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

Abstract

IkB kinase (IKK) has been identified as a serine-threonine kinase complex, which phosphorylates the inhibitor of NFkB (IkB). [1][2][3] This complex is composed of three subunits, i.e. the catalytic subunits IKKa and IKKb, and the regulatory subunit IKKg, also called IKK-1, IKK-2, and NEMO, respectively. The complex plays a critical role in a signaling pathway leading to NF-kB (nuclear factor-kB) activation. 4) The activation of IKK by cytokine signals (tumor necrosis factor (TNF)-a, interleukin (IL)-1 etc.), lipopolysaccharide (LPS), and stress leads to phosphorylation of IkB, which triggers poly-ubiquitinylation and proteasome-dependent degradation of IkB, resulting in transcriptional activation of NF-kB. It has been recognized that the kinase IKKb plays a major role in activation of NF-kB via classical (canonical) pathway, and activation of the classical pathway promotes the production of TNF-a, IL-1, intercellular adhesion molecule (ICAM)-1, and cyclooxygenase (COX)-2, which indicates that this pathway is important for inflammation and the innate immune system. Therefore, IKKb inhibitors are expected to be useful for the treatment of acute and chronic inflammatory diseases and autoimmune disorders, such as rheumatoid arthritis (RA). 5) Alternatively, IKKb inhibitors are also thought to be useful for the treatment of type 2 diabetes because activation or overexpression of the IKKb attenuated insulin signaling.6) In addition, IKKb inhibitors may also have application for the treatment of asthma, chronic obstructive pulmonary disease (COPD), 7) and cancer. 8) Because of the key role played by the IKK complex in the NF-kB mediated transcription, and of the druggability of kinases as a target class, numerous companies have been pursuing discovery programs aimed at identifying small molecule inhibitors of this enzyme. 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. From this point of view and taking into consideration of patentability issues, we designed tricyclic fused furan derivatives for the development of novel IKK inhibitors. In this manuscript, we describe the synthesis and the SAR of the series of tricyclic furan derivatives. ChemistryThe synthesis of benzothieno[3,2-b]furans 13a-i and 16a-o having a 2-carbamoyl and 3-urea group, is outlined in Chart 1. The substituted thiopheno...

IKKβ inhibitors identification part I: Homology model assisted structure based virtual screening

“…Importance of hinge region, Glu97 and Cys99 hydrogen bonding has already been explained by other researchers, who working on the IKK inhibitor design and synthesis. 4,9,10 Our docking simulation study can be correlated with the previous study and exhibits the hinge region hydrogen bonding with ligand. 11 We have successfully employed the homology model in the structure based VS scheme to search ChemDiv database that contains 26,953 compounds.…”

“…IL-1, intercellular adhesion molecule (ICAM)-1, and cycloxygenase (COX)-2. 4 The IKK complex comprises of two catalytic subunits, such as, IKKa and IKKb and a regulatory subunit IKKc. Although both the catalytic subunits can catalyze the phosphorylation of IjBa, the IKKb subunit seems to have the dominant role in the canonical pathway in cells and IKKa has a crucial role in mediating p52 activation through the 'non-canonical' pathway.…”

Concise Synthesis of Highly Substituted Benzo[a]quinolizines by a Multicomponent Reaction/Allylation/Heck Reaction Sequence

“…In addition, nicotinonitrile 2f (entry 6) failed to provide the 3,4-dihydropyridin-2-one 5f. Aromatic and heteroaromatic aldehydes gave the expected 3,4-DHP-2-ones in reasonable to excellent yields (entries [13][14][15][16][17]. The reaction using highly electron-deficient p-nitrobenzaldehyde 3g presents an exception and leads directly to 2-pyridone 8r.…”

“…3-Hydroxy-1-benzothiophene-2-carbonitrile is efficiently synthesized in large quantities from readily available, cheap starting materials. [16] The triflate protected derivative 2j can be used in our envisioned sequence towards polycyclic compounds 7 since triflates are good reaction partners in Heck reactions. Unfortunately, the corresponding DHP-2-one 5j was not formed.…”

Identification of Human IKK-2 Inhibitors of Natural Origin (Part I): Modeling of the IKK-2 Kinase Domain, Virtual Screening and Activity Assays

“…To achieve these goals, we (1) developed a homology model for the hIKK-2 kinase domain which could stand the test of our validation criteria, (2) docked ATP-competitive molecules known to be potent and specific inhibitors of hIKK-2 with this model [10], [11], [13], [15], [16], [18], [20]–[31], (3) identified which of the resulting poses were knowledge-based coherent by analyzing whether they satisfied the experimentally known generic binding features of ATP-competitive inhibitors of kinases [45], (4) used the knowledge-based coherent poses to derive a structure-based common pharmacophore containing the key intermolecular interactions between hIKK-2 and its inhibitors, (5) obtained exclusion volumes from our homology model and added them to the pharmacophore, (6) validated the selectivity of the resulting pharmacophore and of the VS process using a large database of kinase decoys [46] and ATP-competitive inhibitors for hIKK-2 that were not used during the pharmacophore building [47], (7) used the previously validated structure-based pharmacophore and VS protocol to find ATP-competitive inhibitors for hIKK-2 in a database of NPs [48], and, finally, (8) proved the reliability of the prediction by testing the inhibitory effect of some selected hits on hIKK-2 in vitro . In addition, all the tools developed during the current study ( i.e.…”