Discovery of Novel TRPM8 Blockers Suitable for the Treatment of Somatic and Ocular Painful Conditions: A Journey through pKa and LogD Modulation

Autor:	Andrea Aramini, Silvia Bovolenta, Chiara Liberati, Lorena Za, Gianluca Bianchini, Mara Tomassetti, Samuele Lillini, Rubina Novelli, Anna Sirico
Rok vydání:	2021
Předmět:	Drug Chemistry media_common.quotation_subject Pharmacology Metabolic stability Transient receptor potential channel chemistry.chemical_compound Ocular tissue In vivo Drug Discovery TRPM8 Chemical groups Molecular Medicine Menthol media_common
Zdroj:	Journal of Medicinal Chemistry. 64:16820-16837
ISSN:	1520-4804 0022-2623
Popis:	Transient receptor potential melastatin 8 (TRPM8) is crucially involved in pain modulation and perception, and TRPM8 antagonists have been proposed as potential therapeutic approaches for pain treatment. Previously, we developed two TRPM8 antagonists and proposed them as drug candidates for topical and systemic pain treatment. Here, we describe the design and synthesis of these two TRPM8 antagonists (27 and 45) and the rational approach of modulation/replacement of bioisosteric chemical groups, which allowed us to identify a combination of narrow ranges of pKa and LogD values that were crucial to ultimately optimize their potency and metabolic stability. Following the same approach, we then pursued the development of new TRPM8 antagonists suitable for the topical treatment of ocular painful conditions and identified two new compounds (51 and 59), N-alkoxy amide derivatives, that can permeate across ocular tissue and reduce the behavioral responses induced by the topical ocular menthol challenge in vivo.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_________::53312ae842dabe5b01fc01282381239f https://doi.org/10.1021/acs.jmedchem.1c01647 Zobrazit plný text záznamu