Discovery and optimisation of 1-acyl-2-benzylpyrrolidines as potent dual orexin receptor antagonists

The vertebrate orexin neuropeptide–receptor system plays a pivotal role in the regulation of sleep and wake states as well as emotional states related to stress or reward. The neuropeptides orexin A and orexin B are synthesised by a small number of neurons in the lateral hypothalamus, a brain region involved in arousal, emotional and metabolic regulation and motivated behaviours, e.g. feeding. Orexin peptides are released at axonal terminals and – pre- or post-synaptically –bind and activate two closely related G protein coupled receptors (GPCR): orexin receptor type 1 (OX1) and orexin receptor type 2 (OX2). Activated neuronal orexin receptors couple to the Gq/phospholipase C/protein kinase C pathway resulting in cellular depolarisation and increased cytosolic Ca2+ concentrations. Thus, orexin receptor signaling is excitatory by enhancing synaptic transmission.

The distribution of OX1 and OX2 in mammalian brains is indicative of their important role in the regulation of vigilance states and circadian activity. Orexin-secreting neurons of the lateral hypothalamus project to the basal forebrain, corticolimbic structures, and brainstem, especially to those regions related to sleep/wake regulation (locus coeruleus, raphe nucleus, tuberomammillary nucleus), regions activated in anxiety/stress-related conditions (paraventricular nucleus) as well as regions involved in reward processing and drug abuse (nucleus accumbens, ventrotegmental area).

Intracerebellar orexin A and orexin B infusion in rats results in enhanced arousal, delayed onset of REM sleep, and maintenance of cortical activation. Pharmacological inhibition of the orexin system in animal models of insomnia, stress/anxiety and drug abuse has demonstrated a central role of an overactive orexin system in these pathologies and suggests orexin receptors as therapeutic targets in insomnia, stress/anxiety-related disorders and addiction. Extensive clinical

trials with two dual orexin receptor antagonists (DORAs) have demonstrated that targeting the orexin system is an effective strategy in treating sleep disorders. In insomnia patients, both almorexant and suvorexant dose-dependently increased sleep efficiency by decreasing latency to persistent sleep and wake after sleep onset. Suvorexant received FDA marketing authorization in 2014 and represents the first-in-class dual orexin receptor antagonist for the treatment of insomnia

characterised by difficulties with sleep onset and/or sleep maintenance. Studies into the respective contributions of pharmacologically blocking OX1 and OX2 on sleep–wake states have revealed a more important role for OX2. Recent reports describing OX2 subtype-selective antagonists suggest that blockade of OX2 alone may be suitable for the treatment of sleep disorders, and future clinical studies should shed light on whether there is an advantage of selectively blocking OX2 over dual OX1 and OX2 blockade.

The ideal profile of a sleep drug from a pharmacokinetic perspective is difficult to achieve. Metabolic stability in particular needs to be carefully assessed; too stable runs the risk of overshooting with the pharmacodynamic effect and could lead to “hangover” phenomena. Too unstable, on the other hand, will lead to lower bioavailability and higher doses may be required to achieve the required duration of action. The latter is then associated with a greater risk for safety findings. It is increasingly recognised that the rate at which a drug associates with and dissociates from its target receptor – its binding kinetics – directly affects the drug’s efficacy and safety. In the context of orexin receptor antagonism and sleep, a desired compound profile may be characterised by relatively slow receptor dissociation kinetics eliciting insurmountable antagonism to allow it to also be effective with increasing orexin peptide concentrations. These two independent features of a potential novel sleep drug, namely pharmacokinetic profile and binding kinetics, need to be carefully evaluated to identify the appropriate balance.

In this manuscript, we describe the structural optimisation of our initial lead compound 1 into the in vivo active compound 27. During the optimisation process, we focus on OX2 potency and monitor the lipophilic ligand efficiency (LLE) metric to assess design progress. DORA 27 shows single digit nM potency at both OX receptors and exhibits insurmountable antagonism in calcium release assays at OX1 and OX2. An investigation into the binding kinetics of 27 reveals an estimated receptor occupancy half-life of 1–5 min at both orexin receptor subtypes. DORA 27 decreases wakefulness and increases sleep efficiency in male Wistar rats after oral administration of 100 mg kg−1.



Jodi T. Williams,* John Gatfield, Catherine Roch. Med. Chem. Commun.,2015, 6, 1054–1064


Related Products: