MK-0493 is a novel, potent, and selective agonist of the melanocortin receptor 4 (MC4R), one of the best-validated genetic targets and considered one of the most promising for the development of antiobesity therapeutics. An ad libitum energy-intake model was qualified with excellent reproducibility: the geometric mean ratio (GMR) with 95% confidence interval (CI) for total energy intake over a period of 24 h for 30 mg sibutramine/placebo was 0.82 (0.76, 0.88), and for 10 mg sibutramine/placebo it was 0.98 (0.91, 1.05). MK-0493 showed a small and marginally significant effect on 24-h energy intake, whereas 30 mg of sibutramine caused a significant reduction in total 24-h energy intake; specifically, the GMR (95% CI) for 30 mg sibutramine/placebo was 0.79 (0.74, 0.85). MK-0493 was associated with modest weight reduction from baseline but had only small, statistically insignificant effects relative to placebo after 12 weeks in a fixed-dose study and also after 18 weeks of stepped-titration dosing. We conclude that agonism of MC4R is not likely to represent a viable approach to the development of antiobesity therapeutics.
A B S T R A C T l-Aryl-4-substituted-1,4-dihydro-5H-tetrazol-5-ones ( I ) represent a newclass of herbicides, which, when appEied pre-or post-emergence in the presence of light, control several agriculturally important weed species. Forty-eight analogues have been synthesized and their herbicidal activities determined in order to study structure-activity relationships. I n general, these compounds demonstrated: (1) optimum herbicidal activity when the 4substituent on the tetrazole ring was -CH,CH,CH,F, and the aryl group 2-~uoro-4-chloro-5-substituted phenyl; (2) optimum herbicidal activity over a broad spectrum of grass and broad leaf weeds, with marginal crop selectivity when the C5 substituent on the phenyl group was -OCH,C-CH;and (3) a high degree of selectivity on several major crops and primarily broadleaf weed control when this substituent was -NHSO,CH,CH,. INTRODUCTIONA large number of herbicides are available to assist in controlling weeds in a variety of circumstances. These herbicides can be classified into families based on their chemical structure and mode of action.' Usually, each family of herbicides has associated with it a weed spectrum and crop selectivity that do not fluctuate greatly with structural changes of the molecule. This paper reports a new class of highly active herbicides of structure I (Fig. 1) whose weed spectrum and crop selectivity can be dramatically modified through manipulation of the substituent groups. The herbicidal activity of these compounds was optimized by varying the groups R,, R,, R, and R,. The nature of R, 259 Pestic. Sci. 0031-613X/90/$03.60 0 1990 SCI. Printed in Great Britain Procedure A: formation of methyl 2,4-disuhstituted benzoates. Methyl chloroformate (0.75 mol) was added dropwise to a mixture of 2,4disubstituted phenol (075 mol) and sodium hydroxide (0.75 mol) in water (150ml), while the temperature was kept below 10°C. The crystals that formed were collected and dried to give almost quantitative yields of the benzoate. With the exception of 4-chloro-2fluorophenol, which was synthesized according to a previously described method," all 2,4disubstituted phenols used in this procedure were commercially available.
Objective To assess the efficacy and safety of DPP‐4 inhibition with sitagliptin in youth with type 2 diabetes (T2D). Study Design This was a 54‐week, double‐blind, randomized, controlled clinical trial evaluating the safety and efficacy of DPP‐4 inhibition with sitagliptin 100 mg once daily as initial oral therapy in youth with T2D. The 190 participants, aged 10–17 years, had HbA1c 6.5%–10% (7.0%–10% if on insulin). All were negative for pancreatic autoantibodies and overweight/obese at screening or diagnosis. The trial was placebo controlled for the first 20 weeks, after which metformin replaced placebo. The primary efficacy endpoint was change from baseline in HbA1c at Week 20. Results Treatment groups were well balanced at baseline (mean ± SD HbA1c = 7.5% ± 1.0, BMI percentile = 97.1% ± 6.8, age = 14.0 years ± 2.0 [57.4% <15], 60.5% female). At Week 20, least squares mean changes from baseline in HbA1c were −0.01% (sitagliptin) and 0.18% (placebo); between‐group difference (95% CI) = −0.19% (−0.68, 0.30), p = 0.448. At Week 54, the changes in HbA1c were 0.45% (sitagliptin) and −0.11 (placebo/metformin). There were no notable between‐group differences in the adverse event profiles through Week 54. Conclusions DPP‐4 inhibition with sitagliptin did not provide significant improvement in glycemic control. In this study, sitagliptin was generally well tolerated with a safety profile similar to that reported in adults. (ClinicalTrials.gov: NCT01485614; EudraCT: 2011‐002528‐42)
Objective To assess the efficacy and safety of sitagliptin in youth with type 2 diabetes (T2D) inadequately controlled with metformin ± insulin. Study Design Data were pooled from two 54‐week, double‐blind, randomized, placebo‐controlled studies of sitagliptin 100 mg daily or placebo added onto treatment of 10‐ to 17‐year‐old youth with T2D and inadequate glycemic control on metformin ± insulin. Participants (N = 220 randomized and treated) had HbA1c 6.5%–10% (7.0%–10% if on insulin), were overweight/obese at screening or diagnosis and negative for pancreatic autoantibodies. The primary endpoint was change from baseline in HbA1c at Week 20. Results Treatment groups were well balanced at baseline (mean HbA1c = 8.0%, BMI = 30.9 kg/m2, age = 14.4 years [44.5% <15], 65.9% female). The dose of background metformin was >1500 mg/day for 71.8% of participants; 15.0% of participants were on insulin therapy. At Week 20, LS mean changes from baseline (95% CI) in HbA1c for sitagliptin/metformin and placebo/metformin were −0.58% (−0.94, −0.22) and −0.09% (−0.43, 0.26), respectively; difference = −0.49% (−0.90, −0.09), p = 0.018; at Week 54 the LS mean (95% CI) changes were 0.35% (−0.48, 1.19) and 0.73% (−0.08, 1.54), respectively. No meaningful differences between the adverse event profiles of the treatment groups emerged through Week 54. Conclusions These results do not suggest that addition of sitagliptin to metformin provides durable improvement in glycemic control in youth with T2D. In this study, sitagliptin was generally well tolerated with a safety profile similar to that reported in adults. (http://clinicaltrials.gov: NCT01472367, NCT01760447; EudraCT: 2011‐002529‐23/2014‐003583‐20, 2012‐004035‐23).
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