RESUMO
Vasopressin 1b (V1b) antagonists have been postulated as possible treatments for depression and anxiety. A novel series of potent and selective V1b antagonists has been identified starting from an in-house screen hit. The incorporation of a sulfonamide linker between a tetrahydroisoquinoline core and amino piperidine lead to the identification of a V1b antagonist with similar affinity for human and rat receptors. Further optimization of the right hand portion afforded potent V1b antagonists that possessed moderate to high selectivity over other receptors.
Assuntos
Antidiuréticos/química , Antagonistas dos Receptores de Hormônios Antidiuréticos , Quinolinas/química , Sulfonamidas/química , Animais , Antidiuréticos/síntese química , Antidiuréticos/farmacologia , Humanos , Quinolinas/síntese química , Quinolinas/farmacologia , Ratos , Receptores de Ocitocina/antagonistas & inibidores , Receptores de Ocitocina/metabolismo , Receptores de Vasopressinas/metabolismo , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/farmacologiaRESUMO
A series of non-imidazole histamine H(3) receptor antagonists based on the (3-phenoxypropyl)amine motif, which is a common pharmacophore for H(3) antagonists, has been identified. A preliminary SAR study around the amine moiety has identified 8a as a potent H(3) antagonist possessing a good pharmacokinetic profile in the rat.
Assuntos
Aminas/síntese química , Aminas/farmacologia , Benzimidazóis/síntese química , Benzimidazóis/farmacologia , Receptores Histamínicos H3/efeitos dos fármacos , Aminas/química , Animais , Benzimidazóis/química , Técnicas de Química Combinatória , Estrutura Molecular , Ratos , Relação Estrutura-AtividadeRESUMO
A novel methodology for parallel liquid-phase synthesis of carbamates suitable for the preparation of sterically hindered molecules is disclosed. The alcohols are converted to 4-nitrophenylcarbonates, followed by the reaction with amines. Side product 4-nitrophenol and the unreacted excess amines are scavenged by appropriately chosen cleanup resins, selected among Amberlyst A26 (hydroxide form) and macroporous sulfonic acid (MP-TsOH) or polystyrene isocyanate (PS-NCO) and polystyrene benzaldehyde (PS-PhCHO) resins. As a part of a medicinal chemistry program directed toward finding gamma-secretase inhibitors as prospective drug candidates for Alzheimer's disease, a 6 x 24 library of carbamates was prepared. Out of 144 library members, 133 had a purity for the targeted compound of 80% or better. The prepared compounds were assessed in the gamma-secretase inhibition assay and demonstrated activity with IC 50 values in the range from 1 microM to 5 nM, with the activity of 7 compounds being better than 10 nM.
Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Carbamatos , Técnicas de Química Combinatória , Inibidores Enzimáticos , Bibliotecas de Moléculas Pequenas , Precursor de Proteína beta-Amiloide/biossíntese , Precursor de Proteína beta-Amiloide/genética , Carbamatos/síntese química , Carbamatos/química , Carbamatos/farmacologia , Linhagem Celular , Membrana Celular/efeitos dos fármacos , Membrana Celular/enzimologia , Membrana Celular/metabolismo , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Humanos , Estrutura Molecular , Mutação , Transição de Fase , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Soluções , Relação Estrutura-AtividadeRESUMO
A novel piperidine series of gamma-secretase inhibitors, potentially useful for the treatment of Alzheimer's disease, is disclosed. SAR investigation revealed the requirement for cis-stereochemistry of the substituents attached to the core, which resulted in the chair-like diaxial conformation of the piperidine ring. The series was optimized to provide inhibitors with IC(50)'s in the single-digit nanomolar range. Absolute stereochemistry of the active enantiomer was assigned.
