistas de Dopamina/síntese química , Antagonistas de Dopamina/farmacologia , Antagonistas dos Receptores de Dopamina D2 , Desenho de Fármacos , Humanos , Receptor 5-HT2A de Serotonina/efeitos dos fármacos , Receptor 5-HT2C de Serotonina/efeitos dos fármacos , Receptores de Dopamina D3/antagonistas & inibidores , Receptores de Serotonina/efeitos dos fármacos , Proteínas Recombinantes/efeitos dos fármacos , Antagonistas da Serotonina/síntese química , Antagonistas da Serotonina/farmacologia , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/farmacologiaRESUMO
We describe here a classical molecular modeling exercise that was carried out to provide a basis for the design of novel antagonist ligands of the CCR2 receptor. Using a theoretical model of the CCR2 receptor, docking studies were carried out to define plausible binding modes for the various known antagonist ligands, including our own series of indole piperidine compounds. On the basis of these results, a number of site-directed mutations (SDM) were designed that were intended to verify the proposed docking models. From these it was clear that further refinements would be necessary in the model. This was aided by the publication of a crystal structure of bovine rhodopsin, and a new receptor model was built by homology to this structure. This latest model enabled us to define ligand-docking hypotheses that were in complete agreement with the results of the SDM experiments.
Assuntos
Receptores de Quimiocinas/antagonistas & inibidores , Receptores de Quimiocinas/metabolismo , Substituição de Aminoácidos , Animais , Sítios de Ligação , Ligação Competitiva , Células CHO , Bovinos , Linhagem Celular , Quimiotaxia/efeitos dos fármacos , Cricetinae , Humanos , Indóis/química , Indóis/metabolismo , Indóis/farmacologia , Cinética , Modelos Moleculares , Monócitos/efeitos dos fármacos , Monócitos/fisiologia , Mutagênese Sítio-Dirigida , Piperidinas/química , Piperidinas/metabolismo , Piperidinas/farmacologia , Ensaio Radioligante , Receptores CCR2 , Receptores de Quimiocinas/química , Receptores de Quimiocinas/genética , Proteínas Recombinantes/antagonistas & inibidores , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Rodopsina/química , Rodopsina/genética , Homologia Estrutural de Proteína , TransfecçãoRESUMO
1 (6-((R)-2-[2-[4-(4-Chloro-phenoxy)-piperidin-1-yl]-ethyl]-pyrrolidine-1-sulphonyl)-1H-indole hydrochloride) (SB-656104-A), a novel 5-hydroxytryptamine (5-HT(7)) receptor antagonist, potently inhibited [(3)H]-SB-269970 binding to the human cloned 5-HT(7(a)) (pK(i) 8.7+/-0.1) and 5-HT(7(b)) (pK(i) 8.5+/-0.2) receptor variants and the rat native receptor (pK(i) 8.8+/-0.2). The compound displayed at least 30-fold selectivity for the human 5-HT(7(a)) receptor versus other human cloned 5-HT receptors apart from the 5-HT(1D) receptor ( approximately 10-fold selective). 2 SB-656104-A antagonised competitively the 5-carboxamidotryptamine (5-CT)-induced accumulation of cyclic AMP in h5-HT(7(a))/HEK293 cells with a pA(2) of 8.5. 3 Following a constant rate iv infusion to steady state in rats, SB-656104 had a blood clearance (CL(b)) of 58+/-6 ml min(-1) kg(-1) and was CNS penetrant with a steady-state brain : blood ratio of 0.9 : 1. Following i.p. administration to rats (10 mg kg(-1)), the compound displayed a t(1/2) of 1.4 h with mean brain and blood concentrations (at 1 h after dosing) of 0.80 and 1.0 micro M, respectively. 4 SB-656104-A produced a significant reversal of the 5-CT-induced hypothermic effect in guinea pigs, a pharmacodynamic model of 5-HT(7) receptor interaction in vivo (ED(50) 2 mg kg(-1)). 5 SB-656104-A, administered to rats at the beginning of the sleep period (CT 0), significantly increased the latency to onset of rapid eye movement (REM) sleep at 30 mg kg(-1) i.p. (+93%) and reduced the total amount of REM sleep at 10 and 30 mg kg(-1) i.p. with no significant effect on the latency to, or amount of, non-REM sleep. SB-269970-A produced qualitatively similar effects in the same study. 6 In summary, SB-656104-A is a novel 5-HT(7) receptor antagonist which has been utilised in the present study to provide further evidence for a role for 5-HT(7) receptors in the modulation of REM sleep.
Assuntos
Fenóis/farmacocinética , Pirrolidinas/farmacocinética , Receptores de Serotonina/efeitos dos fármacos , Antagonistas da Serotonina/farmacocinética , Serotonina/análogos & derivados , Sono REM/efeitos dos fármacos , Sono REM/fisiologia , Animais , Células CHO , Linhagem Celular , Membrana Celular/fisiologia , Cricetinae , AMP Cíclico/metabolismo , Vias de Administração de Medicamentos , Regulação da Expressão Gênica , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Cobaias , Humanos , Hipotermia/induzido quimicamente , Fenóis/administração & dosagem , Pirrolidinas/administração & dosagem , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Receptores de Serotonina/genética , Serotonina/administração & dosagem , Serotonina/farmacocinética , Serotonina/farmacologia , Serotonina/fisiologia , Antagonistas da Serotonina/administração & dosagem , TrítioRESUMO
Novel 5-HT(7) receptor antagonists containing the benzocycloheptanone core were identified from high throughput screening. Molecular modelling and SAR studies have converted these intractable hits into a more potent, selective and tractable series, exemplified by compound (25), SB-691673.
Assuntos
Receptores de Serotonina/efeitos dos fármacos , Antagonistas da Serotonina/síntese química , Antagonistas da Serotonina/farmacologia , Sistema Enzimático do Citocromo P-450/efeitos dos fármacos , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Humanos , Indicadores e Reagentes , Isoenzimas/efeitos dos fármacos , Modelos Moleculares , Relação Estrutura-AtividadeRESUMO
A focused SAR study around the previously reported selective 5-HT(7) receptor antagonist, SB-269970-A has resulted in the identification of a structurally related analogue having an improved pharmacokinetic profile. Replacement of the phenolic group in SB-269970-A with an indole moiety, and replacement of the piperidinyl 4-methyl group with a heterocyclic ring system proved to be the key changes leading to the identification of SB-656104-A.