I. Optimization and analysis of the central heterocycle of alpha-ketoheterocycle inhibitors of fatty acid amide hydrolase. II. Total synthesis of chloropeptin II (complestatin) and progress towards a second generation total synthesis of chloropeptin I and

The synthesis and evaluation of a series of alpha-ketoheterocycles that incorporate systematic changes in the central heterocycle, which provided extraordinarily potent (Ki = 300 pM) inhibitors of fatty acid amide hydrolase, have been completed. The nature of the central heterocycle, even with the modest and systematic perturbations explored herein, significantly influenced the inhibitor activity and can be summarized as 1,3,4-oxadiazoles (50) and 1,2,4-oxadiazoles (50) > tetrazoles (5), the isomeric 1,2,4-oxadiazoles (7), 1,3,4-thiadiazoles (2--30) > oxazoles (rel. activity = 1) > 1,2-diazines (0.3) > thiazoles (0.06) > 1,3,4-triazoles (--). Most evident in the results is that the introduction of an additional position 4 heteroatom (oxazole numbering) substantially increases the activity (N > O > CH), by the addition of a H-bonding interaction between the heteroatom and the cytosolic port water molecule H-bonding network, which has been validated through X-ray crystallographic studies. Within each heterocycle series, the impact of an added substituent was systematically explored and was found to follow well defined trends. Exemplifying these effects, additional aryl substituents (e.g., 2-pyr or 2-pyr-6-CO 2H) placed on the central heterocycle increase FAAH potency, and significantly modify physical properties (e.g., solubility) in a manner that may impact pharmacokinetic and pharmacodynamic behavior of the inhibitors. Just as significantly, the nature of the substituent substantially impacts the selectivity of the FAAH inhibitors and these trends proved general across the range of inhibitors examined.;In the course of these studies, we have solidified the use of a novel disconnection strategy to complete the first total synthesis of complestatin (chloropeptin II). Key to the synthesis of this complex natural product is the preparation of several unnatural amino acids in a scalable fashion, the optimization of the Larock heteroannulation to close what has been a challenging macrocycle, and use of a novel SNAr cyclization to form the biaryl ether portion of complestatin.