RESUMO
The synthesis and preliminary structure-activity relationships (SAR) of a novel class of vasopressin V(1B) receptor antagonists are described. Hit compound 5, identified via high throughput screening of the corporate collection, showed good activity in a V(1B) binding assay (K(i) 63 nM) but did not possess the lead-like physicochemical properties typically required in a hit compound. A 'deletion approach' on the HTS hit 5 was performed, with the focus on improvement of physicochemical properties, yielding the selective V(1B) antagonist 9f (K(i) 190 nM), with improved druglike characteristics.
Assuntos
Antagonistas dos Receptores de Hormônios Antidiuréticos , Sulfonamidas/síntese química , Sulfonamidas/farmacologia , Estrutura Molecular , Ligação Proteica/efeitos dos fármacos , Relação Estrutura-Atividade , Sulfonamidas/químicaRESUMO
Synthesis and structure-activity relationships (SAR) of a novel series of vasopressin V(1b) (V(3)) antagonists are described. 2-(4-Oxo-2-aryl-quinazolin-3(4H)-yl)acetamides have been identified with low nanomolar affinity for the V(1b) receptor and good selectivity with respect to related receptors V(1a), V(2) and oxytocin (OT). Optimised compound 12j demonstrates a good pharmacokinetic profile and activity in a mechanistic model of HPA dysfunction.
Assuntos
Antagonistas dos Receptores de Hormônios Antidiuréticos , Quinazolinas/síntese química , Quinazolinas/farmacologia , Animais , Humanos , Quinazolinas/química , Quinazolinas/farmacocinética , Ratos , Relação Estrutura-AtividadeRESUMO
High-throughput screening of 3.87 million compounds delivered a novel series of non-steroidal GR antagonists. Subsequent rounds of optimisation allowed progression from a non-selective ligand with a poor ADMET profile to an orally bioavailable, selective, stable, glucocorticoid receptor antagonist.
Assuntos
Receptores de Glucocorticoides/antagonistas & inibidores , Animais , Avaliação Pré-Clínica de Medicamentos , Ensaios de Triagem em Larga Escala , Humanos , Hidrocortisona/química , Microssomos/metabolismo , Ratos , Receptores de Glucocorticoides/metabolismo , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química , Sulfonamidas/farmacocinéticaRESUMO
The discovery, synthesis, and preliminary structure-activity relationship (SAR) of a novel class of vasopressin V3 (V1b) receptor antagonists is described. Compound 1, identified by high throughput screening of a diverse, three million-member compound collection, prepared using ECLiPS technology, had good activity in a V3 binding assay (IC50=0.20 microM), but less than desirable physicochemical properties. Optimization of compound 1 yielded potent analogs 19 (IC50=0.31 microM) and 24 (IC50=0.12 microM) with improved drug-like characteristics.
Assuntos
Acetamidas/química , Acetamidas/farmacologia , Antagonistas dos Receptores de Hormônios Antidiuréticos , Quinazolinas/química , Quinazolinas/farmacologia , Receptores de Vasopressinas/metabolismo , Acetamidas/síntese química , Animais , Transtorno Depressivo/tratamento farmacológico , Humanos , Quinazolinas/síntese química , Ratos , Relação Estrutura-AtividadeRESUMO
A study into the effect of reaction variables on the quaternization of REM resin-bound tertiary amines was undertaken. The influence of resin matrix, solvent, reaction time, temperature, and amount of quaternization agent on the outcome of reaction was evaluated by reaction monitoring using (19)F NMR. The highest yields of tertiary amine products were seen when DMSO was used as reaction solvent in conjunction with a reaction time of 18 h at room temperature. The use of heating for extended reaction times tended to depress yields, indicating product cleavage during quaternization. Quaternization on PS-DVB resin was found to be more robust than reaction on PS-PEG matrices where yields were generally considerably lower than the observed conversions. DMSO was the most efficient reaction solvent for both resins despite poor swelling of the quaternization starting material.
Assuntos
Aminas/síntese química , Técnicas de Química Combinatória/métodos , Aminação , Flúor , Espectroscopia de Ressonância Magnética , Resinas Sintéticas/química , Resinas Sintéticas/normas , Solventes/farmacologia , Temperatura , Fatores de TempoRESUMO
Structure-activity studies on benzamide 1 obtained from library screening led to the discovery of a novel series of potent and selective glycine transporter type-2 inhibitors.