The Azaindole Framework in the Design of Kinase Inhibitors

Abstract

This review article illustrates the growing use of azaindole derivatives as kinase inhibitors and their contribution to drug discovery and innovation. The different protein kinases which have served as targets and the known molecules which have emerged from medicinal chemistry and Fragment-Based Drug Discovery (FBDD) programs are presented. The various synthetic routes used to access these compounds and the chemical pathways leading to their synthesis are also discussed. An analysis of their mode of binding based on X-ray crystallography data gives structural insights for the design of more potent and selective inhibitors.

Design Principles for Fragment Libraries: Maximizing the Value of Learnings from Pharma Fragment-Based Drug Discovery (FBDD) Programs for Use in Academia

“…Indeed, the azaindole scaffold is such a fruitful source of fragments that an entire review was devoted to it. 97 A more serious objection to target-based libraries is that sometimes the most interesting hits are the least expected; it is hard to design for serendipity. For example, a screen against PAK1 identified a fragment with scant resemblance to adenine.…”

7-Azaindole: A Versatile Scaffold for Developing Kinase Inhibitors

“…Therefore recent years have seen growing interest in this 7-azaindole scaffold; more than 100000 chemical structures having 7-azaindole framework have been registered in the CAS chemical database, 9) which is steadily increasing by the synthetic innovation and enrichment of commercially available derivatives. 10) Figure 1b shows representative kinase inhibitors having a number of substituents at various positions in the 7-azaindole ring. [11][12][13][14][15][16] Among them, vemurafenib (1), a B-RAF kinase (serinethreonine kinase [STK]) inhibitor, is the first FDA-approved 7-azaindole-based kinase drug for the treatment of melanoma.…”

Investigation about the complexation of trimethylammonium‐derived pillar[5]arene with indole and azaindole derivatives

“…The drug‐like properties of the molecules such as: oral bioavailable (Lipinski's rules), aqueous solubility, acid‐base properties, target binding, and the properties of absorption‐distribution‐metabolism‐excretion and toxicity (ADME‐Tox properties) can be modulated and finely tuned using the azaindole nucleus instead of other bicyclic fused heterocycles . Indoles and their azaindole derivatives exhibit significant biological activities, and the use of this framework has contributed to the generation of new therapeutic agents . The four azaindole isomers, which merge a π‐deficient ring (pyridine) and a π‐rich ring (pyrrole), possess all of the criteria necessary to be excellent bioisosteres of the indole or purine systems .…”