RESUMO
The SAR of the lead compound 3, a novel ligand for the alpha(2)delta subunit of voltage-gated calcium channels, was rapidly explored. Utilizing a parallel solution-phase Sn2Ar coupling approach, a focused library was obtained. The library was evaluated in vitro and afforded a series of analogues with improved potencies. The SAR trends of the library are also described.
Assuntos
Canais de Cálcio/metabolismo , Técnicas de Química Combinatória/métodos , Ativação do Canal Iônico , Subunidades Proteicas/metabolismo , Canais de Cálcio/química , Canais de Cálcio/efeitos dos fármacos , Humanos , Ligantes , Subunidades Proteicas/química , Soluções/química , Relação Estrutura-AtividadeRESUMO
The SAR of the lead compounds 2a and 2b was rapidly explored. Utilizing a parallel solution-phase Suzuki coupling approach, in tandem with strong cation exchange resin (SCX) purification afforded the desired focused library. The library was evaluated in vitro, a ninefold potency increase was achieved and the preference for ortho substitution of moderate steric bulk of the fourth, phenyl ring was identified. In addition, dimethylisoxazole, as a heterocyclic replacement for the phenylic ring of the lead compound, was also identified by this approach.
Assuntos
Isoxazóis , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Técnicas de Química Combinatória/métodos , Isoxazóis/síntese química , Isoxazóis/química , Isoxazóis/farmacologia , Estrutura Molecular , Receptor de Glutamato Metabotrópico 5 , Soluções/química , Relação Estrutura-AtividadeRESUMO
A novel class of 2H-pyrrolo[3,4-c]pyridazine ligands of the alpha (2) delta subunit of voltage-gated calcium channels is described. Compound 4a with high affinity toward alpha (2) delta was identified through structure-activity relationship studies of the lead compound. Tritiated ligand [(3)H]-4b was synthesized to demonstrate that this ligand binds to the same site as Gabapentin toward alpha (2) delta subunit of voltage-gated calcium channels.
Assuntos
Canais de Cálcio/efeitos dos fármacos , Ativação do Canal Iônico , Piridazinas/síntese química , Piridazinas/farmacologia , Avaliação Pré-Clínica de Medicamentos , Ligantes , Piridazinas/química , Relação Estrutura-AtividadeRESUMO
A novel class of 6-aryl-6H-pyrrolo[3,4-d]pyridazine ligands for the alpha2delta subunit of voltage-gated calcium channels has been described. Substitutions in the aryl ring of the molecule were generally not tolerated, and resulted in diminished binding to the alpha2delta subunit. Modifications to the pyridazine ring revealed numerous permissive substitutions, and detailed SAR studies were carried out in this portion of the molecule. Replacement of the pyridazine ring methyl group with an aminomethyl functionality provided greatly improved potency over the initial lead. The initial lead compound displayed good rat pharmacokinetic properties, and was shown to be efficacious in the Chung model for neuropathic pain in rats.