848472-26-4Relevant articles and documents
Generation of Highly Selective, Potent, and Covalent G Protein-Coupled Receptor Kinase 5 Inhibitors
Rowlands, Rachel A.,Chen, Qiuyan,Bouley, Renee A.,Avramova, Larisa V.,Tesmer, John J. G.,White, Andrew D.
, p. 566 - 585 (2021)
The ability of G protein-coupled receptor (GPCR) kinases (GRKs) to regulate the desensitization of GPCRs has made GRK2 and GRK5 attractive targets for treating diseases such as heart failure and cancer. Previously, our work showed that Cys474, a GRK5 subfamily-specific residue located on a flexible loop adjacent to the active site, can be used as a covalent handle to achieve selective inhibition of GRK5 over GRK2 subfamily members. However, the potency of the most selective inhibitors remained modest. Herein, we describe a successful campaign to adapt an indolinone scaffold with covalent warheads, resulting in a series of 2-haloacetyl-containing compounds that react quickly and exhibit three orders of magnitude selectivity for GRK5 over GRK2 and low nanomolar potency. They however retain a similar selectivity profile across the kinome as the core scaffold, which was based on Sunitinib.
NEW COMPOUNDS
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Page/Page column 48, (2008/06/13)
The present invention relates to new compounds of formula Ia or Ib wherein P represents a 5- or 6-membered heteroaromatic ring containing one or two heteroatoms selected independently from N, O and S of which at least one heteroatom is nitrogen; R is hydrogen; R is selected from: C1-6alkyl, cyano, halogen, (CO)OR, and CONRR; R is selected from: C1-6alkyl, cyano, nitro, (CO)OR, C1-6alkylNRR, OC2-6alkylNRR, CONRR, and (SO2)NRR; m is 0, 1, 2, 3 or 4; n is 0, 1, 2, 3 or 4; as a free base or a salt thereof, a process for their preparation and new intermediates used therein, pharmaceutical formulations containing said therapeutically active compounds and to the use of said active compounds in therapy.
