Thiazole‐Based σ₁ Receptor Ligands: Diversity by Late‐Stage C−H Arylation of Thiazoles, Structure–Affinity and Selectivity Relationships, and Molecular Interactions

Abstract

Spirocyclic thiophene derivatives represent promising σ ligands with high σ affinity and selectivity over the σ subtype. To increase ligand efficiency, the thiophene ring was replaced bioisosterically by a thiazole ring, and the pyran ring was opened. Late-stage diversification by regioselective C-H arylation of thiazoles 9 a-c resulted in a set of 53 compounds with high diversity. This set of compounds was analyzed with respect to σ affinity, σ /σ selectivity, lipophilicity (logD ), lipophilicity-corrected ligand efficiency (LELP), and molecular target interactions. The most promising candidates were pyridyl-substituted thiazole derivatives 33 c (2-(1-benzyl-4-ethoxypiperidin-4-yl)-5-(pyridin-3-yl)thiazole) and 34 c (2-(1-benzyl-4-ethoxypiperidin-4-yl)-5-(pyridin-4-yl)thiazole), possessing low-nanomolar σ affinity (K =1.3 and 1.9 nm), high σ /σ selectivity (>1500-fold), low lipophilicity (logD =1.8) and very good ligand efficiency (LELP=5.5), indicating promising pharmacodynamics and pharmacokinetics. Molecular simulation studies, including docking and deconvolution of the free binding energy into its major components, led to decreased hydrophobic stabilization of pyridyl derivatives 33 c and 34 c, which was compensated by lower desolvation energy.

Recent Advances in the Development of Sigma Receptor Ligands as Cytotoxic Agents: A Medicinal Chemistry Perspective

“…Thus, we suggest that this chemical scaffold may be further exploited by structural simplification or bioisosteric replacements. 114 …”

“…In general, spirocyclic piperidines seemed to act as σ 1 R antagonists with cytotoxic properties. Thus, we suggest that this chemical scaffold may be further exploited by structural simplification or bioisosteric replacements …”

Small Molecules Selectively Targeting Sigma-1 Receptor for the Treatment of Neurological Diseases

“…However, the C5-arylated thiazole 73 shows higher σ 1 receptor selectivity over σ 2 receptors. The 5-pyridyl substituted thiazole derivatives 75 and 76 were the most promising candidates and exhibit low nanomolar affinity at the σ 1 receptor ( K i = 1.3–1.9 nM), high σ 1 /σ 2 selectivity (>1500-fold), and good ligand efficiency . Additionally, Efange and colleagues described a series of ring-opening spipethiane analogues by replacing the sulfur atom with a carbonyl ( 77 ), hydroxylmethenyl ( 78 – 79 ), or 3-bromobenzylamine ( 80 ) bridge (Figure ).…”

“…In contrast to the other three isomers which behaved as σ 1 receptor antagonists, trans-(+)-70 exhibited a σ 1 receptor agonist profile. 177 To reduce lipophilicity and enhance polarity, the Wunsch group 178,179 designed thiazole-based σ 1 receptor ligands by bioisosterically replacing the thiophene ring and opening the pyran ring of spirocyclic thiophene derivatives 71−72 (Figure 15). Although spirocyclic thiophene 71 with an aryl substituent at the β-position shows considerably higher σ 1 affinity than its regioisomer 72 with the aryl moiety at the α-position, their corresponding ring-opened thiazole derivatives 73 and 74, separately arylated at the C5-and C4-position, display conserved σ 1 receptor affinity due to free rotation around the piperidine−thiazole bond.…”

Isothermal Titration Calorimetry for the Screening of Aflatoxin B1 Surface-Enhanced Raman Scattering Sensor Affinity Agents

“…Methods have been developed for aptamer screening, such as systematic evolution of ligands by exponential enrichment (SELEX) and DNA microarray technology, but these are not easily adapted to other synthetic affinity agents. The screening of small molecule/target binding has been accomplished virtually − and empirically, by ligand assays, , NMR, and MS . Polymers, whether used linearly or as cross-linked molecular imprinted systems, have used similar virtual methods , and empirical assays .…”