Cambridge MedChem Consulting

Bioisosteric Replacements

Basic Bioisosteres

Whilst basic centres offer the advantage of water solubility and crystalline salts they can also lead to off-target activities eg hERG. Bioisosteres offer the opportunity to modulate the pKa of the basic center, to mask very hydrophilic functional groups capable of forming multiple hydrogen bonding interactions. Constrained analogues may no longer be substrates for mono amine oxidase.

Basic ring systems occur in many drugs with 4 in the top 8 ring systems found in drugs DOI (with phenyl being the most common ring system With 727 examples).


Piperazines are particularly popular rings, offering easy derivatization and favourable physicochemical properties. Many sample collections contain many, many structures containing the Piperazine motif the bioisosteres described below offer the opportunity to modify the pKa of the nitrogens but also subtly alter the directionality of the vectors from the nitrogens. DOI.


The effect of some of these piperazine bioisosteres have on bioavailability has been described DOI.


Starting with Suvorexant an extensive exploration of homopiperazine mimics allowed improvement in the antagonistic potency on both orexin 1 and orexin 2 receptors (Ox1 and Ox2, respectively), but also to increase metabolic stability in human liver microsomes (HLM), decrease time-dependent inhibition of cytochrome P450 (CYP) 3A4, and decrease P-glycoprotein (Pgp)-mediated efflux DOI. Some of the examples are shown below.


Hahn et al DOI in their exploration of 3-substituted azetidine based triple reuptake inhibitors described the bioisosteric replacement of 3-akpha-oxyazetidine with 3-aminoazetidine. One advantage of this replacement is the elimination of a chiral centre.


Worth reading

Applications of Isosteres of Piperazine in the Design of Biologically Active Compounds: Part 1 DOI.

Last Update 5 July 2022