Hit-to-lead studies: the discovery of potent, orally active, thiophenecarboxamide IKK-2 inhibitors

Chemical biology of inflammatory cytokine signaling

“…28 On the basis of the thiophenecarboxamide structure, more potent thiophenecarboxamide-type IKKb inhibitors, such as 2-((aminocarbonyl)amino)-5-(4-fluorophenyl)-3-thiophenecarboxamide (TPCA-1), as well as benzothieno(3,2-b)furan derivatives as novel IKKb inhibitors, have been developed independently by four individual groups. [29][30][31][32] The identification of a 2-amino-3-cyano-4-aryl-6-(2-hydroxyphenyl)pyridine analog as a lead compound by highthroughput screening assay and subsequent chemical optimization have led to the identification of 2-amino-6-(2-(cyclopropylmethoxy)-6-hydroxyphenyl)-4-piperadin-4-yl nicotinonitrile (ACHP) as a potent and selective IKKb inhibitor. [33][34][35] In the course of in vitro screening of a series of anilinopyrimidine derivatives and ATP competitors for their inhibitory effects on a constitutively active version of IKKb in which two serine residues within the activation loop of the catalytic domain are replaced with glutamic acids, AS602868 was identified to be a potent, reversible and ATP-competitive IKKb inhibitor, 36,37 and has been thus far used in various cell Chemical biology of inflammatory cytokine signaling T Kataoka types and animal models.…”

Effects of IKK inhibitor PS1145 on NF-κB function, proliferation, apoptosis and invasion activity in prostate carcinoma cells

“…Thus, IKKs, especially IKKb that is critical for NF-kB activation, represent a novel important target for NFkB blockage in PC and other tumor cells. Very recently, several pharmaceutical companies have started working on the design of potent orally active IKKb inhibitors (Burke et al, 2003;Kishore et al, 2003;Baxter et al, 2004;Murata et al, 2004;Ziegelbauer et al, 2005). PS1145 is one of these highly specific IKK inhibitors (ICo0.1 mM) recently developed by Millenium Pharmaceuticals, Inc. (Hideshima et al, 2002;Lam et al, 2005).…”

Synthesis and Structure Activity Relationship Studies of Benzothieno[3,2-b]furan Derivatives as a Novel Class of IKK.BETA. Inhibitors

“…9,10) As part of our program to discover new IKK inhibitors, we identified 1 (MAYBRIDGE) as a potent hit compound. However, AstraZeneca has previously reported that the structurally-analogous urea derivative 2, 11) which could be derived from the compound 1, exhibited excellent inhibitory activity. The introduction of a urea group resulted in the improvement of activity by as much as 100-fold compared with the amino derivative 1 (Fig.…”

“…1). Because the benzene ring of 2 was considered to be coplanar to the thiophene ring in it's active conformation, 11) it seemed that the relative orientation of the urea, carbamoyl, and benzene was important for IKKb inhibition. Thus, it was also thought that constraining the terminal benzene to be in the active conformation could improve activity.…”