A Scaffold‐Hopping Strategy toward the Identification of Inhibitors of Cyclin G Associated Kinase

Abstract

We recently reported the discovery of isothiazolo[4,3‐b]pyridine‐based inhibitors of cyclin G associated kinase (GAK) displaying low nanomolar binding affinity for GAK and demonstrating broad‐spectrum antiviral activity. To come up with novel core structures that act as GAK inhibitors, a scaffold‐hopping approach was applied starting from two different isothiazolo[4,3‐b]pyridines. In total, 13 novel 5,6‐ and 6,6‐fused bicyclic heteroaromatic scaffolds were synthesized. Four of them displayed GAK affinity with Kd values in the low micromolar range that can serve as chemical starting points for the discovery of GAK inhibitors based on a different scaffold.

Recent Scaffold Hopping Applications in Central Nervous System Drug Discovery

“…61 Similarly to the exploration discussed previously, these 6,6-bicyclic replacements also saw significant losses in activity (Figure 9a). 61 The best candidate in this case (32) saw a 10-fold reduction in activity compared to 28. The third 1°s caffold hopping that was performed explored the isothiazole portion of 35.…”

“…The isothiazolo [3,4b]pyrazine (29), isothiazolo [3,4-b]pyridine (30), and isothiazolo [3,4-d]pyrimidine (31) replacements all showed a significant reduction in affinity compared to the lead 28 (Figure 9a). 61 This application of 1°scaffold hopping highlighted key structural features required for activity, particularly the nitrogen at the 4-position of 28 (Figure 9a). A second 1°scaffold hopping exploration of 28 focused on the introduction of several 6,6-bicyclic heterocycle scaffolds as replacements of the 6,5-bicyclic core of 28; a selection of these is shown in Figure 9a.…”

“…60−62 This work focused on three clear 1°s caffold hopping explorations based on the leads 28 and 35 (Figure 9). 61 The first of these strategies looked to explore the importance of the position of the nitrogen in the pyridine ring of the isothiazolo [4,3-b]pyridine scaffold of 28. A selection of these replacements is shown in Figure 9a.…”

“…A second 1°scaffold hopping exploration of 28 focused on the introduction of several 6,6-bicyclic heterocycle scaffolds as replacements of the 6,5-bicyclic core of 28; a selection of these is shown in Figure 9a. 61 This included the replacements of the isothiazolo [4,3-b]pyridine scaffold of 28 with quinazoline (32), pyrido [3,2-d]pyrimidine (33), and pteridine (34) cores. 61 Similarly to the exploration discussed previously, these 6,6-bicyclic replacements also saw significant losses in activity (Figure 9a).…”

“…61 This included the replacements of the isothiazolo [4,3-b]pyridine scaffold of 28 with quinazoline (32), pyrido [3,2-d]pyrimidine (33), and pteridine (34) cores. 61 Similarly to the exploration discussed previously, these 6,6-bicyclic replacements also saw significant losses in activity (Figure 9a). 61 The best candidate in this case (32) saw a 10-fold reduction in activity compared to 28.…”