RESUMO
A six-stage stereoselective synthesis of indanyl-7-(3'-pyridyl)-(3R,6R,7R)-2,5-diketopiperazines oxytocin antagonists from indene is described. SAR studies involving mono- and disubstitution in the 3'-pyridyl ring and variation of the 3-isobutyl group gave potent compounds (pK(i) > 9.0) with good aqueous solubility. Evaluation of the pharmacokinetic profile in the rat, dog, and cynomolgus monkey of those derivatives with low cynomolgus monkey and human intrinsic clearance gave 2',6'-dimethyl-3'-pyridyl R-sec-butyl morpholine amide Epelsiban (69), a highly potent oxytocin antagonist (pK(i) = 9.9) with >31000-fold selectivity over all three human vasopressin receptors hV1aR, hV2R, and hV1bR, with no significant P450 inhibition. Epelsiban has low levels of intrinsic clearance against the microsomes of four species, good bioavailability (55%) and comparable potency to atosiban in the rat, but is 100-fold more potent than the latter in vitro and was negative in the genotoxicity screens with a satisfactory oral safety profile in female rats.
Assuntos
Dicetopiperazinas/síntese química , Morfolinas/síntese química , Ocitocina/metabolismo , Receptores de Ocitocina/antagonistas & inibidores , Administração Oral , Animais , Disponibilidade Biológica , Inibidores das Enzimas do Citocromo P-450 , Dicetopiperazinas/administração & dosagem , Dicetopiperazinas/farmacocinética , Dicetopiperazinas/farmacologia , Cães , Feminino , Humanos , Técnicas In Vitro , Macaca fascicularis , Masculino , Microssomos Hepáticos/metabolismo , Morfolinas/administração & dosagem , Morfolinas/farmacocinética , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Solubilidade , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
In this paper synthesis of macrolones 1-18 starting from azithromycin is reported. Two key steps in the construction of the linker between macrolide and quinolone moiety, are formation of central ether bond by alkylation of unactivated OH group, and formation of terminal C-C bond at 6-position of the quinolone unit. Due to the difficulty in formation of these two bonds the study of alternative synthetic methodologies and optimization of the conditions for the selected routes was required. Formation of C-4''-O-ether bond was completed by modified Michael addition, whereas O-alkylation via diazonium cation proved to be the most effective in formation of the central allylic or propargylic ether bond. Comparison of Heck and Sonogashira reaction revealed the former as preferred route to the C-C bond formation at C(6) position of the quinolone unit. Most of the target compounds exhibited highly favorable antibacterial activity against common respiratory pathogens, without significant cytotoxicity profile when tested in vitro on eukaryotic cell lines.
Assuntos
Azitromicina/análogos & derivados , Reagentes de Ligações Cruzadas/química , Éteres/química , Macrolídeos/química , Reagentes de Ligações Cruzadas/síntese química , Éteres/síntese química , Humanos , Macrolídeos/síntese química , Modelos Químicos , Estrutura MolecularRESUMO
Optimisation of a series of oxazole diketopiperazines has led to the discovery of a very potent and selective oxytocin antagonist GSK221149A. GSK221149A has been shown to inhibit oxytocin-induced uterine contractions in the anaesthetised rat.
Assuntos
Ocitocina/antagonistas & inibidores , Piperazinas/química , Piperazinas/farmacologia , Animais , Feminino , Humanos , Cinética , Ocitocina/metabolismo , Piperazinas/farmacocinética , Ratos , Ratos Sprague-Dawley , Receptores de Ocitocina/metabolismo , Relação Estrutura-Atividade , Contração Uterina/efeitos dos fármacosRESUMO
Spontaneous and induced uterine contractions in the rat were found to be inhibited by a novel and selective oxytocin receptor antagonist GSK221149A (3R,6R)-3-Indan-2-yl-1-[(1R)-1-(2-methyl-1,3-oxazol-4-yl)-2-morpholin-4-yl-2-oxoethyl]-6-[(1S)-1-methylpropyl]-2,5-piperazinedione. GSK221149A displayed nanomolar affinity (K(i) = 0.65 nM) for human recombinant oxytocin receptors with >1,400-fold selectivity over human V1a, V1b, and V2 receptors. GSK221149A had similar affinity (K(i) = 4.1 nM) and selectivity for native oxytocin receptors from rat and produced a functional, competitive block of oxytocin-induced contractions in isolated rat myometrial strips with a pA(2) value of 8.18. Intravenous administration of GSK221149A produced a dose-dependent decrease in oxytocin-induced uterine contractions in anesthetized rats with an ID(50) = 0.27 +/- 0.60 mg/kg (corresponding plasma concentrations were 88 ng/ml). Oral administration of GSK221149A (5 mg/kg) was effective in inhibiting oxytocin-induced uterine contractions after single and multiple (4-day) dosing. Spontaneous uterine contractions in late-term pregnant rats (19-21 days gestation) were significantly reduced by intravenous administration of 0.3 mg/kg of GSK221149A. These results provide further evidence that selective oxytocin receptor antagonism may offer an effective treatment for preterm labor.
