5-HT_2C Receptor Agonists for the Treatment of Obesity

Important Compound Classes

Title

5-HT_2C Receptor Agonists and Compositions and Methods of use

Patent Application Number

WO 2018/035477 A1

Publication Date

February 22, 2018

Priority Application

US 62/377,119

Priority Date

August 19, 2016

Inventors

Semple, G.; Ren, A. S.; Schrader, T. O.; Kasem, M.; Zhu, X.

Assignee Company

Arena Pharmaceuticals, Inc.

Disease Area

Obesity

Biological Target

5-HT_2C Receptor

Summary

The worldwide prevalence of obesity represents great economical and global human health burden. Major risk factors are coronary heart disease, type II diabetes, heart failure, and stroke, which account for a growing number of worldwide deaths. Conceptually, the prevention and treatment of obesity can be accomplished through diet and exercise. However, many people are unable to attain significant lasting body weight reduction through these methods alone. There is urgent unmet need for drug-based therapy, which may provide an opportunity for patients to achieve clinically beneficial weight loss.

Serotonin (5-HT), a major monoamine neurotransmitter found in the central nervous system (CNS), plays an important role in numerous physiological processes. These biological functions are mediated by a variety of serotonin receptors, which constitutes the mechanism of many drug actions. Type 2 serotonin receptors (5-HT₂) mediate the actions of many disease processes such as feeding disorders, depression, perception, schizophrenia, anxiety, hallucinations, and so forth. In particular, the three 5-HT₂ receptor subtypes (5-HT_2A, 5-HT_2B, and 5-HT_2C) show significant homology at structural, genetic, and functional levels.

The regulation of 5-HT for feeding behavior is believed to function by inducing a feeling of satiety in the region of the brain located in the ventromedial nucleus of the hypothalamus and the hunger center present in the lateral hypothalamus. Stimulatory action of 5-HT on the 5-HT_2C receptor results in an enhanced 5-HT; the subject stops eating earlier, and fewer calories are consumed. In addition, the 5-HT_2C receptor, which is minimally expressed or absent in the peripheral tissues, is a major receptor target for the treatment of obesity, psychiatric disorder, and sexual dysfunction. However, the lack of truly selective ligands that are able to distinguish among these receptor subtypes, especially as regards to the differentiation between 5-HT_2B and 5-HT_2C receptors, has hampered development of drug-based therapy. For instance, the once popular d-fenfluramine drug for the treatment of obesity, acting by enhancement of serotonergic function in the brain, was withdrawn from the U.S. market due to reports of heart valve disease and pulmonary hypertension. Activation of the 5-HT_2A receptors leads to a number of adverse central nervous system (CNS) effects, including hallucination and perception. However, activation of the 5-HT_2B receptor causes adverse effects in the cardiovascular system, including heart valve disease and pulmonary hypertension.

There are very few drugs available for the treatment of obesity. Lorcaserin, classified as a schedule 4 drug (low risk for abuse), was approved by the Food and Drug Administration (FDA) in June 2013. Lorcaserin is an agonist of the 5-HT_2C receptor and effective at reducing obesity in humans and animal models. Since lorcaserin affects the serotonin receptors, an adverse effect such as serotonin syndrome can be triggered with drugs or substances that affect levels of serotonin neurotransmitters, including selective serotonin reuptake inhibitors (SSRIs).

Tobacco use is the leading cause of preventable illness and early cause of deaths worldwide. According to the United States Centers for Disease Control and Prevention (CDC), the major causes of excess mortality among smokers are diseases that are related to smoking, including cancer and respiratory and vascular diseases. In addition, smokeless tobacco is a known cause of cancer [https://www.cdc.gov/tobacco/data_statistics/fact_sheets/health_effects/tobacco_related_mortality/index.htm (accessed July 15, 2018)]. The vast majority of smokers may attempt to quit; however, continued abstinences are difficult to achieve. Existing smoking cessation treatments such as Zyban (bupropion SR) and Chantix (varenicleine) have black box warnings such as serious neuropsychiatric events, depressed mood changes, suicidal ideation or suicidal behavior, and so forth. The well-recognized side effects of quitting smoking are bigger appetites, slower metabolism, triggers, and cravings, which may lead to weight gain in about 80% of smoke-free individuals. However, these side effects are considered modest inconveniences compared to the health benefits of smoking cessation. There is possibly a complex relationship between body weight and smoking, in which heavy smokers tend to have higher body weight and a higher likelihood of obesity than lighter smokers. Smoking cessation is a significant unmet need as existing therapies lack long-term success rates.

Compounds of this invention modulate the activity of the 5-HT_2C receptor and are useful in the treatment of 5-HT_2C receptor-mediated disorders like weight management, decreasing food intake, preventing and treating of obesity, antipsychotic-induced weight gain, type 2 diabetes, drug and alcohol addition, sleep disorders, urinary incontinence, and so forth.

Definitions

n is 1 or 2; X² is N or CR²; X³ is N or CR³; X⁴ is N or CR⁴; R⁶, R⁷, and R⁸ is hydrogen or C₁–C₆ alkyl; R⁹ is hydrogen or C₁–C₆ alkyl. R¹, R², R³, and R⁴ is hydrogen or C₁–C₆ alkyl.

Key Structures

Biological Assay: Inositol Phosphate (IP) Accumulation Assays

The biological activities of compounds in this invention were tested using IP accumulation assay. HEK293 cells that expressed recombinant 5-HT₂ receptors were radiolabeled with [³H]inositol phosphates and measured by a PerkinElmer scintillation counter. Compound 152 showed a significant decrease in cumulative food intake relative to placebo in the male Sprague–Dawley rat.

Biological Data

The Table below shows observed IP accumulation EC₅₀ values for the compounds of this Patent Highlight that were tested at the 5-HT_2C, 5-HT_2B, and 5-HT_2A receptors.

Recent Review Articles

• 1.Ikarashi Y.; Sekiguchi K.; Mizoguchi K.. Curr. Med. Chem. 2018, 25, 1036.
• 2.Barros M. L. D.; Manhães-de-Castro R.; Alves D. T.; Quevedo O. G.; Toscano A. E.; Bonnin A.; Galindo L.. Eur. J. Pharmacol. 2018, 833, 298.
• 3.Palacios J. M.; Pazos A.; Hoyer D.. Psychopharmacology 2017, 234, 1395.
• 4.Morris E. V.; Edwards C. M.. J. Cell. Physiol. 2018, DOI: 10.1002/jcp.26884.

The author declares no competing financial interest.