isosteres & bioisosteres in lead optimization

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Isosteres are interchangeable functional groups. When one isostere is swapped for another, the effect on potency is usually very small, but the impact on other properties (especially ADME properties or PK) can be much larger. So, isosteres are most often considered later in lead optimization, especially when the potency of a compound is satisfactory but the ADME properties need improvement and the changes required to fix the ADME problem may impact key drug-target binding features.
There are two types of isosteres. One type includes the classical isosteres. These are functional groups that are similar in size and shape. These groups are sorted into different categories based on the nature of the groups - univalent, divalent, and ring substitutions. So, swapping a hydrogen with a fluorine is considered an isosteric substitution. The size of a hydrogen atom is about the same as a fluorine atom. A methyl group is about the same size as a chlorine atom or an OH or an NH2. A t-butyl group is about the same size and volume as an iodine atom. Similarly, a CH2 can be replaced with an NH or oxygen. C-H groups on a benzene ring can be replaced with a nitrogen. These exchanges should not greatly impact potency and target binding, but they might influence metabolism or solubility, two key ADME properties.
Another type of isostere are the non-classical isosteres, sometimes called bioisosteres. These are functional groups that may not be so similar in size or shape but duplicate each other’s hydrogen bonding and charge properties. Non-classical isosteres are less easy to categorize because they sometimes do not look very similar. On the screen is a drug with a carboxylic acid. Some possible isosteres for a carboxylic acid include a phosphonic acid, sulfonic acid, and a tetrazole ring. All of these, including the tetrazole, are over 99% deprotonated as anions at physiological pH. Why would you replace a carboxylic acid with one of these groups? Well, sometimes carboxylic acids undergo rapid phase II conjugations, especially glucuronidations. These isosteres for carboxylic acids preserve the properties of the original acid and are less prone to undergo glucuronidation.
Here is an example of a classical isostere. On the left is tolbutamide, a diabetes drug. It has a half-life of 7 hours and a possible daily dose of up to 2 grams per day. Its main route of metabolism is oxidation of the methyl group. Tolbutamide was dramatically improved by simply replacing the methyl with a chloro group. This is a classical isosteric replacement. The chlorine resists oxidative metabolism, then half-life of extends to 36 hours. With the lower clearance, the daily dose can be reduced to 500 mg per day. A lower daily dose generally correlates with increased safety. As we finish with this compound… Yes, the carbon chain is a bit shorter in chlorpropamide, but the isosteric replacement of the methyl for a chloro is the main driver for the half-life change.

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