Drug Discovery for Soft Drugs on TRPV1 and TRPM8 Channels Using the Passerini Reaction
Multicomponent transformations, such as Ugi and Passerini reactions, allow for the fast synthesis of libraries of medium complexity, avoiding the formation of waste residues and significantly reducing time and money expenditure. Although the Ugi reaction has found a vast number of uses in medicinal chemistry, the employment of the Passerini reaction has received scant attention due to the formation of an α-acyloxyamide, which hardly resists the hydrolytic enzymes in the body. On the other hand, an overlooked possibility with the Passerini products is to exploit the presence of an ester group in the design and synthesis of soft drugs. We started to fill this gap, designing and synthesizing a series of TRPV1 and TRPM8 agonists able to act as soft drugs by using the Passerini reaction.
Key wordsTRPV1 TRPM8 Passerini reaction Isocyanide Multicomponent reactions Soft drugs
Financial support from Università del Piemonte Orientale—Novara—Italy and from Compagnia di San Paolo (Grant No. C61J12000280007) is acknowledged.
- 1.Zhu J, Wang Q, Wang M-X (2015) Multicomponent reactions in organic synthesis. Wiley-VCH Verlag GmbH & Co., WeinheimGoogle Scholar
- 3.Passerini M (1921) Sopra gli Isonitrili (I). Composto del p-Isonitrilazobenzolo con Acetone ed Acido Acetico. Gazz Chim Ital 51:126–129Google Scholar
- 4.Ugi I, Meyr U, Fetzer U, Steinbrückner C (1959) Versuche mit isonitrilen. Angew Chem 71:386–388Google Scholar
- 7.Leffingwell JC (2009) Cooling ingredient and their mechanism of action. In: Barel AO, Paye M, Maibach HI (eds) Handbook of cosmetic science and technology, Chapter 65. Informa Healthcare, New YorkGoogle Scholar
- 8.Welschoff N, Waldvogel SR (2010) Practical synthesis of optically pure menthylamines starting from racemic neomenthol. Synthesis 21:3596–3601; (1R,2S,5R)-2-isopropyl-5-methylcyclohexan-1-amine was synthesized according to the procedure reported by Welschoff et alGoogle Scholar