Ester and Amide Bioisosteres
Need to adopt correct geometry and mimic potential H-bonding interactions
For examples of heterocycles as bioisosteric replacements for esters/amides see:
Benzodiazepine partial agonists J. Med. Chem. 1989,32, 2282
Muscarinic agonists J. Med. Chem., 1990, 33 (10), pp 2690–2697 DOI, Muscarinic agonists J. Med. Chem. 1997, 40, 4265
The image below shows the electrostatic surfaces generated using MOE.
The image below shows the field surfaces generated using FieldView, this analysis also demonstrates the influence the substituent can have on the oxadiazole, the electron-donating -NMe2 increasing the size of the negative potential, potentially increasing the strength of any hydrogen bond. The physicochemical properties of the isomeric substituted oxadiazoles has been investigated, as might be expected increasing the H-bonding ability reduces LogP and solubility.
A series of nAChR ligands based on an isoxazole-ether scaffold as a bioisosteric replacement for the acetyl group of acetylcholine have been designed. Early stage absorption, distribution, metabolism, excretion, and toxicity studies also suggested favourable drug-like properties DOI.
Triazole-linked reduced amide isosteres DOI easy prepared using “click” chemistry as potential BACE1 inhibittors.
Oxadiazolines and Oxadiazines have been shown to be excellent bioisosteric replacements for an amide yielding a series of potent and Highly Efficacious γ-Secretase Modulators in Vivo DOI. Compounds from these series are well absorbed in rat, dog and monkey (F = 40-100%) and are not PGP substrates in vitro. In contrast to the amide the oxadiazolines and oxadiazines were found to be weaky basic allowing salt formation.
The replacement of the amide carbonyl by CF3 has been demonstrated in the development of Odanacatib (MK-0822) an inhibitor of cathepsin K, it should be noted however that the bioisosteric transformation in it’s self did not improve metabolic stability.
CGRP is a popular target for pain DOI and as might be expected a number of the leads resemble modified peptides, work by BMS has shown that pyridyl can act as an amide bioisostere with improved membrane permeability DOI.
A recent publication by Wermuth (DOI: 10.1039/c1md00074h) describes pyridazines as aromatic bioisosteres, interestingly the pyridazine ring has also served as an amide biosiosteric replacement DOI to mimic the the D2 antagonist Sulpiride.
Last Update 26 March 2017