A novel class of AMPA receptor allosteric modulators. Part 1: design, synthesis, and SAR of 3-aryl-4-cyano-5-substituted-heteroaryl-2-carboxylic acid derivatives

Maria-Carmen Fernandez; Ana Castaño; Esteban Dominguez; Ana Escribano; Delu Jiang; Alma Jimenez; Eric Hong; William J Hornback; Eric S Nisenbaum; Nancy Rankl; Eric Tromiczak; Grant Vaught; Hamideh Zarrinmayeh; Dennis M Zimmerman

doi:10.1016/j.bmcl.2006.07.035

A novel class of AMPA receptor allosteric modulators. Part 1: design, synthesis, and SAR of 3-aryl-4-cyano-5-substituted-heteroaryl-2-carboxylic acid derivatives

Bioorg Med Chem Lett. 2006 Oct 1;16(19):5057-61. doi: 10.1016/j.bmcl.2006.07.035. Epub 2006 Aug 1.

Authors

Maria-Carmen Fernandez¹, Ana Castaño, Esteban Dominguez, Ana Escribano, Delu Jiang, Alma Jimenez, Eric Hong, William J Hornback, Eric S Nisenbaum, Nancy Rankl, Eric Tromiczak, Grant Vaught, Hamideh Zarrinmayeh, Dennis M Zimmerman

Affiliation

¹ Lilly S.A., Avenida de la Industria, 30, 28108 Alcobendas, Madrid, Spain. fernandez_maria-carmen@lilly.com

PMID: 16879964
DOI: 10.1016/j.bmcl.2006.07.035

Abstract

The synthesis and initial SAR studies of novel, highly potent positive allosteric modulators of AMPA receptors based on 3-(4-tert-butylphenyl)-4-cyano-5-methylsulfanyl-thiophene-2-carboxylic acid (6a) are described. SAR studies at the thioether moiety indicated that substitution at this position was mandatory and better potency was achieved with small groups.

MeSH terms

Allosteric Regulation
Carboxylic Acids
Drug Design
Excitatory Amino Acid Agents / chemical synthesis*
Excitatory Amino Acid Agents / pharmacology
Heterocyclic Compounds / chemical synthesis*
Heterocyclic Compounds / pharmacology
Humans
Receptors, AMPA / drug effects*
Structure-Activity Relationship
Sulfides

Substances

Carboxylic Acids
Excitatory Amino Acid Agents
Heterocyclic Compounds
Receptors, AMPA
Sulfides