Novel N-substituted 2-phenyl-1-sulfonylamino-cyclopropane carboxylates as selective ADAMTS-5 (Aggrecanase-2) inhibitors

Further insights into the SAR of α-substituted cyclopropylamine derivatives as inhibitors of histone demethylase KDM1A

“…The synthesis of the spiro amides 63 and 66 was achieved through the key intermediate 61, already reported [39]. Briefly, the inexpensive precursors benzaldehyde and diethyl malonate were first reacted in toluene at 80 C for 48 h. The use of MW irradiation drastically reduced the reaction time, although with no improvement in the yield.…”

Pharmacophore-Based Design of Phenyl-[hydroxycyclohexyl] Cycloalkyl-Carboxamide Mitofusin Activators with Improved Neuronal Activity

“…Here, we extended mitofusin activator design by employing the previously described pharmacophore-based strategy . We considered that structurally more rigid and metabolically stable compounds resulting from introduction of cycloalkyl modifications into the hexanamide linker − might have a greater engagement of neuronal mitochondria. In particular, introduction of cyclopropyl rings into different compounds has increased potency, selectivity, oral bioavailability, metabolic and chemical stability, or neurological system exposure.…”

Arylcyclopropanes: Properties, Synthesis and Use in Medicinal Chemistry

“…Cyclopropanes have also been used to lock biologically relevant compounds into their bioactive conformations, thus providing enhancement in potency. For these reasons, it is not surprising to find this smallest cycloalkyl group in many structure activity relationship In one example, researchers at Japan Tobacco reported the preparation of compound 30 as potent ADAMTS-5 (A Disintegrin and Metalloprotease with Thrombospondin Motifs) inhibitor 42 and observed an important increase in potency following the introduction of a cyclopropyl linker in the structure (compound 31, Scheme 8, Agg-2 = aggrecanase-2). This improvement in activity was attributed to the rigidifying effect provided by the cyclopropyl group which positioned the pharmacophores in the optimal binding conformation.…”