Robert B. Kargbo

Toll-like Receptors for the Treatment of Autoimmune, Inflammation, and Infectious Diseases

Toll-like receptors (TLRs) are a class of proteins that play a key role in the cellular pathogen recognition system. In human, TLRs comprise a gene family of 10 receptors with various functions, including defense against a variety of diseases such as infections, cancers, autoimmune, inflammation, and so forth. They are expressed on sentinel cells, for example in macrophages and natural killer cells, which recognize molecules from microorganism. In functional recognition mode, TLRs activate immune cell responses in the release of interferons. The binding of ligands to TLRs depends on their functional expression in tissues or cell surfaces (where TLR4 is highly expressed). In addition, TLR3, 7, 8, and 9 are activated by nucleic acids and are located at the endosomal membranes in specified immune cells. For example, TLR 7 and 8 are activated by single-stranded RNA of viruses like HIV and HCV, whereas TLR9 is activated by single-stranded DNA containing unmethylated CpG dinucleotides. TLR7 has been implicated in the pathogenesis of autoimmune disorders such as systemic lupus erythematosus and also in the regulation of antiviral immune responses. However, TLR8 has been implicated in some cancers, rheumatoid arthritis, and susceptibility to pulmonary diseases such as tuberculosis. n nThere have been considerable efforts to explore the agonism of TLRs in cancer immunotherapy, combination therapies, or as vaccine adjuvant. However, many of these efforts in clinical development have ended up in failures. These approaches involve the TLR agonistic activity on cytokines, interferons, or monovalent vaccinations. The present approach involves TLR pleiotropic agonism, where specified immune cells such as primary dendritic cells, B-cells, and so forth generate an innate or adaptive immune response to include many different isoforms. n nCompounds in this invention are dual antagonists of TLR7 and 8 to treat and/or prevent disorders related to TLR7 and 8 such as autoimmune disorder, inflammation, and infectious diseases.

5-HT2C Receptor Agonists for the Treatment of Obesity

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. n nSerotonin (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-HT2A, 5-HT2B, and 5-HT2C) show significant homology at structural, genetic, and functional levels. n nThe 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-HT2C receptor results in an enhanced 5-HT; the subject stops eating earlier, and fewer calories are consumed. In addition, the 5-HT2C 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-HT2B and 5-HT2C 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-HT2A receptors leads to a number of adverse central nervous system (CNS) effects, including hallucination and perception. However, activation of the 5-HT2B receptor causes adverse effects in the cardiovascular system, including heart valve disease and pulmonary hypertension. n nThere 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-HT2C 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). n nTobacco 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. n nCompounds of this invention modulate the activity of the 5-HT2C receptor and are useful in the treatment of 5-HT2C 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.

