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isosteres & bioisosteres

directory of Chem Help ASAP videos: https://www.chemhelpasap.com/youtube/ On the screen are a series of functional groups that can often be exchanged on a lead with very little impact on the lead's potency. These functional groups are called isosteres. Why in the world would anyone want to make structural changes that do not affect potency? Well, in some cases, the lead has excellent potency, but other properties like ADME or toxicity need to be improved. The isosteres on the screen are called classical isosteres. Classical isosteres interchange groups of similar size. Here are two examples of classical isosteres. In the first example we are replacing a hydrogen with a fluorine. Escitaprolam, which is on the top right, has a fluorinated benzene ring. This fluorine was likely added because the corresponding, non-fluorinated ring likely underwent phase 1 oxidation. This phase 1 oxidation would reduce the half-life of the molecule and so, blocking that oxidation was important. The electronegative fluorine blocks the oxidation without adding steric bulk. So the atomic radius of hydrogen is about 1.2 A and fluorine is just a little bit larger at 1.35 A. So we're replacing a small group with another small group and not affecting binding, not affecting potency. In the second example, we can replace a methyl group with a chlorine. Tolbutamide, which is our bottom left structure, is an antidiabetic. It contains this methyl group that undergoes phase 1 oxidation. So again we have this metabolic soft spot, this methyl group. If we replace the methyl with a chlorine, you can't perform oxidations on the chlorine. So this actually changes the half-life. The half-life of tolbutamide is about 7 h, and once we put in the chlorine, (and we also had one change over here on the chain), but if we... The chlorine essentially increases the half-life to 36 h. So this is a big change in the pharmacokinetics of the molecule, but the methyl group and chlorine have about the same size -- very little impact on binding. Another type of isostere is the bioisosteres. These are often called non-classical isosteres. Non-classical isosteres or bioisosteres emphasize swapping groups that preserve the same charges and hydrogen bonding activity. By far, the most common use of non-classical isosteres is with carboxylic acids. Carboxylic acids readily undergo phase 2 conjugations, specifically glucuronidations. Replacement of a carboxylic acid with another group that can preserve the negative charge of the carboxylic acid while suppressing phase 2 conjugation (reducing clearance and extending half-life) is a valuable tool. So let's look at three bioisosteres of carboxylic acids. There's the phosphonate. This phosphonate will be deprotonated -- one of these O-Hs (perhaps even both of them at biological pH). Sulfonic acids are deprotonated, and then there's this weird structure on the end. This is a tetrazole. A tetrazole doesn't look much like a carboxylic acid, but it has a similar pKa and it preserves some of the hydrogen bonding activity. So as you notice, with bioisosteres we're not worried about the size of this group. We're worried about the charge and hydrogen bonding properties. That's the difference between classical and non-classical bioisosteres.