Discovery and Characterization of 2-Aminooxazolines as Highly Potent, Selective, and Orally Active TAAR1 Agonists

Abstract

2-Aminooxazolines were discovered as a novel structural class of TAAR1 ligands. Starting from a known adrenergic compound 1, structural modifications were made to obtain highly potent and selective TAAR1 ligands such as 12 (RO5166017), 18 (RO5256390), 36 (RO5203648), and 48 (RO5263397). These compounds exhibit drug-like physicochemical properties, have good oral bioavailability, and display in vivo activity in a variety of animal models relevant for psychiatric diseases and addiction. KEYWORDS: TAAR1 agonist, 2-aminooxazoline, SAR, schizophrenia T race amines (TAs) are metabolites of amino acids with structural similarity to biogenic amines and represent the endogenous ligands of the trace amine associated receptor 1 (TAAR1). 1,2 Dysregulation of TAs in the brain has been linked to a variety of psychiatric diseases and selective TAAR1 ligands have gained much interest as potential therapeutics for depression, schizophrenia, bipolar disorder, ADHD, and psychostimulant addiction. 3 The modulatory role of this G protein-coupled receptor on monoaminergic neurotransmission has recently been investigated and confirmed by characterization of a transgenic mouse line overexpressing TAAR1 in central nervous system neurons. 4 Further efforts were made to identify potent and selective TAAR1 agonists with favorable pharmacokinetic properties in order to prove the modulatory effect on dopaminergic signaling in vivo. 5 In an endeavor to discover a novel and selective TAAR1 chemotype, we considered application of the SOSA approach (Selective Optimization of Side Activities) to adrenergic ligands as a viable lead identification strategy. 6 Structural similarity of TAAR1 agonists with adrenergic agonists was already known from our previous work 5 pointing toward a similarity of the binding regions of both receptors. 7,8 Therefore, we searched the literature and in-house databases for adrenergic ligands reported as drugs or development candidates, whereupon the alpha 2 adrenergic receptor partial agonist S18616 from Servier (1) caught our attention. 9 Pleasingly, testing this candidate revealed (besides its expected activity at the human α 2A receptor) a high functional activity at human TAAR1 (EC 50 = 15 nM). 10 A medicinal chemistry optimization program was then started aiming for compounds selective for TAAR1, where the known TAAR1 pharmacophore motif (aromatic moiety linked to a basic headgroup) of S18616 was kept, but the linker region was modified by opening the central six-membered ring (Figure 1). For all such derived compounds selectivity data was obtained by measuring functional activity at the human TAAR1 receptor (EC 50 hTAAR1) and in addition at the human adrenergic α 2A receptor (hα 2A ) (Table 1).All 2-aminooxazolines were synthesized from the corresponding amino alcohols 15 and cyanogen bromide in the presence of a base as depicted in Scheme 1. The enantiomerically pure amino alcohols were obtained from the chiral pool (e.g., via reduction of amino acids or their derivatives). The procedures are describ...

Trace Amines and Their Receptors

“…This has been confirmed after expression of TAAR1 in a variety of cell types and with various approaches to analyze cAMP concentrations used (Reese et al, 2007;Wainscott et al, 2007;Barak et al, 2008;Hu et al, 2009;Espinoza et al, 2011;Revel et al, 2011;Liu et al, 2014). In fact, cAMP assays are now a central component of TAAR1 ligand screening programs (Bradaia et al, 2009;Revel et al, 2011Revel et al, , 2012aRevel et al, , 2013Stalder et al, 2011;Galley et al, 2012Galley et al, , 2015.…”

“…Starting from the known adrenergic ligand S18616 [(S)-spiro[(1-oxa-2-amino-3azacyclopent-2-ene) -4,29-(89-chloro-19,29,39,49-tetrahydronaphthalene)]], modifying the linker region and exploring additional structureactivity relationships, 2-aminooxazolines were discovered as a chemical series of novel, highly potent, selective, and orally active TAAR1 full and partial agonists (Galley et al, 2015). Besides functional activity at human TAAR1 and selectivity versus the adrenergic a 2A receptor, metabolic stability as measured in hepatocytes was used as a key parameter to select the four molecules that have been extensively characterized in the literature: (Fig.…”

“…Besides functional activity at human TAAR1 and selectivity versus the adrenergic a 2A receptor, metabolic stability as measured in hepatocytes was used as a key parameter to select the four molecules that have been extensively characterized in the literature: (Fig. 2) (Galley et al, 2015). The safety, tolerability, pharmacokinetics, and pharmacodynamics after oral administration of one of these molecules, RO5263397, a TAAR1 partial agonist that is well tolerated in rat and cynomolgus monkey toxicity studies, was determined in a singleascending dose, randomized, double-blind, placebocontrolled study in healthy male volunteers.…”

Pharmacological characterization of a high-affinity p-tyramine transporter in rat brain synaptosomes

“…TAAR1 is well established to be either constitutively active or tonically activated by endogenous ligands57, and this raises the possibility that the deficits observed in OCT2 knock-out animals may be, at least in part, due to a decrease in tonic TAAR1 activation due to decreased membrane passage of p -tyramine in the absence of OCT2. In such a situation one would predict that TAAR1 agonists such as RO516601777 may reverse the phenotype associated with OCT2 knock-out. Finally, a high affinity transport of p -tyramine by OCT2 also suggests that alterations in trace amine homeostasis should be considered with respect to the “off target” pharmacological profiles of the diverse therapeutics7879 that are known to interact with OCT2.…”

Synthesis of enantiomerically pure [14C]‐labelled morpholine derivatives for a class of trace amine‐associate receptor 1 agonists

“…Their dysregulation is linked to highly prevalent psychiatric disorders such as depression, schizophrenia, and bipolar disorders . In recent years, novel synthetic agonists of TAAR1 have gained attention as potential therapeutic agents for psychiatric diseases …”