Expedited SAR study of an mGluR5 antagonists: generation of a focused library using a solution-phase Suzuki coupling methodology

The SAR of the lead compounds 2a and 2b was rapidly explored. Utilizing a parallel solution-phase Suzuki coupling approach, in tandem with strong cation exchange resin (SCX) purification afforded the desired focused library. The library was evaluated in vitro, a ninefold potency increase was achieved and the preference for ortho substitution of moderate steric bulk of the fourth, phenyl ring was identified. In addition, dimethylisoxazole, as a heterocyclic replacement for the phenylic ring of the lead compound, was also identified by this approach.