ckd732 and Body-Weight

Participants were randomised (via a centralised interactive web response system) to placebo, 1.2 or 1.8 mg beloranib s.c. twice weekly for 26 weeks. Participants, investigators and the sponsor were blinded to group assignment. The primary endpoint was the change in weight from baseline to week 26. The trial was terminated early when beloranib development was stopped because of an imbalance of venous thromboembolism events in beloranib-treated individuals vs placebo that became evident during late-stage development of the drug.. MetAP2 inhibitors represent a novel mechanism for producing meaningful weight loss and improvement in HbA. ClinicalTrials.gov NCT02324491 FUNDING: The study was funded by Zafgen, Inc.

Topics: Adolescent; Adult; Aged; Aminopeptidases; Anti-Obesity Agents; Blood Glucose; Body Weight; Cinnamates; Cyclohexanes; Diabetes Mellitus, Type 2; Double-Blind Method; Epoxy Compounds; Female; Glucose; Glycated Hemoglobin; Glycoproteins; Humans; Hypoglycemic Agents; Male; Metalloendopeptidases; Methionyl Aminopeptidases; Middle Aged; Obesity; Sesquiterpenes; Weight Loss; Young Adult

Hypothalamic lesions or deficient melanocortin (MC) signaling via MC4 receptor (MC4r) mutations often lead to hyperphagia and severe treatment-resistant obesity. We tested the methionine aminopeptidase 2-inhibitor beloranib (ZGN-440) in 2 male rat models of obesity, one modeling hypothalamic obesity with a combined medial hypothalamic lesion (CMHL) and the other modeling a monogenic form of obesity with MC4r mutations (MC4r knockout [MC4rKO]). In CMHL rats (age 3 months), postsurgery excess weight gain was significantly inhibited (ZGN-440, 0.2 ± 0.7 g/d; vehicle, 3.8 ± 0.6 g/d; P < 0.001) during 12 days of ZGN-440 treatment (0.1 mg/kg daily subcutaneously) together with a 30% reduction of daily food intake vs vehicle injection. In addition, ZGN-440 treatment improved glucose tolerance and reduced plasma insulin, and circulating levels of α-melanocyte stimulating hormone were increased. Serum lipid levels did not differ significantly in ZGN-440-treated vs vehicle-treated rats. Similar results were found in MC4rKO rats: ZGN-440 treatment (14-21 d) was associated with significant reductions of body weight gain (MC4rKO, -1.7 ± 0.6 vs 2.8 ± 0.4 g/d; lean wild-type controls, -0.7 ± 0.2 vs 1.7 ± 0.7 g/d; ZGN-440 vs vehicle, respectively), reduction of food intake (MC4rKO, -28%; lean controls, -7.5%), and insulin resistance, whereas circulating levels of interleukin-1β did not change. In both obesity models, body temperature and locomotor activity were not affected by ZGN-440 treatment. In conclusion, the robust reduction of body weight in response to ZGN-440 observed in rats with severe obesity is related to a strong reduction of food intake that is likely related to changes in the central regulation of feeding.

Topics: Aminopeptidases; Animals; Body Temperature; Body Weight; Cinnamates; Cyclohexanes; Disease Models, Animal; Drug Evaluation, Preclinical; Eating; Epoxy Compounds; Gene Expression; Glucose Tolerance Test; Hyperphagia; Hypothalamus, Middle; Insulin Resistance; Leptin; Lipid Metabolism; Liver; Male; Metalloendopeptidases; Obesity; Rats, Sprague-Dawley; Rats, Transgenic; Receptor, Melanocortin, Type 4; Sesquiterpenes

In vivo osteogenic responses to anabolic stimuli are expected to be accompanied by angiogenesis as well as in the process of remodeling of bone. Consequently, angiogenesis might play an important role in mediating bone forming stimulating effect of parathyroid hormone (PTH). To investigate this relationship, we used actively growing young Sprague-Dawley rats and CKD-732, one of the angiogenesis inhibitor (AI) to reveal the relationship of angiogenesis in the effect of PTH. The groups were divided as (1) vehicle [VEH group], (2) PTH(1-84) [PTH group], (3) AI alone [AI group], (4) PTH(1-84)+AI concomitance [PTH-AI group] and were treated for 6 weeks. The bone mineral density (BMD) of PTH group was higher than VEH group and the gain of bone mass was attenuated in PTH-AI group. The maximal failure load in PTH group was higher than VEH group, but it was definitely attenuated by concurrent use of AI. Moreover, the toughness showed similar significant deterioration in PTH-AI group. General bone turnover was also significantly decreased in PTH-AI group as shown by the absence of increase in osteocalcin and beta-crosslaps and by decrease in metaphyseal length. The BMD or the biomechanic data of AI only group were similar to the VEH group, suggesting the minimal effect of AI itself on the normal modeling phase of the growing rats. In conclusion, the angiogenesis seemed to contribute to completing the anabolic effect of PTH especially for bone strength.

Topics: Angiogenesis Inhibitors; Animals; Body Weight; Bone and Bones; Bone Density; Cinnamates; Cyclohexanes; Epoxy Compounds; Female; Parathyroid Hormone; Rats; Rats, Sprague-Dawley; Sesquiterpenes

The systemic treatment with angiogenesis inhibitor has been shown to result in weight reduction and adipose tissue loss in various models of obesity. To verify the mechanism of CKD-732 (TNP-470 analog) against obesity, we evaluated CKD-732's peripheral and central anti-obesity effects. CKD-732 was injected subcutaneously (s.c.) for 7 days in various animal models and intracerebroventricularly (i.c.v.) in arcuate nucleus (ARC) lesion mice, ob/ob mice, and normal littermates. Modulation of the hypothalamic neuropeptide mRNAs after i.c.v. injection was evaluated in ARC lesion mice and normal littermates. A conditioned taste aversion (CTA) was performed using lithium chloride (LiCl) as a positive control agent in Long-Evans Tokushima Otsuka and Otsuka Long-Evans Tokushima fatty (OLETF) rats. As a result, 7 days of CKD-732 s.c. injection reduced the cumulative food intake and the body weight significantly in both treated obese (e.g. 114.8 +/- 13.4 g vs 170.7 +/- 20.6 g, 7.9 +/- 0.5% decrease vs 0.3 +/- 2.2% decrease; in treated OLETF rat versus control OLETF rat, P < 0.01 respectively) and non-obese models. Epididymal and mesenteric fat pads, and the size of adipocytes were significantly decreased in treated rats. A single i.c.v. injection decreased food intake and body weight in ARC lesion mice and ob/ob mice but not in normal littermates. Unexpectedly, the hypothalamic neuropeptide mRNAs were not altered by single i.c.v. injection. CKD-732 also induced a dose-dependent CTA comparable with LiCl injection, which is a commonly used agent to produce a CTA. In conclusion, CKD-732 causes significant body weight and appetite reduction, possibly by decreasing adiposity directly and inducing central anorexia, which is partly explained by a CTA. These results should be carefully verified to assess the utility of CKD-732 as an anti-obesity drug.

Topics: Adipocytes; Adipose Tissue; Animals; Anti-Obesity Agents; Arcuate Nucleus of Hypothalamus; Body Weight; Cell Size; Cinnamates; Cyclohexanes; Eating; Epoxy Compounds; Hypothalamus; Lithium Chloride; Male; Mice; Mice, Obese; Neuropeptides; O-(Chloroacetylcarbamoyl)fumagillol; Obesity; Rats; Rats, Inbred OLETF; Sesquiterpenes; Taste