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January 21, 2010
In Hoc Signo Non Vinces
I am here to confess to a deep-seated prejudice, one that has been with me for many years now. I know that others feel differently, but I'm sticking to my rule: No Naphthyls.
OK, pile on me now for having a closed mind. I know that there are drugs that are more successful than anything I'll ever make that have a naphthalene in them. (At least that structure's a small one). It's just that I see a naphthyl as the worst sort of "potency through greasiness" move in drug design. They hurt your solubility, drive up your molecular weight, open you to metabolites that you may not care for, and all for what? A little activity in your in vitro assay.
I'm getting close to putting cyclohexyl on the same list, if you want to know the truth. Problem is, people make these things "just as SAR compounds". You know, they'll trowel this hunk of grease onto the side of the molecule, just to see what happens, and if it really looks good, well, they'll. . .find some way to make it better. Right. Tetrahydropyranyl instead, that'll do it. But my attitude is, why not just make the THP derivative in the first place, if that's where you're going to go?
SAR is long, and life is short. There isn't time to make everything. So I decided a long time ago that I'd try to only make structures that I could live with. That still admits a lot of weird stuff, don't get me wrong. I have functional groups on my go-to lists that make people roll their eyes. But I draw the line at flat slabs of lard. No naphthalenes.
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