In this work, we synthesized achiral derivatives of five profen scaffolds and evaluated them for substrate-selective inhibition using in vitro and cellular assays. selleck chemical The selleck size of the substituents dictated the inhibitory strength of the analogs, with smaller substituents enabling greater potency but less selectivity. Inhibitors based on the flurbiprofen scaffold Inhibitors,Modulators,Libraries possessed the greatest potency and selectivity, with desmethylflurbiprofen (3a) exhibiting an IC50 of 0.11 mu M for inhibition of 2-AG oxygenation. The crystal structure of desmethylflurbiprofen complexed to mCOX-2 demonstrated a similar binding mode to other profens. Desmethylflurbiprofen exhibited a half-life in mice comparable to that of ibuprofen.
The data presented suggest that achiral profens can act as lead molecules toward in vivo probes of substrate-selective COX-2 inhibition.
3-[4-((1S,2S,3R,5S,7S)-5-Hydroxyadamantan-2-ylcarbamoyl)benzyl]-4-oxo-1-phenyl-1,4-dihydro-[1,8]naphthyridine-2-carboxylic Inhibitors,Modulators,Libraries Inhibitors,Modulators,Libraries acid methyl ester (4) was identified as a novel, druglike and selective quinolone pan JNK inhibitor. In this communication, some of the structure activity relationship of the azaquinolone analogues leading to 4 Inhibitors,Modulators,Libraries is discussed. The focus is on how changes at the amide functionality affected the biochemical potency, cellular potency, metabolic properties, and solubility of this class of JNK Inhibitors,Modulators,Libraries inhibitors. Optimization of these properties led to the identification of the adamantyl analogue, 4. 4 achieved proof of mechanism in both rat and mouse TNF-alpha challenge models.
Guided by computational methods, a set of 1920 compounds were selected from the AstraZeneca Inhibitors,Modulators,Libraries corporate collection and screened for Kv1.5 activity. To facilitate rapid generation of structure activity relationships, special attention Inhibitors,Modulators,Libraries was given to selecting subsets of structurally similar molecules by using a maximum common substructure similarity-based procedure. The focused screen hit rate was relatively high (12%). More importantly, a structural series featured by the symmetric 1,2-diphenylethane-1,2-diamine substructure was identified as potent Kv.1.5 blockers. The property profile for the series is shown to meet stringent lead-optimization criteria, providing a springboard for the development of a new and safe treatment for atrial fibrillation.
Exchange of the lipophilc part of ortho-substituted cinnamic Inhibitors,Modulators,Libraries acid lead structures with different small molecule fluorophoric moieties via a dimethylene Inhibitors,Modulators,Libraries spacer resulted in hEP(3)R ligands selleck chemicals with affinities in the nanomolar concentration range. Synthesized compounds emit fluorescence in the Inhibitors,Modulators,Libraries blue, green, and red range of light and have been tested concerning their potential as a pharmacological tool. hEP(3)Rs were visualized by confocal selelck kinase inhibitor laser scanning microscopy on HT-29 cells, on murine kidney tissues, and on human brain tissues and functionally were characterized as antagonists on human platelets.