2-Aminothiophene scaffolds: Diverse biological and pharmacological attributes in medicinal chemistry

Scheme 20.
2.10. 2-ATs as allosteric EP2 receptor potentiators
Based on the ethyl 2-(furan-2-carboxamido)-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-3-carboxylate (73) [78, 79] and its analogues, Jiang et al. estimated the neuroprotective effects of allosteric EP2 receptor potentiators in 2010 [80]. Indeed, thiophene-3-carboxylate 73 (Scheme 21) potentiates EP2 receptors with EC₅₀=7.8 μM in a cAMP assay and also displays selective potentiation of EP2 receptors versus EP4 and β2-AR receptors. However, derivatives containing a COOH group at the 3-position and 3-carboxylates exhibit poor solubility. Notably, the water solubility of thiophene-3-carboxylates has not yet been improved, although in some cases, this improvement is not necessary, particularly when ATs are used as lead compounds. In addition, the ring size of the cycloalkane fragment, including the aliphatic ring, the ester linkage and the furan ring, was a critical determinant of activity. Moreover, a furan group or a similar sized thiophene or phenyl group maintained activity, whereas replacing the furan or thiophene ring with another cyclohetero ring, such as a pyridine or piperidine ring, caused a complete loss of activity.
Scheme 21.
2.11. 2-ATs as retinoid X receptor α agonists
In 2015, Sun et al. suggested that a small molecule, ethyl 2-amino-6-(tert-butyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate 74 (Scheme 22), functions as a selective RXRα agonist by inducing the heterodimerization of LXR/RXRα and PPAR-γ/RXRα [81]. Compound 74 effectively enhances β-amyloid clearance and improves daily life activities in amyloid precursor protein–PS1 transgenic mice by inducing the expression of the apolipoprotein E, ATP-binding cassette A1 and ATP-binding cassette G1 genes. In addition, thiophene derivatives might hold potential as a lead drug compound for the treatment of Alzheimer’s disease. Compound 74 is synthesized from 4-t-Bu-cyclohexanone, ethyl cyanoacetate, and elementary sulphur by a condensation reaction under basic conditions.