This post was written by K.C. McGinley.
We are all aware of the rising rates of obesity in our world today. Just in the United States, the rate of obesity has doubled in adults and tripled in children within the past 30 years and is currently affecting one-third of adults as well as sixteen percent of children. This serious health risk is the cause of several medical conditions including type 2 diabetes, hypertension, cardiovascular disease, cancer, and arthritis. Obviously, one solution to this issue is a change in lifestyle such as an increase in physical activity as well as a decrease in calorie intake. However, for many people, it is simply not enough. Consequently, this epidemic has lead the pharmaceutical industry on a search for possible drugs that could help people reduce their weight by reducing the amount of food intake as well as speeding up their metabolism. The drawback is that many of these drugs have major health risks. Recently, the drug Sibutramine was withdrawn from the market because it increased the likeliness of strokes and/or heart attacks leaving Orlistat as the only drug on the market approved to treat obesity in the United States. However, the scientists at Merck Research Laboratories have made some major strides in pursuing new drugs to fight the obesity problem.
Introduction:
The scientists at Merck Research Laboratories have made an enormous advancement in the fight to fight obesity. These scientists along with many others have identified that BRS-3 (Bombesin Receptor Subtype 3) receptors could possibly serve as a potential treatment for obesity. They are a primary role in regulating energy homeostasis. This has been proved in experiments using mice. Furthermore, mice lacking functional BRS-3 tend develop obesity. Thus, these scientists have set out on a mission to find which BRS-3 agonists could yield the most effective results. What makes the experiments and data of Merck Research Laboratories significant, however, is the discovery of a novel family of BRS-3 agonists which exhibited unusual chirality.
Experiment:
In their experiments, the scientists began with a high-throughput screening lead to determine if the diazepine ring was the best option to use in the BRS-3 agonist. In each case that included moving the pyridine or breaking the diazepine ring, the effectiveness of the drug was completely lost. Hence, they focused their studies around varying the substituents of the aromatic rings while keeping the diazepine core. After the synthesis of diazepine sulfonamide, silica gel chromatography and reverse-phase high performance liquid chromatography were used in attempt to separate the undesired regioisomer. However, these processes were not enough to separate the mixture. Therefore, the scientists used a ChiralCel OD column to separate the two. They expected to get two different peaks which would represent the two regioisomers but instead got three peaks. While one of these peaks represented the undesired regioisomer they were originally trying to separate, the other two appeared to be possible enantiomers. They contained the exact same molecular structure just opposite rotation. One of them was rotated -157˚; the other was rotating in the positive direction 155˚. The odd thing about this particular molecule is it does not have a chiral center. There are several factors that could explain the observed atropisomerism. These include the restricted rotation about the N-S single bond, hindered inversion of the sulfonamide nitrogen, and the restriction of the diazepine ring. Even further baffling, they conducted an X-ray analysis of the two enantiomers and found that the sulfonamide N has typical single-bond lengths connecting to the surrounding atoms, but the geometry is almost planar. The scientists then attempted a variety of substituent groups on the phenol rings to compare potencies of the HBRS-3 agonists using IC50 and EC50 values. They looked into 17 different compounds starting with the one found using the high-throughput screening lead with the two methyl substituents on one of the phenol ring as a control.
Next, the scientists also decided to experiment with a number of different substitutes on the aryl sulfonyl group as well. There nine different substituents used to compare and contrast the potencies and pharmacokinetic properties of each.
Results and Discussion:
It was clear that for the BRS-3 agonist to be most potent, the compound needed to contain the diazepine ring. This is because the ring was conformationally constrained and caused severe steric hinderance when the phenol ring attached to it. When the phenol ring was flipped one way, the substituents were very close to the sulfonyl group creating major steric hindrance. Consequently, the compounds could be separated and exhibited atropisomerism.
In comparing the two original atropisomers, the 8a) (S)-isomer was very potent with an hBRS-3 IC50 rate of 1.4 nM. However, the 8b) (R)-isomer was not very potent at all with an hBRS-3 IC50 rate of 169 nM.
Compared to the initial lead, potency also increased from the initial lead when CF3 occupied the 2 position. The 2 position could tolerate several substituents. However, the 3 position preferred none. For the left phenol ring, potency was slightly improved with the deletion of 8-methyl. It did decrease potency when both the 7-methyl and 8-methyl were both deleted. Comparable potency occurred when 7-methyl was replaced by chloro, fluoro, or hydroxyl substituents. When a phenol substituent was added, the potency was very high with an hBRS-3 IC50 of 0.7 nM. In fact, it was among the most potent of the compounds used in the experiment.
I think after looking at the results the larger the steric hindrance, the more potent a compound was. There was also definite relationship between the compound 8a) which was the (S)-isomer and BRS-3 receptors. In the mice, the compound caused a significant amount of weight loss in the wild type and established diet-induced obese mice. However, it did not have any affect at all on the mice that the BRS-3 receptor had been inactivated in.
Conclusion:
In conclusion, I think there is definitely a correlation between the BRS-3 receptors and weight loss. I also think a number of compounds can be synthesized and experimented with to find those that will exhibit the greatest effectiveness as medication. The chirality of the compounds found by the scientists at Merck Research Laboratories also plays an important role in the potency levels.
I think the experiment done was valid. They began with one compound as a control and then added different substituents to different places to test the amount of potency in each. I do find it interesting they stuck with the diazepine ring for all compounds because benzodiazepine is a drug used in the pharmaceutical world to treat anxiety, insomnia, muscle spasms, seizure disorders, and alcohol withdrawals. So I think moving forward, it might prove interesting to see if other types of drugs could utilize the diazepine ring which seems to work phenomenally for our bodies. Another thing I think could be done with this experiment is testing more of the compounds on the mice to see if they affect weight. The only one they actually tested on the mice was compound 8a) which was successful in the mice that had the BRS-3 receptors. One final problem I had with the article was some of the abbreviations and figures were rather confusing and not necessarily labeled very well. I think it would have been beneficial to the readers the authors had been a little more informative about the different terms being used throughout the paper. Overall, I found the experiment to be highly interesting
References:
Liu, Ping (2011). Discovery of Benzodiazepine Sulfonamide-Based Bombesin Receptor Subtype 3 Agonists and Their Unusual Chirality. ACS Medicinal Chemistry Letters.
