Cambridge MedChem Consulting

Bioisosteric Replacements

Aromatic Bioisosteres

Simple replacements

Phenyl Pyridyl Thiophene 4-Fluorophenyl

The CF2H group has been proposed as a bioisosteric replacement for the phenol group, it can act as a similar hydrogen bond donor, as confirmed by crystallographic, spectroscopic, and computational methods 10.1021/jacs.7b04457DOI.


Substitution of a CH group with a N atom in aromatic and heteroaromatic ring systems is a common bioisosteric transformation. Cdc7 kinase is responsible for the initiation and regulation of DNA replication and is a target for cancer therapy. An indole based class of Cdc7 inhibitors were identified. Introduction of a nitrogen at the 7-position dramatically improved affinity suggested to be due to conformational preferences DOI, they also report that both the 7- and 5-aza analogues show improved metabolic stability.


Comparison of Adenine and Deazaadenine Derivatives as Ligands for Adenine Receptors DOI demonstrates a significant reduction in affinity for the deaza compound. Improved metabolic stability for aza analogues has also been reported for a series of inhibitors of nicotinamide phosphoribosyl- transferase (Nampt) DOI, introduction of nitrogen into the benzyl ring affording a 160-fold improvement in metabolic stability, replacement of the piperidine with the 8-oxa-3-azabicyclo[3.2.1]octane gave a further improvement, this compound also showed excellent in vivo antitumor efficacy when dosed orally in an A2780 ovarian tumor xenograft model (TGI of 97% was observed on day 17). nampt

A recent publication by Wermuth DOI describes the influence that introduction of a pyridazine can have on the properties of a molecule. When used as a bioisosteric replacement for a phenyl ring the resulting LogP is reduced by two log units, in other examples they improve water solubility of crystallinity of salts.


Teddy Zartler drew my attention to my attention to recent publication describing the use of the Bicyclo[1.1.1]pentane Motif as a Nonclassical Phenyl Ring Bioisostere DOI. In this paper they took BMS-708163 (Avagacestat) and replaced one of the phenyl rings with the bicyclo[1.1.1]pentane motif as shown below.


Both compounds have similar γ-secretase inhibition and selectivity suggesting the bicyclo[1.1.1]pentane preserves geometric constraints of the phenyl ring, however it would not be expected to have the same electrostatics or be capable of pi-stacking. Interestingly introduction of the bicyclo[1.1.1]pentane resulted in a significant increase in the aqueous solubility from 0.6 uM to 216 uM. In addition this bioisostere exhibited a greater resistance toward metabolic turnover in cryo-preserved human hepatocytes, and a considerable increase in intrinsic permeability in the RRCK assay.

In a very comprehensive study Buschauer et al DOI looked at a wide variety of 5- and 6-membered heterocycles as possible bioisosteric replacements for the imidazole of the histamine H2 agonist UR-AK24. They evaluated all ligands at hH1R, hH2R, hH3R and hH4R in the steady-state GTPase assay, they concluded that in general the replacement of the 1H-imidazol-4-yl ring with isomers or other heterocycles resulted in considerably reduced potency and efficacy. Interestingly the 1H-1,2,4-triazol-3-yl ring provided compounds exhibiting partial to full agonist activity at the hH2R, with little activity at other receptor subtypes. It was also suggested to be relatively stable to enzymic degradation but no data was presented.


Two benzazaborinine analogues of propranolol have been synthesized and extensively profiled in vitro and in vivo DOI. They showed that the Benzazaborinine analogues showed excellent bioavailability and brain penetration following subcutaneous administration in a pharmacokinetic study in rats.


Worth reading

The Necessary Nitrogen Atom: A Versatile High-Impact Design Element for Multiparameter Optimization. DOI.

Last Update 29 October 2018