1188265-73-7Relevant articles and documents
Structure-based design and pharmacokinetic optimization of covalent allosteric inhibitors of the mutant gtpase krasg12c
Kettle, Jason G.,Bagal, Sharan K.,Bickerton, Sue,Bodnarchuk, Michael S.,Breed, Jason,Carbajo, Rodrigo J.,Cassar, Doyle J.,Chakraborty, Atanu,Cosulich, Sabina,Cumming, Iain,Davies, Michael,Eatherton, Andrew,Evans, Laura,Feron, Lyman,Fillery, Shaun,Gleave, Emma S.,Goldberg, Frederick W.,Harlfinger, Stephanie,Hanson, Lyndsey,Howard, Martin,Howells, Rachel,Jackson, Anne,Kemmitt, Paul,Kingston, Jennifer K.,Lamont, Scott,Lewis, Hilary J.,Li, Songlei,Liu, Libin,Ogg, Derek,Phillips, Christopher,Polanski, Radek,Robb, Graeme,Robinson, David,Ross, Sarah,Smith, James M.,Tonge, Michael,Whiteley, Rebecca,Yang, Junsheng,Zhang, Longfei,Zhao, Xiliang
supporting information, p. 4468 - 4483 (2020/06/08)
Attempts to directly drug the important oncogene KRAS have met with limited success despite numerous efforts across industry and academia. The KRASG12C mutant represents an "Achilles heel" and has recently yielded to covalent targeting with small molecules that bind the mutant cysteine and create an allosteric pocket on GDP-bound RAS, locking it in an inactive state. A weak inhibitor at this site was optimized through conformational locking of a piperazine-quinazoline motif and linker modification. Subsequent introduction of a key methyl group to the piperazine resulted in enhancements in potency, permeability, clearance, and reactivity, leading to identification of a potent KRASG12C inhibitor with high selectivity and excellent cross-species pharmacokinetic parameters and in vivo efficacy.
Novel 6-fused heteroaryldihydropyrimidines for the treatment and prophylaxis of hepatitis B virus infection
-
Paragraph 0441; 0442; 0443, (2015/11/02)
The invention provides novel compounds having the general formula: wherein R1, R2, R3, R4, R5, R6, X, Y, W and n are as described herein, compositions including the compounds and methods of using the compounds.
INHIBITORS OF THE RENAL OUTER MEDULLARY POTASSIUM CHANNEL
-
Page/Page column 49, (2013/03/26)
The present invention provides compounds of Formula Ia and the pharmaceutically acceptable salts thereof, which are inhibitors of the ROMK (Kir1.1) channel. The compounds may be used as diuretic and/or natriuretic agents and for the therapy and prophylaxis of medical conditions including cardiovascular diseases such as hypertension, heart failure and conditions associated with excessive salt and water retention.