RESUMO
Hit-to-lead optimization of a HTS hit led to new carbamoyloxime derivatives. After identification of an advanced hit (8d) the CYP enzyme inhibitory activity of this class of compounds was successfully eliminated. Systematic exploration of different parts of the advanced hit led us to some promising lead compounds with mGluR5 affinities comparable to that of MPEP.
Assuntos
Carbamatos/química , Oximas/química , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Animais , Carbamatos/síntese química , Carbamatos/farmacologia , Ensaios de Triagem em Larga Escala , Oximas/síntese química , Oximas/farmacologia , Piridinas/química , Piridinas/farmacologia , Ratos , Receptor de Glutamato Metabotrópico 5 , Receptores de Glutamato Metabotrópico/metabolismo , Especificidade por SubstratoRESUMO
Here we report the discovery and early SAR of a series of mGluR5 negative allosteric modulators (NAMs). Starting from a moderately active HTS hit we synthesized 3,5-disubstituted-oxadiazoles and tetrazoles as mGluR5 NAMs. Based on the analysis of ligand efficiency and lipophilic efficiency metrics we identified a promising lead candidate as a starting point for further optimization.
Assuntos
Regulação Alostérica/efeitos dos fármacos , Oxidiazóis/síntese química , Receptores de Glutamato Metabotrópico/efeitos dos fármacos , Tetrazóis/síntese química , Animais , Descoberta de Drogas , Humanos , Ligantes , Oxidiazóis/química , Oxidiazóis/farmacologia , Receptor de Glutamato Metabotrópico 5 , Relação Estrutura-Atividade , Tetrazóis/química , Tetrazóis/farmacologiaRESUMO
A high throughput luminescent assay based on the Kinase-Glo() system (Promega, Madison, WI) has been developed for screening against glycogen synthase kinase-3beta (GSK-3beta). Careful optimization of assay parameters allowed us to develop a robust, reproducible, and sensitive assay. Its usefulness has been demonstrated in a high throughput screening run when screening 55,000 compounds. This campaign yielded five chemical classes of hits, including several highly potent GSK-3beta inhibitors.
Assuntos
Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Medições Luminescentes/métodos , Inibidores de Proteínas Quinases/análise , Inibidores de Proteínas Quinases/química , Linhagem Celular , Glicogênio Sintase Quinase 3 betaRESUMO
Negative allosteric modulators (NAM) of metabotropic glutamate receptor 5 (mGluR5) have been implicated as a potential pharmacotherapy for a number of psychiatric diseases, including anxiety and depression. Most of the mGluR5 NAM clinical candidates can be characterized by the central acetylenic moiety that connects the terminal pharmacophores. Identification of a sulfoquinoline hit via high throughput screening (HTS) followed by optimization provided a 4-phenyl-3-aryl-sulfoquinoline lead compound with the minimal pharmacophore. Optimization of the core and aryl appendages was performed by scanning and matrix libraries synthesized by the multiple parallel synthesis approach. Biological evaluation of matrix libraries provided a number of potent, metabolically stable, and in vivo active compounds. One of these compounds, 25 showed high efficacy and safety in preclinical in vivo models; this allowed its nomination as a novel, nonacetylenic mGluR5 NAM clinical candidate. Compound 25 was advanced to first-in-man trials for the treatment of psychiatric conditions.
Assuntos
Ansiolíticos/química , Ansiolíticos/farmacologia , Nitrilas/química , Nitrilas/farmacologia , Quinolinas/química , Quinolinas/farmacologia , Receptor de Glutamato Metabotrópico 5/metabolismo , Regulação Alostérica/efeitos dos fármacos , Animais , Ansiolíticos/uso terapêutico , Cães , Feminino , Halogenação , Humanos , Macaca fascicularis , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Simulação de Acoplamento Molecular , Nitrilas/uso terapêutico , Quinolinas/uso terapêutico , RatosRESUMO
Negative allosteric modulators of metabotropic glutamate receptor 5 (mGlu5) showed efficacy in a number of animal models of different CNS diseases including anxiety and depression. Virtually all of the compounds which reached the clinic belong to the same chemotype having an acetylenic linker that connects (hetero)cyclic moieties. Searching for new chemotypes we identified a morpholino-sulfoquinoline derivative (1) by screening our corporate compound deck. The HTS hit showed reasonable affinity and selectivity towards mGlu5 receptors, however, its inferior metabolic stability prevented its testing in vivo. In a chemical program we aimed to improve the affinity, physicochemical properties and metabolic stability exploring three regions of the hit. Systematic variation of different amines at position 4 (region I) led to the identification of 4-methyl-piperidinyl analogues. Substituents of the quinoline core (region II) and the phenylsulfonyl moiety (region III) were mapped by parallel synthesis. Evaluation of both morpholino- and 4-methyl-piperidinyl-sulfoquinoline libraries of about 270 derivatives revealed beneficial substituent combinations in regions II and III. Blood levels of optimized 4-methyl-piperidinyl-sulfoquinolines, however, were still insufficient for robust in vivo efficacy. Finally, introducing 4-hydoxymethyl-piperidinyl substituent to region I resulted in new sulfoquinolines with greatly improved solubility and reasonable affinity coupled with affordable metabolic stability. The most promising analogues (24 and 25) showed high blood levels and demonstrated significant efficacy in the experimental model of anxiety.
