This SAR work led to the identification

This SAR work led to the identification of compound 10r ((±)-2-[3-fluoro-4-[3-(hexylcarbamoyloxy)phenyl]phenyl]propanoic acid, ARN2508) [51] as a potent in vivo active inhibitor of intracellular FAAH and COX activities, which exerts profound anti-inflammatory effects in mouse models of IBD without causing COX-dependent gastric toxicity [51]. In the present study, (a) we outline the in-depth SAR investigations that led to the discovery of compound 10r[51]; (b) we report an expansion of this SAR work, which culminated in the identification of several new and potent multitarget inhibitors (18b, 29a-c and 29e); and, finally (c) we describe the absolute configurational assignment and pharmacological properties of single enantiomers of 10r, identifying (S)-(+)-10r as the first chiral inhibitor of FAAH-COX with marked in vivo activity.
Results and discussion
Conclusions The present study outlines key SAR properties of a novel class of dual inhibitors of intracellular FAAH and COX activities, which are based on the hybrid scaffold 1. Several chemical variations of this scaffold were considered, which involved the carbamate moiety at the 3′-position of the A phenyl ring, the R groups, and the propionic SB202190 moiety and fluorine atom in the B phenyl ring. Introduction of different alkyl and aromatic groups in the N-terminal region of the carbamate functionality improved inhibitory potency toward both FAAH and COX. A more focused exploration around the potent, selective and orally available racemic inhibitor 10r[51] led to the identification of novel potent analogs, 29a-c, and e. Because of the problems associated with the development of racemic compounds, we extended our studies and identified two additional molecules, the achiral compound 18b and the enantiomer (S)-(+)-10r, which also display high inhibitory potency for FAAH/COX-1/COX-2. The in vivo activity of (S)-(+)-10r suggests that this agent may be used to probe the therapeutic utility of simultaneous FAAH-COX inhibition, especially in pathologies in which these enzymes are abnormally expressed.
Experimental part
Conflict of interest
Acknowledgment The authors thank Dr Angelo Reggiani for helpful discussions, Ms Silvia Venzano and Mr Luca Goldoni for technical support and the National Institute on Drug Abuse (grant DA012413 to D.P.) for financial support.
The brain is the primary moderator of numerous biological processes for which pharmacological intervention may be of clinical benefit. However, it is effectively separated from circulating blood by the blood–brain barrier (BBB) and the blood-cerebrospinal fluid barrier. Of the two, the BBB is the most important as its surface area is several thousand fold greater than that of the blood-cerebrospinal fluid barrier., , The BBB lines the vasculature of the CNS and consists of endothelial cells with continuous tight intercellular junctions overlaying the basement membrane which in turn overlays astrocytes. The BBB is also armed with an assortment of efflux transporters and metabolic enzymes that collectively tend to keep proteins and other large molecules (mw>500) as well as small polar or charged species from entering the brain., , , , , While a certain amount of lipophilic character is required for passive diffusion into the CNS, the relationship between lipophilicity and brain uptake tends to be parabolic in nature, with neither the exceptionally polar nor excessively lipophilic compounds penetrating readily., , Published reports suggest that a molecule’s ability to pass the BBB tends to be poor when it possesses any of the following characteristics: mw>450g/mol; Log>4; hydrogen bond donors>5; ∑N+O>10., , , For many classes of CNS drugs, it has been found that the ideal Log lies between 2 and 3.5., , , , , , Correlations between the topological polar surface areas (TPSAs) of molecules and their ability to penetrate the CNS have also been found., CNS penetrant compounds typically have TPSAs below 90Å, with many below 60Å.