RESUMO
A novel series of AMPAR positive modulators is described that were identified by high throughput screening. The molecules of the series have been optimized from a high quality starting point hit to afford excellent developability, tolerability, and efficacy profiles, leading to identification of a clinical candidate. Unusually for an ion channel target, this optimization was integrated with regular generation of ligand-bound crystal structures and uncovered a novel chemotype with a unique and highly conserved mode of interaction via a trifluoromethyl group.
Assuntos
Indazóis/síntese química , Receptores de AMPA/fisiologia , Regulação Alostérica , Animais , Cálcio/metabolismo , Cristalografia por Raios X , Cães , Ensaios de Triagem em Larga Escala , Humanos , Técnicas In Vitro , Indazóis/farmacocinética , Indazóis/farmacologia , Ligantes , Macaca fascicularis , Masculino , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Conformação Molecular , Técnicas de Patch-Clamp , Multimerização Proteica , Ratos , Ratos Sprague-Dawley , Receptores de AMPA/química , Proteínas Recombinantes/química , Solubilidade , Relação Estrutura-Atividade , Suínos , Porco MiniaturaRESUMO
Following the discovery of 4-(substituted amino)-1-alkyl-pyrazolo[3,4-b]pyridine-5-carboxamides as potent and selective phosphodiesterase 4B inhibitors, [Hamblin, J. N.; Angell, T.; Ballentine, S., et al. Bioorg. Med. Chem. Lett.2008, 18, 4237] the SAR of the 5-position was investigated further. A range of substituted heterocycles showed good potencies against PDE4. Optimisation using X-ray crystallography and computational modelling led to the discovery of 16, with sub-nM inhibition of LPS-induced TNF-α production from isolated human peripheral blood mononuclear cells.
Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/química , Compostos Heterocíclicos/química , Inibidores de Fosfodiesterase/química , Pirazóis/química , Piridinas/química , Sítios de Ligação , Simulação por Computador , Cristalografia por Raios X , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Humanos , Modelos Químicos , Modelos Moleculares , Inibidores de Fosfodiesterase/síntese química , Inibidores de Fosfodiesterase/farmacologia , Estrutura Terciária de Proteína , Pirazóis/síntese química , Pirazóis/farmacologia , Piridinas/síntese química , Piridinas/farmacologia , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/metabolismoRESUMO
A series of AMPA receptor positive allosteric modulators has been optimized from poorly penetrant leads to identify molecules with excellent preclinical pharmacokinetics and CNS penetration. These discoveries led to 17i, a potent, efficacious CNS penetrant molecule with an excellent pharmacokinetic profile across preclinical species, which is well tolerated and is also orally bioavailable in humans.
Assuntos
Indenos/síntese química , Piridinas/síntese química , Receptores de AMPA/fisiologia , Sulfonamidas/síntese química , Administração Oral , Regulação Alostérica , Animais , Disponibilidade Biológica , Proteínas Sanguíneas/metabolismo , Barreira Hematoencefálica/metabolismo , Callithrix , Linhagem Celular , Cristalografia por Raios X , Cães , Humanos , Indenos/farmacocinética , Indenos/farmacologia , Macaca fascicularis , Masculino , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Ligação Proteica , Estrutura Terciária de Proteína , Piridinas/farmacocinética , Piridinas/farmacologia , Ratos , Ratos Sprague-Dawley , Especificidade da Espécie , Estereoisomerismo , Relação Estrutura-Atividade , Sulfonamidas/farmacocinética , Sulfonamidas/farmacologiaRESUMO
Crystallography driven optimisation of a lead derived from similarity searching of the GSK compound collection resulted in the discovery of quinoline-3-carboxamides as highly potent and selective inhibitors of phosphodiesterase 4B. This series has been optimized to GSK256066, a potent PDE4B inhibitor which also inhibits LPS induced production of TNF-alpha from isolated human peripheral blood mononuclear cells with a pIC(50) of 11.1. GSK256066 also has a suitable profile for inhaled dosing.
Assuntos
Anti-Inflamatórios/química , Inibidores da Fosfodiesterase 4 , Inibidores de Fosfodiesterase/química , Quinolinas/química , Administração por Inalação , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/farmacocinética , Sítios de Ligação , Domínio Catalítico , Cristalografia por Raios X , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Humanos , Leucócitos Mononucleares/metabolismo , Lipopolissacarídeos/farmacologia , Inibidores de Fosfodiesterase/síntese química , Inibidores de Fosfodiesterase/farmacocinética , Quinolinas/síntese química , Quinolinas/farmacocinética , Ratos , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/metabolismoRESUMO
A PDE4B over 4D-selective inhibitor programme was initiated to capitalise on the recently discovered predominance of the PDE4B subtype in inflammatory cell regulation. The SAR of a tetrahydrobenzothiophene (THBT) series did not agree with either of two proposed docking modes in the 4B binding site. A subsequent X-ray co-crystal structure determination revealed that the THBT ligand displaces the Gln-443 residue, invariably ligand-anchoring in previous PDE4 co-crystal structures, and even shifts helix-15 by 1-2A. For the first time, several residues of the C-terminus previously proposed to be involved in subtype selectivity are resolved and three of them extend into the ligand binding site potentially allowing for selective drug design.
Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Inibidores da Fosfodiesterase 4 , Tiofenos/química , Tiofenos/metabolismo , Sequência de Aminoácidos , Sítios de Ligação , Cristalografia por Raios X , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/química , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/genética , Humanos , Modelos Moleculares , Estrutura Molecular , Mutação , Ligação Proteica , Conformação Proteica , Relação Estrutura-AtividadeRESUMO
Optimisation of a high-throughput screening hit resulted in the discovery of 4-(substituted amino)-1-alkyl-pyrazolo[3,4-b]pyridine-5-carboxamides as potent and selective inhibitors of Phosphodiesterase 4 (PDE4). Herein, we describe early SAR studies around this novel template highlighting preferred substituents and rationalization of SAR through X-ray crystal structures of analogues bound to the PDE4 active site. Pyrazolopyridine 20a was found to be a potent and selective PDE4 inhibitor which also inhibits LPS induced TNF-alpha production from isolated human peripheral blood mononuclear cells and has an encouraging rat PK profile suitable for oral dosing.