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A highly potent and selective DGAT-1 inhibitor was identified and used in rodent models of obesity and postprandial chylomicron excursion to validate DGAT-1 inhibition as a novel approach for the treatment of metabolic diseases. Specifically, compound 4a conferred weight loss and a reduction in liver triglycerides when dosed chronically in DIO mice and depleted serum triglycerides following a lipid challenge in a dose-dependent manner, thus, reproducing major phenotypical characteristics of DGAT-1(-/-) mice.

The discovery and pharmacological evaluation of potent, selective, and orally bioavailable growth hormone secretagogue receptor (GHS-R) antagonists are reported. Previously, 2,4-diaminopyrimidine-based GHS-R antagonists reported from our laboratories have been shown to be dihydrofolate reductase (DHFR) inhibitors. By comparing the X-ray crystal structure of DHFR docked with our GHS-R antagonists and GHS-R modeling, we designed and synthesized a series of potent and DHFR selective GHS-R antagonists with good pharmacokinetic (PK) profiles. An amide derivative 13d (Ca2+ flux IC50 = 188 nM, [brain]/[plasma] = 0.97 @ 8 h in rat) showed a 10% decrease in 24 h food intake in rats, and over 5% body weight reduction after 14-day oral treatment in diet-induced obese (DIO) mice. In comparison, a urea derivative 14c (Ca2+ flux IC50 = 7 nM, [brain]/[plasma] = 0.0 in DIO) failed to show significant effect on food intake in the acute feeding DIO model. These observations demonstrated for the first time that peripheral GHS-R blockage with small molecule GHS-R antagonists might not be sufficient for suppressing appetite and inducing body weight reduction.

Dexfenfluramine (DEX) and sibutramine (SIB) are effective antiobesity agents. Their effects on weight control and hormone profile have not been previously studied in diet-switched diet-induced obese (DIO) mice, in which treatment is initiated upon cessation of a low-fat diet and resumption of a high-fat diet. Furthermore, their effects on circulating ghrelin in obese humans or in animal models of obesity have not yet been reported. Male C57Bl/6J DIO mice after 16 wk on a high-fat diet (HF, 60 kcal% fat) were switched to a low-fat diet (LF, 10 kcal% fat) for 50 d. HF diet resumed concurrently with treatment for 28 d with DEX 3 and 10 mg/kg, twice a day (BID); SIB 5 mg/kg BID; or vehicle. Rapid weight regain ensued in vehicle-treated DIO mice. DEX or SIB treatment significantly blunted the body weight gain. Caloric intake was decreased acutely by DEX or SIB vs vehicle during the first 2 d treatment, but returned to control after 5 d. At the end of study, epididymal fat weight and whole body fat mass determined by DEXA scan were decreased by DEX 10 mg/kg, and whole body lean mass decreased with DEX 3 mg/kg treatment. Circulating ghrelin on d 28 was increased with either DEX 3 or 10 mg/kg treatment, while growth hormone and insulin were decreased. Leptin was also decreased in the DEX 10 mg/kg group. SIB did not significantly affect fat mass, ghrelin, growth hormone, insulin, or leptin. Mice chronically fed LF diet maintained a lower caloric intake, gained less weight and fat mass than diet-switched mice, and had higher ghrelin and lower insulin and leptin. In summary, weight regain in diet-switched DIO mice is delayed with either DEX or SIB treatment. DEX treatment of diet-switched DIO mice decreased growth hormone, insulin, leptin, fat mass, lean mass, and increased ghrelin, while SIB only decreased body weight.

Histamine is a key neurotransmitter that alters central nervous system functions in both behavioural and homeostatic contexts through its actions on the histamine (H) subreceptors H(1), H(2) and H(3) G-protein-coupled receptors. H(3)receptors have a diverse central nervous system distribution where they function as both homo- and hetero-receptors to modulate the synthesis and/or release of several neurotransmitters. H(3) receptors are constitutively active, which implies that antagonists of H(3) receptors may also function as inverse agonists to alter the basal state of the receptor and uncouple constitutive receptor-G-protein interactions. Reference H(3) antagonists such as thioperamide and ciproxifan, administered either centrally or systemically, have been shown to cause changes in food consumption and/or body weight in proof-of-concept studies. More recently, several non-imidazole-based H(3) antagonists/inverse agonists have also been described with efficacy in at least one animal model of human obesity. Considerable preclinical effort remains necessary before such compounds achieve therapeutic success or failure. Moreover, ongoing research in a number of laboratories has shed new insights into the effects of H(3) ligands in the control of feeding, appetite and body weight, which offer different results and conclusions. The goal of this review is to appraise these findings and forecast whether any H(3) antagonists/inverse agonists will provide clinical utility to treat human obesity.