Liquid chromatography/tandem mass spectrometry (LC/MS/MS) methods developed for quantification using rapid ('ballistic') gradients on narrow bore, short HPLC columns have been previously described by this laboratory. This paper compares the fast gradient approach with the more traditional high-organic isocratic LC/MS/MS methods. The comparison is based on an analysis of the effectiveness of the chromatographic separations when using the two approaches (i.e. k', N, and W). The data presented herein are derived from actual biological samples analyzed as part of the drug discovery process.

The design and synthesis of a novel class of 2,3-dihydrobenzofuran-2-carboxylic acids as highly potent and subtype-selective PPARalpha agonists are reported. Systematic study of structure-activity relationships has identified several key structural elements within this class for maintaining the potency and subtype selectivity. Select compounds were evaluated in animal models of dyslipidemia using Syrian hamsters and male Beagle dogs, and all these compounds displayed excellent cholesterol- and triglyceride-lowering activity at dose levels that were much lower than the marketed weak PPARalpha agonist fenofibrate.

ABSTRACT:We report herein the identification of MK-4409, a potent and selective fatty acid amide hydrolase (FAAH) inhibitor. Starting from a high throughput screening (HTS) hit, medicinal chemistry efforts focused on optimizing of FAAH inhibition in vitro potency, improving the pharmacokinetic (PK) profile, and increasing in vivo efficacy in rodent inflammatory and neuropathic pain assays. KEYWORDS:Fatty acid amide hydrolase, FAAH, oxazole, pyrazole, neuropathic pain, inflammatory pain, MK-4409, enzyme, inhibitor, CNS F atty acid amide hydrolase (FAAH) is an integral, membrane-bound enzyme responsible for the breakdown of fatty acid ethanolamide (FAE) signaling molecules, such as the endocanabinoid arachidonyl ethanolamide (anandamide, AEA), N-palmitoyl ethanolamide (PEA), and N-oleoyl ethanolamide (OEA). FAAH is a member of the serine hydrolase amidase signature family, which utilizes an unusual serine−serine−lysine catalytic triad. 1,2 Inhibition of FAAH leads to elevated levels of these endogenous FAEs, which act on cannabinoid receptors implicated in the suppression of pain transmission. 3 Levels of these FAEs were shown to be significantly elevated in FAAH knockout (KO) mice as compared to wild-type controls. 4 Both genetic knockout of FAAH and pharmacological modulation of FAAH activity demonstrated reduced sensitivity to pain. 5 Thus, FAAH inhibitors are expected to provide therapeutic benefits in the management of inflammatory and neuropathic pain. 6−9 Several classes of covalent and noncovalent FAAH inhibitors have been reported to date (Figure 1). Several covalent FAAH inhibitors that irreversibly inhibit FAAH by carbamylation of Ser241 have been reported and are exemplified by [10][11][12] A second subclass of FAAH inhibitors are the keto-oxazole class of FAAH inhibitors as exemplified by OL-135, 13 which reversibly forms an enzymestabilized hemiketal through a particularly reactive electrophilic carbonyl. More recently, however, several scaffolds have been disclosed as reversible noncovalent modifying inhibitors of

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