Chain branching approach in structure modification of TRPV1 receptor antagonist MK056 and its analogs

Article abstract of DOI:10.1007/s12272-012-0212-x

A series of chain branched 1,3-dibenzylthiourea derivatives were designed, synthesized, and evaluated for their antagonist activity against TRPV1. The synthesized chain branched 1,3dibenzylthioureas 9a-g were tested for their antagonist activities against TRPV1 by ⁴⁵ Ca ²⁺ influx assay using neonatal rat cultured spinal sensory neurons. Fluorinated ethyl-branched analog 9g showed the most potent antagonist activity with an IC₅₀ value of 0.41 μM, but all of the chain branched analogs were less potent than the parent compounds MK-056 and SC0030, indicating that chain branching on the benzylic position of B-ring is detrimental to potency. Optimized receptor binding seems to be interfered by chain branching, and resulted in decrease in potency.