Spirocyclic Delta Opioid Receptor Agonists for the Treatment of Pain: Discovery of N,N-Diethyl-3-hydroxy-4-(spiro[chromene-2,4′-piperidine]-4-yl) Benzamide (ADL5747)

Abstract

Selective, nonpeptidic delta opioid receptor agonists have been the subject of great interest as potential novel analgesic agents. The discoveries of BW373U86 (1) and SNC80 (2) contributed to the rapid expansion of research in this field. However, poor drug-like properties and low therapeutic indices have prevented clinical evaluation of these agents. Doses of 1 and 2 similar to those required for analgesic activity produce convulsions in rodents and nonhuman primates. Recently, we described a novel series of potent, selective, and orally bioavailable delta opioid receptor agonists. The lead derivative, ADL5859 (4), is currently in phase II proof-of-concept studies for the management of pain. Further structure activity relationship exploration has led to the discovery of ADL5747 (36), which is approximately 50-fold more potent than 4 in an animal model of inflammatory pain. On the basis of its favorable efficacy, safety, and pharmacokinetic profile, 36 was selected as a clinical candidate for the treatment of pain.

δ-Opioid Mechanisms for ADL5747 and ADL5859 Effects in Mice: Analgesia, Locomotion, and Receptor Internalization

“…Analgesia produced by ADL5747 and ADL5859 in the mouse differed somehow from analgesia obtained in the rat study (Le Bourdonnec et al, 2009). First, the reduction of inflammatory pain in CFA mice seemed weaker compared with antiallodynia observed in the rat (3-to 10-fold higher doses required for an analgesic effect).…”

“…SNC80 is well known to increase locomotor activity in rats and mice (Jutkiewicz et al, 2005;Scherrer et al, 2006;Ito et al, 2008;Pradhan et al, 2010), whereas ADL compounds did not induce hyperlocomotion in rats (Le Bourdonnec et al, 2008Bourdonnec et al, , 2009). Therefore, we investigated the locomotor effects of ADL compounds in naive WT mice.…”

“…The novel nonpeptidic compounds N,N-diethyl-4-(5-hydroxyspiro[chromene-2,4Ј-piperidine]-4-yl)benzamide (ADL5859) (Le Bourdonnec et al, 2008) and N,N-diethyl-3-hydroxy-4-(spiro[chromene-2,4Ј-piperidine]-4-yl)benzamide (ADL5747) (Le Bourdonnec et al, 2009) were developed with structures distinct from other ␦-agonist classes to obtain molecules with higher selectivity for ␦ receptors (Fig. 1).…”

“…1). They showed ␦-opioid selectivity based on nanomolar affinities and signaling potencies for the receptor in vitro, with no detectable binding at more than 100 nonopioid receptors, channels, or enzymes (Le Bourdonnec et al, 2008Bourdonnec et al, , 2009. In rats, the two drugs display good oral bioavailability and produce antidepressant (ADL5859) and antihyperalgesic effects in a model of inflammatory pain (Le Bourdonnec et al, 2008).…”

Molecular Pharmacology ofδ-Opioid Receptors

“…At the same time, they may also underlie the proconvulsant effects of exogenous DOPr agonists (Broom et Importantly, the potential to generate seizures is not the same for all DOPr agonists. This potential is associated with SNC80 (Broom et al, 2002;Jutkiewicz et al, 2005Jutkiewicz et al, , 2006, BW373U86 (Jutkiewicz et al, 2006), and deltorphin II (De Sarro et al, 1992;Di Giannuario et al, 2001) but not by KNT-127 (Saitoh et al, 2011), ADL5859 (Le Bourdonnec et al, 2008), or ADL5747 (Le Bourdonnec et al, 2009). ADL compounds that were devoid of proconvulsive actions in preclinical models have also been tested for acute (ClinicalTrials.gov identifier NCT00993863) and chronic (ClinicalTrials.…”