The nitro group is generally not regarded as being “drug-like”, despite its presence in a number of major drugs, including nifedipine, chloramphenicol, ranitidine and metronidazole, and this is particularly true for aliphatic nitro groups. Nitro groups are often present in hit or lead compounds resulting from medicinal chemistry campaigns, therefore its removal or replacement is an important step in the refinement of these structures before progressing to clinical studies. However, there are few successful case studies in which a nitro group has been successfully replaced by an appropriate bioisostere, which may be indicative of the difficulty of replicating its binding interactions. An ongoing research programme in our groups aims at developing ligands targeting the allosteric binding site on the CB1 cannabinoid receptor using positive allosteric modulators (PAMs), which have the advantage of increasing endocannabinoid effects only at the site of endocannabinoid release (e.g. spinal and brain pain processing centres), thus they can be predicted to be free of the psychoactive side-effects associated with direct agonism of CB1. The first generation of these ligands (such as ZCZ011) features a 3-indolyl-nitromethane structure. In spite of its interesting pharmacological properties, ZCZ011 was shown to be highly unstable in the rat liver microsomal assay (T1/2 &lt;10 min), with modest stability in human liver microsomes. In addition to the potential toxicological concerns, the methylene adjacent to the nitro group was expected to be strongly acidic and potentially a metabolic liability, contributing to the short half-life of ZCZ011 and analogues. In this communication we describe the successful replacement of the aliphatic nitro group with a trifluoromethyl group. Our results demonstrate that the trifluoromethyl can be a viable bioisostere for an aliphatic nitro group and thus that it is possible to remove the non-drug-like nitro group from the most-commonly-studied CB1 PAMs to give compounds with improved potency and metabolic stability. Preliminary in vivo data in preclinical models will be also described.

Trifluoromethyl group as a bioisosteric replacement of aliphatic nitro group in CB1 receptor positive allosteric modulators (PAMs)

2019 Spring National Meeting

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