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  • The in vivo IC M in


    The in vivo IC (0.0003μM) in the adipose tissue assay is in very good agreement with the in vitro IC (0.0005μM), and it is larger than the one measured in the OLTT assay (0.00005μM) for this compound. These differences in in vivo IC between OLTT and TAG synthesis are expected as we used free Blebbistatin receptor concentration in plasma as a surrogate for compound concentration at the target. In the OLTT assay we believe that local compound concentrations in the gut are driving effects and therefore using systemic exposure as a surrogate will underestimate the compound concentrations at the target leading to a smaller IC. For the adipose TAG synthesis assay that does not seem to be the case and the observed in vivo IC using free compound concentration in plasma is in very good agreement with the in vitro one. To assess the activity in a model of diet-induced obesity (DIO), was tested for effects on body weight loss in DIO mice (). Treatment for 3days resulted in a statistically significant reduction in body weight compared to start weight and in comparison with age-matched vehicle treated control mice on the same diet. In the mouse DIO study for , free compound concentrations in plasma were maintained >20-fold above the in vitro IC (0.0011μM) for the whole dosing interval. At these compound concentrations, based on the rat PK/PD knowledge, it is expected that compound has fully inhibited DGAT-1 both in the gut and in the adipose tissue. These effects on body weight appear specific and consistent with the mechanism of action. Accordingly had no effects on body weight at similar or even higher exposures in lean animals, and effects on food intake were only observed in animals fed a high fat diet. In summary, the novel oxadiazole DGAT-1 inhibitor was identified and SAR exploitation enabled a design strategy to improve both potency and LLE leading to the clinical candidate , which displayed good pharmacokinetics and demonstrated in vivo efficacy in obesity related models. Results from the further development of as a drug to treat metabolic disease will be reported in due course. Acknowledgments
    Increases in lipid stores in peripheral tissues, especially skeletal muscle, have been implicated in the development of insulin resistance and the constellation of lipotoxic disorders associated with metabolic syndrome. Lipid burden is largely controlled by triglyceride biosynthetic pathways. Acyl-CoA:diacylglycerol acyltransferases (DGAT) catalyze the terminal and rate-determining step in triglyceride biosynthesis. DGAT-1 is expressed in key tissues involved in lipotoxicity, including skeletal muscle, heart, liver, as well as high expression in small intestine and adipose. Inhibition of this key enzymatic step has thus garnered significant attention as a potential target for the treatment of disease states driven by excessive triglyceride burdens. Our team recently disclosed the discovery and pharmacology profile of the selective DGAT-1 inhibitor (PF-04620110). Compound is currently in Phase I human clinical trials for the treatment of Type I diabetes. Design priorities leading to centered on mimicking the key pharmacophore attributes present in and minimizing the potential for phototoxicity/photostability associated with the pyrimido[4,5-]oxazine core of . Following the discovery of , our research efforts shifted to the identification of a follow-on candidate with an orthogonal risk profile. Given the excellent preclinical attributes of , there were limited options for improvement/differentiation. While the fraction absorbed of is moderate to high in preclinical species, it has poor passive membrane permeability (1×10cm/s) which is driven by the high polarity (log=−0.15) of this compound. Targeting reduced polarity became a goal for the design of second generation DGAT-1 inhibitors in our laboratory. Two key design elements drove the search for alternative chemotypes related to : (1) retention of the key pharmacophore elements and (2) proper spatial relationship of these recognition elements as they are expressed in and . In evaluating a range of aminobicyclic cores, the dioxino[2,3-]pyrimidine-based system () looked promising based on overlays of the minimized structure with either or (). Structural constraints imposed on this 6,6-fused bicyclic suggested that both enantiomers of would possess the desired near in-plane relationship between the core and the phenylcyclohexyl sidechain. We were encouraged by the finding that the dihydropyrimido[4,5-]oxazine-based analog is within fourfold of in potency (). In addition, substitution of this dioxinyl core for the lactam-based system of was predicted to substantially increase lipophilicity (Log differential ∼1.5 units) and thus favorably impact passive permeability.