Investigations on the 4-Quinolone-3-carboxylic Acid Motif. 7. Synthesis and Pharmacological Evaluation of 4-Quinolone-3-carboxamides and 4-Hydroxy-2-quinolone-3-carboxamides as High Affinity Cannabinoid Receptor 2 (CB2R) Ligands with Improved Aqueous Solubility

  • J Med Chem. 2016 Feb 11;59(3):1052-67. doi: 10.1021/acs.jmedchem.5b01559.
Claudia Mugnaini  1 ,  Antonella Brizzi  1 ,  Alessia Ligresti  2 ,  Marco Allarà  2 ,  Stefania Lamponi  1 ,  Federica Vacondio  3 ,  Claudia Silva  3 ,  Marco Mor  3 ,  Vincenzo Di Marzo  2 ,  Federico Corelli  1
Affiliations
  • 1. Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena , Via Aldo Moro 2, 53100 Siena, Italy.
  • 2. Endocannabinoid Research Group, Istituto di Chimica Biomolecolare, Consiglio Nazionale delle Ricerche , Via dei Campi Flegrei 34, 80078 Pozzuoli (Napoli), Italy.
  • 3. Dipartimento di Farmacia, Università degli Studi di Parma , Parco Area delle Scienze 27/A, 43124 Parma, Italy.
PMID: 26756097 DOI: 10.1021/acs.jmedchem.5b01559
Abstract

4-Quinolone-3-carboxamide derivatives have long been recognized as potent and selective cannabinoid type-2 receptor (CB2R) ligands. With the aim to improve their physicochemical properties, basically aqueous solubility, two different approaches were followed, entailing the substitution of the alkyl chain with a basic replacement or scaffold modification to 4-hydroxy-2-quinolone structure. According to the first approach, compound 6d was obtained, showing slightly reduced receptor affinity (K(i) = 60 nM) compared to the lead compound 4 (0.8 nM) but greatly enhanced solubility (400-3400 times depending on the pH of the medium). On the Other hand, shifting from 4-quinolone to 4-hydroxy-2-quinolone structure enabled the discovery of a novel class of CB2R ligands, such as 7b and 7c, characterized by K(i) < 1 nM and selectivity index [SI = K(i)(CB1R)/K(i)(CB2R)] > 1300. At pH 7.4, compound 7c resulted by 100-fold more soluble than 4.