Using click chemistry toward novel 1,2,3-triazole-linked dopamine D3 receptor ligands

Abstract

The dopamine D3 receptor (D3R) is a target of pharmacotherapeutic interest in a variety of neurological disorders including schizophrenia, Parkinson's disease, restless leg syndrome, and drug addiction. A common molecular template used in the development of D3R-selective antagonists and partial agonists incorporates a butylamide linker between two pharmacophores, a phenylpiperazine moiety and an extended aryl ring system. The series of compounds described herein incorporates a change to that chemical template, replacing the amide functional group in the linker chain with a 1,2,3-triazole group. Although the amide linker in the 4-phenylpiperazine class of D3R ligands has been previously deemed critical for high D3R affinity and selectivity, the 1,2,3-triazole moiety serves as a suitable bioisosteric replacement and maintains desired D3R-binding functionality of the compounds. Additionally, using mouse liver microsomes to evaluate CYP450-mediated phase I metabolism, we determined that novel 1,2,3-triazole-containing compounds modestly improves metabolic stability compared to amide-containing analogues. The 1,2,3-triazole moiety allows for the modular attachment of chemical subunit libraries using copper-catalyzed azide-alkyne cycloaddition click chemistry, increasing the range of chemical entities that can be designed, synthesized, and developed toward D3R-selective therapeutic agents.

Evaluation of 1,2,3‐Triazoles as Amide Bioisosteres In Cystic Fibrosis Transmembrane Conductance Regulator Modulators VX‐770 and VX‐809

“…[2] These examples span diverse therapeutic contexts including antiviral agents, [8] chemotherapeutics, [9][10][11] antibiofilm agents, [12] antinociceptives, [13] and antipsychotics. [14] Advantageously,u se of the 1,2,3-triazole in place of the amide often affords increased biological activity, as demonstrated for viral infectivity factor (Vif)i nhibitors 1 and 2 ( Figure 2). [8] In this example, the potencyo fa mide 1 (IC 50 = 6 mm)w as improved substantially in triazole 2 (IC 50 = 1.2 mm).…”

“…Impressively, numerous successful applications of the 1,2,3‐triazole as an amide bioisostere have been reported as recently reviewed by Passarella and coauthors . These examples span diverse therapeutic contexts including antiviral agents, chemotherapeutics, antibiofilm agents, antinociceptives, and antipsychotics . Advantageously, use of the 1,2,3‐triazole in place of the amide often affords increased biological activity, as demonstrated for viral infectivity factor (Vif) inhibitors 1 and 2 (Figure ) .…”

“…For example, the discovery that the amide in imatinib ( 4 ) could be substituted with the 1,2,3‐triazole led to further studies demonstrating that the Abl protein could assemble triazole inhibitor 5 from click fragments 6 and 7 in situ, making possible the use of the isCC strategy for the discovery of new classes of Abl inhibitors . Finally, in addition to enabling rapid analogue exploration using CuAAC or isCC, substitution with the 1,2,3‐triazole has also been demonstrated to improve physiochemical properties such as aqueous solubility and metabolic stability …”

“…[10] Finally,i na ddition to enabling rapid analoguee xploration using CuAACo ri sCC, substitution with the 1,2,3-triazole has also been demonstrated to improvep hysiochemical properties such as aqueous solubility [13] and metabolic stability. [14] Due to the widespread successo ft he 1,2,3-triazolea sa n amide bioisostere, we sought to evaluate the utility of this bioisostericr eplacement within amide-containing small molecule modulators of the cystic fibrosis transmembrane conductance regulator (CFTR)p rotein. CFTR is am ember of the ATP-binding cassette( ABC) transporter superfamily and is comprised of two membrane spanning domains (MSD1,M SD2), two nucleotide binding domains (NBD1, NBD2), and ar egulatory domain that controlsp rotein function via PKA-dependentp hosphorylation.…”

Varying Chirality Across Nicotinic Acetylcholine Receptor Subtypes: Selective Binding of Quinuclidine Triazole Compounds

“…22 There is not only the pharmacological benefit of using the anti-1,2,3-triazole as the linker, but the triazole moiety itself is stable and largely resistant to metabolic degradation. 23,24 In the present design, four different approaches were applied to the lead compound, (RS)-QND8 ( Figure 1B) to improve the potency and selectivity profiles at the most important neuronal nAChR subtypes (α7, α3β4, α4β2). First, the chirality at position 3 of the quinuclidine scaffold was investigated by individual analysis of the two enantiomers of the racemic compounds.…”