3‐Heterocycle‐Phenyl N‐Alkylcarbamates as FAAH Inhibitors: Design,Synthesis and 3D‐QSAR Studies |
| |
| Authors: | Heikki Käsnänen Mikko J Myllymäki Anna Minkkilä Antti O Kataja Susanna M Saario Dr Tapio Nevalainen Dr Ari M P Koskinen Prof Dr Antti Poso Prof Dr |
| |
| Affiliation: | 1. Department of Chemistry, Helsinki University of Technology, P.O.Box 6100, 02015 TKK (Finland);2. Department of Pharmaceutical Chemistry, University of Kuopio, P.O.Box 1627, 70211 Kuopio (Finland), Fax: (+358)?17‐162‐456;3. The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037 (USA) |
| |
| Abstract: | Carbamates are a well‐established class of fatty acid amide hydrolase (FAAH) inhibitors. Here we describe the synthesis of meta‐substituted phenolic N‐alkyl/aryl carbamates and their in vitro FAAH inhibitory activities. The most potent compound, 3‐(oxazol‐2yl)phenyl cyclohexylcarbamate ( 2 a ), inhibited FAAH with a sub‐nanomolar IC50 value (IC50=0.74 nM ). Additionally, we developed and validated three‐dimensional quantitative structure–activity relationships (QSAR) models of FAAH inhibition combining the newly disclosed carbamates with our previously published inhibitors to give a total set of 99 compounds. Prior to 3D‐QSAR modeling, the degree of correlation between FAAH inhibition and in silico reactivity was also established. Both 3D‐QSAR methods used, CoMSIA and GRID/GOLPE, produced statistically significant models with coefficient of correlation for external prediction (R2PRED) values of 0.732 and 0.760, respectively. These models could be of high value in further FAAH inhibitor design. |
| |
| Keywords: | ab initio calculations molecular modeling FAAH inhibitors phenyl N‐alkylcarbamates structure– activity relationships |
|
|
