Literature DB >> 17210250

Challenges in the development of mGluR5 positive allosteric modulators: the discovery of CPPHA.

Zhijian Zhao1, David D Wisnoski, Julie A O'Brien, Wei Lemaire, David L Williams, Marlene A Jacobson, Marion Wittman, Sookhee N Ha, Herve Schaffhauser, Cyrille Sur, Doug J Pettibone, Mark E Duggan, P Jeffrey Conn, George D Hartman, Craig W Lindsley.   

Abstract

This Letter describes, for the first time, the synthesis and SAR, developed through an iterative analog library approach, that led to the discovery of the positive allosteric modulator (PAM) of the metabotropic glutamate receptor mGluR5 CPPHA. Binding to a unique allosteric binding site distinct from other mGluR5 PAMs, CPPHA has been the focus of numerous pharmacology studies by several laboratories.

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Year:  2006        PMID： 17210250     DOI： 10.1016/j.bmcl.2006.11.081

Source DB:  PubMed          Journal:  Bioorg Med Chem Lett        ISSN： 0960-894X            Impact factor:   2.823


  44 in total

1.  Discovery of novel allosteric modulators of metabotropic glutamate receptor subtype 5 reveals chemical and functional diversity and in vivo activity in rat behavioral models of anxiolytic and antipsychotic activity.

Authors:  Alice L Rodriguez; Mark D Grier; Carrie K Jones; Elizabeth J Herman; Alexander S Kane; Randy L Smith; Richard Williams; Ya Zhou; Joy E Marlo; Emily L Days; Tasha N Blatt; Satyawan Jadhav; Usha N Menon; Paige N Vinson; Jerri M Rook; Shaun R Stauffer; Colleen M Niswender; Craig W Lindsley; C David Weaver; P Jeffrey Conn
Journal:  Mol Pharmacol       Date:  2010-10-05       Impact factor: 4.436

2.  Allosteric modulation of seven transmembrane spanning receptors: theory, practice, and opportunities for central nervous system drug discovery.

Authors:  Bruce J Melancon; Corey R Hopkins; Michael R Wood; Kyle A Emmitte; Colleen M Niswender; Arthur Christopoulos; P Jeffrey Conn; Craig W Lindsley
Journal:  J Med Chem       Date:  2012-01-06       Impact factor: 7.446

3.  Discovery of molecular switches within the ADX-47273 mGlu5 PAM scaffold that modulate modes of pharmacology to afford potent mGlu5 NAMs, PAMs and partial antagonists.

Authors:  Jeffrey P Lamb; Darren W Engers; Colleen M Niswender; Alice L Rodriguez; Daryl F Venable; P Jeffrey Conn; Craig W Lindsley
Journal:  Bioorg Med Chem Lett       Date:  2010-12-03       Impact factor: 2.823

4.  Discovery of heterobicyclic templates for novel metabotropic glutamate receptor subtype 5 antagonists.

Authors:  Santosh S Kulkarni; Amy Hauck Newman
Journal:  Bioorg Med Chem Lett       Date:  2007-03-24       Impact factor: 2.823

5.  Cyclopropyl-containing positive allosteric modulators of metabotropic glutamate receptor subtype 5.

Authors:  Sirish K Lakkaraju; Hannah Mbatia; Marie Hanscom; Zaorui Zhao; Junfang Wu; Bogdan Stoica; Alexander D MacKerell; Alan I Faden; Fengtian Xue
Journal:  Bioorg Med Chem Lett       Date:  2015-04-20       Impact factor: 2.823

6.  Synthesis and SAR of analogues of the M1 allosteric agonist TBPB. Part I: Exploration of alternative benzyl and privileged structure moieties.

Authors:  Thomas M Bridges; Ashley E Brady; J Phillip Kennedy; R Nathan Daniels; Nicole R Miller; Kwango Kim; Micah L Breininger; Patrick R Gentry; John T Brogan; Carrie K Jones; P Jeffrey Conn; Craig W Lindsley
Journal:  Bioorg Med Chem Lett       Date:  2008-09-10       Impact factor: 2.823

7.  Synthesis and SAR of a mGluR5 allosteric partial antagonist lead: unexpected modulation of pharmacology with slight structural modifications to a 5-(phenylethynyl)pyrimidine scaffold.

Authors:  Sameer Sharma; Alice L Rodriguez; P Jeffrey Conn; Craig W Lindsley
Journal:  Bioorg Med Chem Lett       Date:  2008-05-29       Impact factor: 2.823

Review 8.  Allosteric modulators of g protein-coupled receptors: future therapeutics for complex physiological disorders.

Authors:  Liyun Wang; Bronwen Martin; Randall Brenneman; Louis M Luttrell; Stuart Maudsley
Journal:  J Pharmacol Exp Ther       Date:  2009-08-10       Impact factor: 4.030

9.  Discovery and SAR of novel mGluR5 non-competitive antagonists not based on an MPEP chemotype.

Authors:  Alice L Rodriguez; Richard Williams; Ya Zhou; Stacey R Lindsley; Uyen Le; Mark D Grier; C David Weaver; P Jeffrey Conn; Craig W Lindsley
Journal:  Bioorg Med Chem Lett       Date:  2009-05-03       Impact factor: 2.823

10.  Synthesis and SAR of analogs of the M1 allosteric agonist TBPB. Part II: Amides, sulfonamides and ureas--the effect of capping the distal basic piperidine nitrogen.

Authors:  Nicole R Miller; R Nathan Daniels; Thomas M Bridges; Ashley E Brady; P Jeffrey Conn; Craig W Lindsley
Journal:  Bioorg Med Chem Lett       Date:  2008-09-11       Impact factor: 2.823
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