RESUMO
The structure-activity relationships of new Aurora A/B kinase inhibitors derived from the previously identified kinase inhibitor 12 are described. Introduction of acetic acid amides onto the pyrazole of compound 12 was postulated to influence Aurora A/B selectivity and improve the profile against off-target kinases. The SAR of the acetic acid amides was explored and the effect of substitution on enzyme inhibition as well as mechanism-based cell activity was studied. Additionally, several of the more potent inhibitors were screened for their off-target kinase selectivity.
Assuntos
Imidazóis/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Pirazinas/farmacologia , Aurora Quinases , Cristalografia por Raios X , Modelos Moleculares , Relação Estrutura-AtividadeRESUMO
A new class of 2-substituted benzoxazole carboxamides are presented as potent functional 5-HT(3) receptor antagonists. The chemical series possesses nanomolar in vitro activity against human 5-HT(3)A receptors. A chemistry optimization program was conducted and identified 2-aminobenzoxazoles as orally active 5-HT(3) receptor antagonists with good metabolic stability. These novel analogues possess drug-like characteristics and have potential utility for the treatment of diseases attributable to improper 5-HT(3) receptor function, especially diarrhea predominant irritable bowel syndrome (IBS-D).
Assuntos
Benzoxazóis/química , Benzoxazóis/farmacologia , Descoberta de Drogas , Receptores 5-HT3 de Serotonina/efeitos dos fármacos , Antagonistas da Serotonina/química , Antagonistas da Serotonina/farmacologiaRESUMO
A concise total synthesis of enantiopure circumdatins E, H and J has been developed using a reductive cyclization of chiral N-prolinoyl-2-nitrobenzamides to construct the core quinazolinone ring.
Assuntos
Benzodiazepinonas/química , Benzodiazepinonas/síntese química , Quinazolinonas/síntese química , Quinazolinonas/química , Estereoisomerismo , Especificidade por SubstratoRESUMO
N,N-Dimethylformamidine and novel N,N-diisopropylformamidine protecting groups were used to carry out a one-pot conversion of aminobenzoic acids into the corresponding amides. General conditions for an in situ transformation of aminobenzoic acids and their heterocyclic analogues into the corresponding formamidine-protected acid chlorides were developed. These chlorides were used in reactions with amines, including poorly reactive anilines. The protected amides were then smoothly deprotected by heating with ethylenediamine derivatives, resulting in a general procedure for the one-pot transformation of aminobenzoic acids into their amides. Our one-pot procedure was successfully applied to the preparation of several compounds of pharmaceutical interest.