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
Store-operated calcium entry (SOCE) is a pivotal mechanism in calcium homeostasis, bioisosteric replacement of a labile ester with an oxadiazole afforded a class of modulators with high metabolic stability. DOI.
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.
VU6012962 is a mGlu7 negative allosteric modulator (NAM), but metabolic instability of the amide linker has limited in vivo studies. In an effort to improve metabolic stability an array of 12 bioisosteric heterocycles were prepared DOI. Whilst many of the replacements proved to be inactive, the 1,3,4- and 1,2,4-oxadiazoles retained useful activity. Both NAMs displayed favourable profiles, with predicted hepatic clearances (CLhep) in rat of around 27 mL/min/kg and modest plasma protein binding.
VE-821 is an ataxia telangiectasia mutated and rad3-related (ATR) kinase inhibitor Ki 4 nM DOI, these enzymes work together to support DNA damage and repair. ATR inhibition has been shown to enhance the toxicity of DNA damaging chemotherapy to many cancer cells in multiple preclinical studies, while healthy tissue with functional ATM can tolerate ATR inhibition. Significant effort was focussed on replacing the amide linkage with a variety of heterocycles, a key observation was a proposed intramolecular hydrogen bonding interaction between the 2-aminopyrazine and the amide carbonyl.
The preference for the alternative conformation of the 1,2,4-oxadiazole was predicted by the positive relative conformational energy, and is in agreement with the observation that aromatic nitrogen atoms are better H-bond acceptors than aromatic oxygens, in contrast the 1,3,4-oxadiazole improved affinity.
Last Update 28 August 2018