206551-23-7Relevant articles and documents
Rational design of selective inhibitors of PARP4
Cohen, Michael,Kirby, Ilsa T.,Person, Ashley
, p. 1950 - 1957 (2021/12/24)
PARPs (PARP1-16 in humans) are a large family of ADP-ribosyltransferases (ARTs) that have diverse roles in cellular physiology and pathophysiology. Most PARP family members mediate mono-ADP-ribosylation (MARylation) of targets. The function of PARP-mediated MARylation in cells is poorly characterized, due in large part to the paucity of selective small molecule inhibitors of the catalytic activity of individual PARP enzymes. Herein we describe the rational design of selective small molecule inhibitors of PARP4 (also known as vPARP). These inhibitors are based on a quinazolin-4(3H)-one scaffold, and contain substituents at the C-8 position designed to exploit a unique threonine (Thr484, human PARP4 numbering) in the PARP4 nicotinamide sub-pocket. Our most potent analog, AEP07, which contains an iodine at the C-8 position, is at least 12-fold selective over other PARP family members. AEP07 will serve as a useful lead compound for the further development of PARP4 inhibitors that can be used to probe the cellular functions of PARP4 catalytic activity. This journal is
Endothelin antagonists: Substituted mesitylcarboxamides with high potency and selectivity for ET(A) receptors
Wu, Chengde,Decker, E. Radford,Blok, Natalie,Bui, Huong,Chen, Qi,Raju,Bourgoyne, Andree R.,Knowles, Vippra,Biediger, Ronald J.,Market, Robert V.,Lin, Shuqun,Dupré, Brian,Kogan, Timothy P.,Holland, George W.,Brock, Tommy A.,Dixon, Richard A. F.
, p. 4485 - 4499 (2007/10/03)
We have previously disclosed the discovery of 2,4-disubstituted anilinothiophenesulfonamides with potent ET(A)-selective endothelin receptor antagonism and the subsequent identification of sitaxsentan (TBC11251, 1) as a clinical development compound (Wu et al. J. Med. Chem. 1997, 40, 1682 and 1690). The orally active 1 has demonstrated efficacy in a phase II clinical trial of congestive heart failure (Givertz et al. Circulation 1998, 98, Abstr. 3044) and was active in rat models of myocardial infarction (Podesser et al. Circulation 1998, 98, Abstr. 2896) and acute hypoxia-induced pulmonary hypertension (Chen et al. FASEB J. 1996, 10 (3), A104). We now report that an additional substituent at the 6-position of the anilino ring further increases the potency of this series of compounds. It was also found that a wide range of functionalities at the 3-position of the 2,4,6-trisubstituted ring increased ETA selectivity by ~10-fold while maintaining in vitro potency, therefore rendering the compounds amenable to fine-tuning of pharmacological and toxicological profiles with enhanced selectivity. The optimal compound in this series was found to be TBC2576 (7u), which has ~10- fold higher ETA binding affinity than 1, high ET(A)/ET(B) selectivity, and a serum half-life of 7.3 h in rats, as well as in vivo activity.
