RESUMEN
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.
Asunto(s)
Antipsicóticos/síntesis química , Antipsicóticos/farmacología , Alquilación , Sistema Enzimático del Citocromo P-450/química , Sistema Enzimático del Citocromo P-450/metabolismo , Antagonistas de Dopamina/síntesis química , Antagonistas de Dopamina/farmacología , Antagonistas de los Receptores de Dopamina D2 , Diseño de Fármacos , Humanos , Receptor de Serotonina 5-HT2A/efectos de los fármacos , Receptor de Serotonina 5-HT2C/efectos de los fármacos , Receptores de Dopamina D3/antagonistas & inhibidores , Receptores de Serotonina/efectos de los fármacos , Proteínas Recombinantes/efectos de los fármacos , Antagonistas de la Serotonina/síntesis química , Antagonistas de la Serotonina/farmacología , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/farmacologíaRESUMEN
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.
Asunto(s)
Receptores de Quimiocina/antagonistas & inhibidores , Receptores de Quimiocina/metabolismo , Sustitución de Aminoácidos , Animales , Sitios de Unión , Unión Competitiva , Células CHO , Bovinos , Línea Celular , Quimiotaxis/efectos de los fármacos , Cricetinae , Humanos , Indoles/química , Indoles/metabolismo , Indoles/farmacología , Cinética , Modelos Moleculares , Monocitos/efectos de los fármacos , Monocitos/fisiología , Mutagénesis Sitio-Dirigida , Piperidinas/química , Piperidinas/metabolismo , Piperidinas/farmacología , Ensayo de Unión Radioligante , Receptores CCR2 , Receptores de Quimiocina/química , Receptores de Quimiocina/genética , Proteínas Recombinantes/antagonistas & inhibidores , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Rodopsina/química , Rodopsina/genética , Homología Estructural de Proteína , TransfecciónRESUMEN
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.
Asunto(s)
Fenoles/farmacocinética , Pirrolidinas/farmacocinética , Receptores de Serotonina/efectos de los fármacos , Antagonistas de la Serotonina/farmacocinética , Serotonina/análogos & derivados , Sueño REM/efectos de los fármacos , Sueño REM/fisiología , Animales , Células CHO , Línea Celular , Membrana Celular/fisiología , Cricetinae , AMP Cíclico/metabolismo , Vías de Administración de Medicamentos , Regulación de la Expresión Génica , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Cobayas , Humanos , Hipotermia/inducido químicamente , Fenoles/administración & dosificación , Pirrolidinas/administración & dosificación , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Receptores de Serotonina/genética , Serotonina/administración & dosificación , Serotonina/farmacocinética , Serotonina/farmacología , Serotonina/fisiología , Antagonistas de la Serotonina/administración & dosificación , TritioRESUMEN
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.
Asunto(s)
Receptores de Serotonina/efectos de los fármacos , Antagonistas de la Serotonina/síntesis química , Antagonistas de la Serotonina/farmacología , Sistema Enzimático del Citocromo P-450/efectos de los fármacos , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Humanos , Indicadores y Reactivos , Isoenzimas/efectos de los fármacos , Modelos Moleculares , Relación Estructura-ActividadRESUMEN
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.