TY - JOUR
T1 - 2,3-Dihydro-1-benzofuran derivatives as a series of potent selective cannabinoid receptor 2 agonists
T2 - Design, synthesis, and binding mode prediction through ligand-steered modeling
AU - Diaz, Philippe
AU - Phatak, Sharangdhar S.
AU - Xu, Jijun
AU - Fronczek, Frank R.
AU - Astruc-Diaz, Fanny
AU - Thompson, Charles M.
AU - Cavasotto, Claudio N.
AU - Naguib, Mohamed
PY - 2009
Y1 - 2009
N2 - We recently discovered and reported a series of N-alkyl-isatin acylhydrazone derivatives that are potent cannabinoid receptor 2 (CB 2) agonists. In an effort to improve the druglike properties of these compounds and to better understand and improve the treatment of neuropathic pain, we designed and synthesized a new series of 2,3-dihydro-1-benzofuran derivatives bearing an asymmetric carbon atom that behave as potent selective CB2 agonists. We used a multidisciplinary medicinal chemistry approach with binding mode prediction through ligand-steered modeling. Enantiomer separation and configuration assignment were carried out for the racemic mixture for the most selective compound, MDA7 (compound 18). It appeared that the S enantiomer, compound MDA104 (compound 33), was the active enantiomer. Compounds MDA42 compound 19) and MDA39 (compound 30) were the most potent at CB2. MDA42 was tested in a model of neuropathic pain and exhibited activity in the same range as that of MDA7. Preliminary ADMET studies for MDA7 were performed and did not reveal any problems.
AB - We recently discovered and reported a series of N-alkyl-isatin acylhydrazone derivatives that are potent cannabinoid receptor 2 (CB 2) agonists. In an effort to improve the druglike properties of these compounds and to better understand and improve the treatment of neuropathic pain, we designed and synthesized a new series of 2,3-dihydro-1-benzofuran derivatives bearing an asymmetric carbon atom that behave as potent selective CB2 agonists. We used a multidisciplinary medicinal chemistry approach with binding mode prediction through ligand-steered modeling. Enantiomer separation and configuration assignment were carried out for the racemic mixture for the most selective compound, MDA7 (compound 18). It appeared that the S enantiomer, compound MDA104 (compound 33), was the active enantiomer. Compounds MDA42 compound 19) and MDA39 (compound 30) were the most potent at CB2. MDA42 was tested in a model of neuropathic pain and exhibited activity in the same range as that of MDA7. Preliminary ADMET studies for MDA7 were performed and did not reveal any problems.
KW - Agonists
KW - Benzofuran derivatives
KW - Cannabinoid receptor 2
KW - Ligand-steered modeling
KW - Receptors
UR - http://www.scopus.com/inward/record.url?scp=70249098305&partnerID=8YFLogxK
U2 - 10.1002/cmdc.200900226
DO - 10.1002/cmdc.200900226
M3 - Article
C2 - 19637157
AN - SCOPUS:70249098305
SN - 1860-7179
VL - 4
SP - 1615
EP - 1629
JO - ChemMedChem
JF - ChemMedChem
IS - 10
ER -