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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.JM

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.

Authors+Show Affiliations

Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena , Via Aldo Moro 2, 53100 Siena, Italy.Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena , Via Aldo Moro 2, 53100 Siena, Italy.Endocannabinoid Research Group, Istituto di Chimica Biomolecolare, Consiglio Nazionale delle Ricerche , Via dei Campi Flegrei 34, 80078 Pozzuoli (Napoli), Italy.Endocannabinoid Research Group, Istituto di Chimica Biomolecolare, Consiglio Nazionale delle Ricerche , Via dei Campi Flegrei 34, 80078 Pozzuoli (Napoli), Italy.Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena , Via Aldo Moro 2, 53100 Siena, Italy.Dipartimento di Farmacia, Università degli Studi di Parma , Parco Area delle Scienze 27/A, 43124 Parma, Italy.Dipartimento di Farmacia, Università degli Studi di Parma , Parco Area delle Scienze 27/A, 43124 Parma, Italy.Dipartimento di Farmacia, Università degli Studi di Parma , Parco Area delle Scienze 27/A, 43124 Parma, Italy.Endocannabinoid Research Group, Istituto di Chimica Biomolecolare, Consiglio Nazionale delle Ricerche , Via dei Campi Flegrei 34, 80078 Pozzuoli (Napoli), Italy.Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena , Via Aldo Moro 2, 53100 Siena, Italy.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26756097

Citation

Mugnaini, Claudia, et al. "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." Journal of Medicinal Chemistry, vol. 59, no. 3, 2016, pp. 1052-67.
Mugnaini C, Brizzi A, Ligresti A, et al. 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;59(3):1052-67.
Mugnaini, C., Brizzi, A., Ligresti, A., Allarà, M., Lamponi, S., Vacondio, F., Silva, C., Mor, M., Di Marzo, V., & Corelli, F. (2016). 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. Journal of Medicinal Chemistry, 59(3), 1052-67. https://doi.org/10.1021/acs.jmedchem.5b01559
Mugnaini C, et al. 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. PubMed PMID: 26756097.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Mugnaini,Claudia, AU - Brizzi,Antonella, AU - Ligresti,Alessia, AU - Allarà,Marco, AU - Lamponi,Stefania, AU - Vacondio,Federica, AU - Silva,Claudia, AU - Mor,Marco, AU - Di Marzo,Vincenzo, AU - Corelli,Federico, Y1 - 2016/01/26/ PY - 2016/1/13/entrez PY - 2016/1/13/pubmed PY - 2016/7/13/medline SP - 1052 EP - 67 JF - Journal of medicinal chemistry JO - J Med Chem VL - 59 IS - 3 N2 - 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. SN - 1520-4804 UR - https://www.unboundmedicine.com/medline/citation/26756097/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_ L2 - https://doi.org/10.1021/acs.jmedchem.5b01559 DB - PRIME DP - Unbound Medicine ER -