Scaffold replacements in VEGFR-2 inhibitors.

I often think about scaffold replacement strategy in my project.

Sometime, scaffold replacement is powerful strategy. However I think brute-force search of another scaffold is not effective. It too heavy task to build new core frame if there are no commercially available starting material.

Recently researcher in Novartis was reported a letter in JMCL. The title is attractive for me.

The author had already potent compound that has some issues, hERG, solubility etc.

To solve these issues, they tried to replace core from indole to any other 56fused rings.

In table1, There are some examples. And Entry 5 showed good potency and improve solubility and hERG. I think the result depends on reduce basicity and break aromaticity of the scaffold.

And the author described some potent derivatives. Azaindole derivative showed good profile (but loss potency…).

SAR expansion of core structure was informative for me, but unfortunately, there aren’t the discussion about why they chose these core structures.

Is it from medchem’s experience, or rationally designed strategy, or ….. ?


Where is the key to open the door?