RESUMO
The nonselective glucocorticoid receptor (GR) antagonist mifepristone has been approved in the U.S. for the treatment of selected patients with Cushing's syndrome. While this drug is highly effective, lack of selectivity for GR leads to unwanted side effects in some patients. Optimization of the previously described fused azadecalin series of selective GR antagonists led to the identification of CORT125134, which is currently being evaluated in a phase 2 clinical study in patients with Cushing's syndrome.
Assuntos
Receptores de Glucocorticoides/antagonistas & inibidores , Animais , Cromatografia Líquida , Células Hep G2 , Humanos , Espectrometria de MassasRESUMO
We report the further optimization of our series 1H-pyrazolo[3,4-g]hexahydro-isoquinoline sulfonamides as GR antagonists. By incorporating a heteroaryl ketone group at the ring junction, we have obtained compounds with excellent functional GR antagonism. Optimization of the sulfonamide substituent has provided compounds with a very desirable overall profile, including minimal hERG activity, good bioavailability and in vivo efficacy.
Assuntos
Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Isoquinolinas/química , Receptores de Glucocorticoides/antagonistas & inibidores , Animais , Sítios de Ligação , Domínio Catalítico , Linhagem Celular , Canal de Potássio ERG1 , Canais de Potássio Éter-A-Go-Go/metabolismo , Células Hep G2 , Humanos , Isoquinolinas/metabolismo , Simulação de Acoplamento Molecular , Ligação Proteica , Pirazóis/química , Ratos , Receptores de Glucocorticoides/metabolismo , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/metabolismoRESUMO
Annulation of ynamides with arylboronic acids or esters containing an electrophilic functional group at the ortho-position proceeds under the action of rhodium catalysis to generate 2-amidoindenols or 2-amidoindenes, usually with good regioselectivity.
Assuntos
Alcinos/química , Ácidos Borônicos/química , Indenos/síntese química , Ródio/química , Catálise , Ciclização , Ésteres , Indenos/química , Estrutura MolecularRESUMO
Rhodium-catalyzed carbozincation of ynamides using diorganozinc reagents or functionalized organozinc halides is described. Using a tri(2-furyl)phosphine-modified rhodium catalyst, the reaction course is altered to hydrozincation when diethylzinc is employed as the organozinc reagent. Trapping of the alkenylzinc intermediates produced in these reactions in further functionalization reactions is possible. Collectively, these processes enable access to a range of multisubstituted enamides in stereo- and regiocontrolled fashion.
Assuntos
Alcinos/química , Amidas/química , Ródio/química , Zinco/química , Catálise , Estrutura MolecularRESUMO
A new rhodium-catalyzed carbozincation of ynamides has been developed, using diorganozinc reagents or functionalized alkylzinc halides. The reactions are highly regio- and stereoselective, allowing access to a wide range of multisubstituted enamides, which are increasingly important building blocks for organic synthesis. Utilization of the alkenylzinc intermediates in further carbon-carbon bond-forming reactions to form trisubstituted enamides is also possible.