Assuntos
Ocitocina/antagonistas & inibidores , Ocitocina/farmacologia , Piperazinas/farmacologia , Receptores de Ocitocina/antagonistas & inibidores , Contração Uterina/fisiologia , Anestesia , Animais , Ligação Competitiva/efeitos dos fármacos , Células CHO , Linhagem Celular , Cricetinae , Cricetulus , Feminino , Humanos , Paridade , Gravidez , Ratos , Ratos Sprague-Dawley , Receptores de Vasopressinas/efeitos dos fármacos , Transfecção , Vasopressinas/farmacologiaRESUMO
The discovery, synthesis and structure-activity relationship (SAR) of novel carboxylic acid agonists for GPR40 are described. Aryl propionic acid 1, identified from a high throughput screen, was selected for chemical exploration. Compound 2 was identified as our lead molecule through efficient solid phase combinatorial array chemistry and had an attractive in vitro and in vivo pharmacokinetic profile in rat. These ligands may prove useful in establishing a role for GPR40 in insulin regulation.
Assuntos
Ácidos Carboxílicos/síntese química , Ácidos Carboxílicos/farmacologia , Receptores Acoplados a Proteínas G/agonistas , Animais , Disponibilidade Biológica , Células CHO , Ácidos Carboxílicos/farmacocinética , Fenômenos Químicos , Físico-Química , Cricetinae , Cricetulus , Avaliação Pré-Clínica de Medicamentos , Indicadores e Reagentes , Ligantes , Ligação Proteica , Ratos , Relação Estrutura-AtividadeRESUMO
A novel series of pyrazolo[3,4-b]pyridines has been identified that are potent inhibitors of glycogen synthase kinase-3 (GSK-3).
Assuntos
Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Pirazóis/síntese química , Piridinas/síntese química , Quinase 3 da Glicogênio Sintase/química , Pirazóis/química , Piridinas/química , Relação Estrutura-AtividadeRESUMO
Introduction of a nitrogen atom into the 6-position of a series of pyrazolo[3,4-b]pyridines led to a dramatic improvement in the potency of GSK-3 inhibition. Rationalisation of the binding mode suggested participation of a putative structural water molecule, which was subsequently confirmed by X-ray crystallography.
Assuntos
Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Pirazóis/síntese química , Piridazinas/síntese química , Modelos Moleculares , Pirazóis/química , Piridazinas/química , Relação Estrutura-AtividadeRESUMO
Modification of the pyrimidone 5-substituent in clinical candidate SB-435495 has given a series of inhibitors of recombinant lipoprotein-associated phospholipase A(2) with sub-nanomolar potency. Cyclopentyl fused derivative 21, SB-480848, showed an enhanced in vitro and in vivo profile versus SB-435495 and has been selected for progression to man.
Assuntos
Inibidores Enzimáticos/farmacologia , Fosfolipases A/antagonistas & inibidores , Pirimidinonas/farmacologia , 1-Alquil-2-acetilglicerofosfocolina Esterase , Animais , Inibidores do Citocromo P-450 CYP2D6 , Inibidores Enzimáticos/química , Humanos , Técnicas In Vitro , Cinética , Fosfolipases A/sangue , Fosfolipases A2 , Pirimidinonas/química , Coelhos , Proteínas Recombinantes/antagonistas & inibidoresRESUMO
The introduction of a functionalised amido substituent into a series of 1-(biphenylmethylacetamido)-pyrimidones has given a series of inhibitors of recombinant lipoprotein-associated phospholipase A(2) with sub-nanomolar potency and very encouraging developability properties. Diethylaminoethyl derivative 32, SB-435495, was selected for progression to man.
Assuntos
Compostos de Bifenilo/farmacologia , Inibidores Enzimáticos/farmacologia , Lipoproteínas/metabolismo , Fosfolipases A/antagonistas & inibidores , Pirimidinonas/farmacologia , Administração Oral , Animais , Compostos de Bifenilo/administração & dosagem , Compostos de Bifenilo/química , Compostos de Bifenilo/metabolismo , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Humanos , Fosfolipases A/metabolismo , Pirimidinonas/administração & dosagem , Pirimidinonas/química , Pirimidinonas/metabolismo , Coelhos , Relação Estrutura-AtividadeRESUMO
A series of 1-(biphenylmethylamidoalkyl)-pyrimidones has been designed as nanomolar inhibitors of recombinant lipoprotein-associated phospholipase A(2) with high potency in whole human plasma. 5-(Pyrazolylmethyl) derivative 16 and 5-(methoxypyrimidinylmethyl) derivative 27 demonstrated excellent pharmacodynamic profiles which correlated well with their pharmacokinetic effects.