TRPV1 modulators: Structure–activity relationships using a rational combinatorial approach

• Published in: Bioorganic & medicinal chemistry letters 2011-06, Vol.21 (12), p.3541-3545
• Main Authors: Zaccaro, Laura, García-López, M. Teresa, González-Muñiz, Rosario, García-Martínez, Carolina, Ferrer-Montiel, Antonio, Albericio, Fernando, Royo, Miriam
• Format: Article
• Language: English
• Subjects: Analgesics; antagonists; Anti-Inflammatory Agents - chemical synthesis; Anti-Inflammatory Agents - chemistry; Anti-Inflammatory Agents - pharmacology; Biological and medical sciences; chemical derivatives; Combinatorial Chemistry Techniques; Combinatorial library; Dipeptides; Dipeptides - chemistry; Humans; Hydantoins; Hydantoins - chemistry; Indoles - chemical synthesis; Indoles - chemistry; Indoles - pharmacology; ion channels; lysine; Medical sciences; Molecular Structure; Neuropharmacology; Pharmacology. Drug treatments; SAR studies; Small Molecule Libraries - chemical synthesis; Small Molecule Libraries - chemistry; Small Molecule Libraries - pharmacology; Structure-Activity Relationship; structure-activity relationships; TRPV Cation Channels - antagonists & inhibitors; TRPV Cation Channels - drug effects; TRPV1; tryptophan; Tryptophan - chemical synthesis; Tryptophan - chemistry; Tryptophan - pharmacology
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2011.04.141

A discrete library of linear and hydantoin-containing dipeptide derivatives, based on the Lys-Trp(Nps) scaffold, was prepared by solid-phase synthesis. SAR studies indicated that potency for TRPV1 blockade and selectivity towards NMDA is mainly dictated by the side-chain length and the basic nature of α, ω-groups in the N-terminal residue. The 2-Nps moiety at position 2 of Trp indole ring is preferred over the 2-pyridine one.