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.

[1]  W. Spooren,et al.  Effects of the prototypical mGlu(5) receptor antagonist 2-methyl-6-(phenylethynyl)-pyridine on rotarod, locomotor activity and rotational responses in unilateral 6-OHDA-lesioned rats. , 2000, European journal of pharmacology.

[2]  P. McKenna,et al.  Expression of the human excitatory amino acid transporter 2 and metabotropic glutamate receptors 3 and 5 in the prefrontal cortex from normal individuals and patients with schizophrenia. , 1998, Brain research. Molecular brain research.

[3]  M. Siegel,et al.  Solution phase synthesis of libraries of variably substituted olefin scaffolds: a library of allylic amines. , 2001, Journal of combinatorial chemistry.

[4]  P Jeffrey Conn,et al.  A family of highly selective allosteric modulators of the metabotropic glutamate receptor subtype 5. , 2003, Molecular pharmacology.

[5]  Boliang Lou,et al.  Novel strategies for solid-phase construction of small-molecule combinatorial libraries. , 2001, Drug discovery today.

[6]  Y. Smith,et al.  Activation of Metabotropic Glutamate Receptor 5 Has Direct Excitatory Effects and Potentiates NMDA Receptor Currents in Neurons of the Subthalamic Nucleus , 2000, The Journal of Neuroscience.

[7]  Mark Washburn,et al.  3-[(2-Methyl-1,3-thiazol-4-yl)ethynyl]-pyridine: a potent and highly selective metabotropic glutamate subtype 5 receptor antagonist with anxiolytic activity. , 2003, Journal of medicinal chemistry.

[8]  R. Sammelson,et al.  Carbon-carbon bond-forming solid-phase reactions. Part II. , 2001, Chemical reviews.

[9]  A. Y. Meyer.  Molecular mechanics and molecular shape. Part 4. Size, shape, and steric parameters , 1987 .

[10]  F. Conquet,et al.  Reinforcing and locomotor stimulant effects of cocaine are absent in mGluR5 null mutant mice , 2001, Nature Neuroscience.

[11]  W. Spooren,et al.  Novel allosteric antagonists shed light on mglu(5) receptors and CNS disorders. , 2001, Trends in pharmacological sciences.

[12]  N. Cosford,et al.  Discovery of novel heteroarylazoles that are metabotropic glutamate subtype 5 receptor antagonists with anxiolytic activity. , 2004, Journal of medicinal chemistry.