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New Class Of Molecules As Histamine-3 Receptor (H3R) Modulators: A New Lead In Clinical Management Of Obesity

If we don’t somehow stem the tide of childhood obesity, we’re going to have a huge problem. —Lance Armstrong

Comprehensive lifestyle management like diet, physical exercise, and behavior modification are the best ways to treat obesity. An alternative to this is drug-based therapy. Although not preferred or prescribed until lifestyle modifications fall short in achieving that goal, pharmacotherapy provides an opportunity for the obese population to achieve weight loss and to reduce the incidence of associated health hazards like cardiovascular disease, diabetes, cancer, and stroke.

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Only a limited number of drugs are currently available that have either serious side effect profiles or modest efficacy for the long-term treatment of obesity. Most of the anti-obesity drugs function by altering the patient’s appetite or by reducing fat absorption. Currently, orlistat is the only drug approved by the FDA for long-term use. Under these circumstances, a novel histamine 3 receptor (H3R) agonist (as shown in Figure 1) was identified recently by a drug discovery research group in CSIR-CDRI Lucknow, India, which could lead to new candidate drugs for the management of obesity.

Credit: Ajay Kumar Srivastava

A systematic exploration of β-lactams and pyrrolidinone derivatives by utilizing an efficient chemistry could result in exciting findings. Most of the molecules were prepared in a single flask chemical transformation often termed as one-pot protocols. Four components were reacted in methanol at room temperature, and the Ugi reaction was monitored by thin layer chromatography (TLC). Once the first reaction was complete, reagents for the second transformation were added followed by monitoring of the reaction by TLC. The products were isolated by filtration, and complicated chromatographic procedures were not required. This type of chemical transformation reduces the amount of chemical waste and thus is useful for developing sustainable chemical processes.

The biological screening of these compounds revealed that they are highly specific to H3R and did not interfere with related isoforms such as H1R, H2R, and H4R. A careful investigation of structural features was performed to understand the pharmacophore that is required to design molecules with improved efficacy and safety.

Figure 1. Most potent compound of the series. Credit: Ajay K. Srivastava

In the next stage of our research, we evaluated the efficacy of the most active molecule in mice. It was also interesting to note that our molecule stimulates a hypophagic response in mice reflecting the reduction in food intake. The computational analysis of physicochemical and pharmacokinetic properties of the identified actives suggest that these molecules might possess good bioavailability and permeability, which are important parameters for developing a candidate drug.

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Additionally, we checked the possible covalent interaction of these molecules with other proteins by performing luciferase assay. Further studies to optimize and develop candidate drugs from the identified actives are currently underway.

These findings are described in the article entitled, Identification of novel β-lactams and pyrrolidinone derivatives as selective Histamine-3 receptor (H3R) modulators as possible anti-obesity agents, recently published in the European Journal of Medicinal Chemistry. This work was conducted bythe teams of Dr. Ajay K. Srivastava, Dr. Prem N. Yadav and Dr. Muhammad Wahajuddin from CSIR-Central Drug Research Institute (CSIR-CDRI), Lucknow, India.

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