Assuntos
Quinolinas/química , Quinolinas/farmacologia , Receptor de Glutamato Metabotrópico 5/antagonistas & inibidores , Receptor de Glutamato Metabotrópico 5/metabolismo , Regulação Alostérica/efeitos dos fármacos , Aminação , Animais , Humanos , Piperazinas/química , Piperazinas/farmacologia , Ratos WistarRESUMO
Metalloporphyrin catalyzed biomimetic oxidation was used for the identification of nitric oxide (NO) donors with diverse chemical structure. Methodology was validated by testing known NO donors. Efficient automation of the test allowed us to investigate a subset of our corporate library. Several hits identified in this campaign were validated in both the chemical and also microsomal model that revealed all hits to be active in the biological system, as well. One of the hits showed comparable activity to V-PYRRO/NO, the prototypic liver selective NO donor.
Assuntos
Avaliação Pré-Clínica de Medicamentos/métodos , Doadores de Óxido Nítrico/farmacologia , Animais , Biomimética , Técnicas de Química Combinatória , Peróxido de Hidrogênio/metabolismo , Masculino , Metaloporfirinas/química , Metaloporfirinas/metabolismo , Metaloporfirinas/farmacologia , Microssomos Hepáticos , Ratos , Ratos Wistar , Reprodutibilidade dos TestesRESUMO
A novel series of arylsulfonamides was prepared either by automated parallel or by traditional solution-phase synthesis. Several members of this compound library were identified as high-affinity dopamine D3 and D2 receptor ligands. The most interesting representative, compound 2, showed potent antipsychotic behaviour coupled with a beneficial cognitive and EPS profile.
Assuntos
Antipsicóticos/síntese química , Antipsicóticos/farmacologia , Cognição/efeitos dos fármacos , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D3/metabolismo , Sulfonamidas/síntese química , Sulfonamidas/farmacologia , Animais , Antipsicóticos/metabolismo , Apomorfina/farmacologia , Aprendizagem da Esquiva/efeitos dos fármacos , Ligação Competitiva/efeitos dos fármacos , Disponibilidade Biológica , Encéfalo/metabolismo , Catalepsia/induzido quimicamente , Humanos , Indicadores e Reagentes , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Transtornos da Memória/induzido quimicamente , Relação Quantitativa Estrutura-Atividade , Ratos , Ratos Wistar , Comportamento Estereotipado/efeitos dos fármacos , Sulfonamidas/metabolismoRESUMO
A readily automated solid-phase approach to the synthesis of diverse N-(phenylalkyl)cinnamides, analogues of the NR2B antagonist 2, is described. The procedure utilizes polymer supported N-(phenylalkyl)amines, (diethylphosphono)acetic acid and a wide range of commercially available hydroxybenzaldehydes. The key step, a Horner-Wadsworth-Emmons reaction is achieved under mild conditions and was found to be general for a large number of benzaldehydes. A 225-member focused library was synthesized using a Tecan Combitec synthesizer.
Assuntos
Cinamatos/síntese química , Antagonistas de Aminoácidos Excitatórios/síntese química , Indicadores e Reagentes , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Relação Estrutura-AtividadeRESUMO
A novel series of indole-2-carboxamide derivatives was prepared and identified as NR2B selective NMDA receptor antagonists. The influence of the number and position of OH groups on the indole skeleton as well as the substitution of the piperidine ring on the biological activity of the compounds was studied.