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

Brian Eastman; Chixu Chen; Nicholas D Smith; Steven Poon; Janice Chung; Grace Reyes-Manalo; Nicholas D P Cosford; Benito Munoz

doi:10.1016/j.bmcl.2004.09.016

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

Bioorg Med Chem Lett. 2004 Nov 15;14(22):5485-8. doi: 10.1016/j.bmcl.2004.09.016.

Authors

Brian Eastman¹, Chixu Chen, Nicholas D Smith, Steven Poon, Janice Chung, Grace Reyes-Manalo, Nicholas D P Cosford, Benito Munoz

Affiliation

¹ Department of Chemistry, Merck Research Laboratories, MRLSDB2, 3535 General Atomics Court, San Diego, CA 92121, USA.

PMID: 15482909
DOI: 10.1016/j.bmcl.2004.09.016

Abstract

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.

MeSH terms

Combinatorial Chemistry Techniques / methods
Isoxazoles* / chemical synthesis
Isoxazoles* / chemistry
Isoxazoles* / pharmacology
Molecular Structure
Receptor, Metabotropic Glutamate 5
Receptors, Metabotropic Glutamate / antagonists & inhibitors*
Solutions / chemistry
Structure-Activity Relationship

Substances

Isoxazoles
Receptor, Metabotropic Glutamate 5
Receptors, Metabotropic Glutamate
Solutions