SBIR-STTR Award

The prevalence of obesity has risen dramatically among all segments of the U.S. population in the last two decades. Recent studies have established a role for melanin-concentrating hormone (MCH) in the control of feeding behavior and body weight. For example, direct central administration of the MCH peptide in rats increases feeding. Also, mice that lack the MCH gene eat significantly less than control mice and have a 25-30 percent reduction in body weight. These observations provide a compelling basis for the development of MCH antagonists as novel drug treatments for obesity and diabetes. In preliminary experiments, we have identified a number of compounds with low micromolar affinity for the MCH receptor, including compounds that have affinities below the micromolar range. In Phase I, we propose a high throughput parallel synthesis approach to generate small molecule libraries in order to develop multiple leads with high affinity. We will also investigate the functional effects of these compounds and determine their specificity for the MCH receptor compared to related receptors. Finally, we will examine selected compounds in a rat MCH-induced feeding model for their ability to block MCH in vivo. The specific aims proposed in Phase I are designed to generate potent small molecule MCH receptor antagonists, together with the data necessary to support the development of these antagonists into valid clinical candidates in Phase II. PROPOSED COMMERCIAL APPLICATION: This research, if successful, will result in small molecule antagonists of the melanin- concentrating hormone receptor that selectively inhibits the feeding response. Orally active forms of a small molecule MCH receptor antagonist would provide a novel therapeutic strategy for indications such as obesity and diabetes

Obesity is a rapidly advancing worldwide epidemic. Within the United States alone, 60% of the population is considered to be overweight. While new treatments for obesity have been introduced in the last decade, these drugs are only capable of reducing body weight by 10%, and patients typically gain back the lost weight following cessation of treatment. The potential for more effective therapeutics may be realized by targeting hormonal systems residing within the hypothalamus, a region of the brain critical for the appropriate regulation of food intake and energy utilization. Melanin concentrating hormone (MCH) is a prominent hormonal system originating within the lateral hypothalamus, which is responsible for initiating food intake. Genetically manipulating the expression of either the MCH ligand, or its receptor, inevitably results in alteration of body weight. Thus, mice overexpressing MCH ligand are obese, while mice lacking either the ligand or the receptor are lean. These data are consistent with the notion that blocking the interaction between MCH and its receptor will provide an effective means by which to reduce food intake in humans, and ultimately cause a loss of body weight. During the first phase of this project, we used high-throughput organic chemistry to develop multiple chemical series of potent MCH antagonists. We have also developed a number of critical in vitro and in vivo assays with which to monitor the bioavailability of these compounds, and their ability to inhibit acute food intake. In the second phase of this project, we propose to further refine these small molecules to improve their bioavailability. This will be accomplished by computer assisted drug design in conjunction with evaluation for a number of biological parameters including receptor affinity, hepatic stability, membrane permeability, and the potential for adverse reactions with liver enzymes necessary for proper drug metabolism. Compounds successfully emerging from this process will be further evaluated in acute and chronic feeding paradigms in order to select candidates suitable for clinical trials.

Thesaurus Terms:
body weight, drug design /synthesis /production, drug screening /evaluation, eating, hormone inhibitor, hormone regulation /control mechanism, melatonin, obesity, receptor expression G protein, nutrient intake activity, pharmacokinetics, receptor coupling chemical synthesis, combinatorial chemistry, high throughput technology, laboratory mouse, laboratory rat, psychometrics