Modulators of the Cystic Fibrosis Transmembrane Conductance Regulator Protein

Cystic fibrosis (CF) is a genetic disorder caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein, which lead to abnormality in water and ion transport across epithelial cells. In particular, the deletion of phenylalanine 508 (F508del) in the cystic fibrosis CFTR anion channel causes misfolding and premature degradation of the protein. The activity of CFTR is essential for the maintenance of electrolyte transport throughout the body, including digestive and respiratory tissues. The main symptom of CF is the fluid imbalance in the lungs, which leads to the accumulation of a highly viscous mucopurulent sputum. Majority of patients affected by CF die from pulmonary disease, even though CF affects other areas including the liver, kidneys, pancreas, and intestine. CF is the most common fatal genetic disease in humans, and up to 10 million people in the United States carry a single copy of the defective gene without ill effects. In contrast, an individual with two copies of the CF associated gene suffers from the debilitating fatal effects of CF. In CF patients, endogenous respiratory epithelial CFTR does not enhance chloride and bicarbonate permeability to the epithelial cells in the lung and other tissues; this lead to disruption in the ion and fluid transport. Consequently, mucus and pathogenic agents accumulate in the lung and cause microbial infections that may turn deadly in CF patients. Furthermore, CF patients may also suffer from gastrointestinal and pancreatic problems. Female subjects may suffer from decreased fertility, while most males with cystic fibrosis are infertile. n nCFTR has been shown to function as a cAMP-activated chloride channel with a small single channel conductance and a nonrectifying connection. The cAMP/ATP-mediated anion channel is commonly associated with disease processes, which express absorptive and secretory epithelia cell types. There are many reported ATP releases associated with CFTR expression in the cardiac myocytes, human airway epithelial cells, C127 cells, retinal pigment epithelium cells, and red blood cells from normal and CF patients with mechanical stress. n nCFTR is a member of the ATP-binding cassette (ABC) transporter subfamily, which serves as a cAMP-dependent chloride channel with a unique cytoplasmic regulator. These are guarded by two large transmembrane domains (TMD1 and TMD2) and two intracellular nucleotide binding domains (NBD1 and NBD2). The mutation in the gene causes two distinct defects: a processing defect and a gating defect. The F508del mutation reduces stability of the NBD1 and destabilizes the interactions between the NBD1 and the nucleotide-binding domains, leading to F508del-CFTR retaining in the endoplasmic reticulum (ER). The ABC transporters regulate the transport of a wide variety of pharmacological agents such as anions, xenobiotics, drugs, and so forth. In addition, these transporters also regulate defensive mechanisms like the resistance of malignant cancer cells against chemotherapeutic agents and provide protection against harmful environmental vectors. Consequently, therapeutic agents that modulate ABC transporters may be beneficial in treating diseases and conditions that are mediated and modulated by CFTR protein. Pharmacological therapeutics act directly on mutant CFTR to improve interactions at the interfaces between NBD1 and membrane-spanning domains (MSD1 or MSD2) or stabilize the NBD1 or NBD2 domain. In addition, CFTR modulators may be beneficial for the treatment of secretory diarrheas, which is found in patients with chronic inflammatory bowel disease and acquired immunodeficiency syndrome, where diarrhea could be a dangerous condition. n nCFTR modulation may be beneficial for other disease areas not directly linked to mutations in CFTR, including chronic obstructive pulmonary disease (COPD), characterized by a progressive and nonreversible airflow blockage, and Sjogren’s syndrome, an autoimmune disease that affects moisture-producing glands throughout the body (eye, mouth, skin, vagina, gut, and so forth). The pyrrolidine substituted compounds in the invention are modulators of the CFRT protein and are useful therapeutics in treating conditions and diseases such as CF.

Novel Triterpenone for Treatment of Viral Diseases-HIV Inhibitors

According to the Joint United Nations Program on HIV and AIDS (UNAIDS, http://www.unaids.org/en/resources/fact-sheet), from the inception of cases of HIV reported, 78 million people have become infected with HIV and 35 million have died from AIDS-related illnesses. There were approximately 36.7 million people worldwide living with HIV/AIDS at the end of 2016. Only about 60% of people with HIV know their HIV/AIDS status. However, in July 2017, 20.9 million people living with HIV were accessing one of the gold standards therapies, the highly active antiretroviral therapy (HAART) globally. One of the key features of antiretroviral therapy is that it reduces the amount of virus in the body to a level that is undetectable with current blood tests. A retrovirus is a single-stranded RNA virus with a DNA intermediate, which targets a host cell. Once inside the host cell, the virus uses its own enzyme to produce DNA from its RNA genome, which is a reverse process from regular sequence and is very difficult to detect until it has infected its host. HIV attacks and destroys the body’s CD4 cell of the immune system, which makes it difficult to fight off infections and certain HIV-related diseases. n nThere are naturally occurring antiretrovirals such as betulinic acid with anti-HIV activity, which is found in the bark of several species of plants. Modification of this compound has led to potent anti-HIV agents such as bevirimat, giving rise to novel mechanisms of action. Bevirimat acts by disrupting the genetic material that codes the proteins of a retrovirus (gag processing) and was a first-in-class maturation inhibitor with a potent activity against HIV-1. In addition, other derivatization of betulinic acid have led to their use in other therapeutics such as inhibition of cancer growth, anti-inflammatory activity, antifeedants for plant pests, and so forth. n nThe staggering statistics of the AIDS epidemic level worldwide has necessitated new and effective drugs for treatment of HIV-infected patients. The global cost of HIV treatment and prevention is estimated to reach

Modulating GluN2B for the Treatment of Neurological and Psychiatric Disorders

35 billion by 2031 (http://www.aidsmap.com). The present invention relates to C-3 triterpenone with C-28 heterocycle derivatives, which is shown to be useful in the treatment of viral diseases such as HIV-mediated diseases.

NLRP3 Modulators for the Treatment of Autoinflammatory Disorders

The N-methyl-D-aspartate receptors (NMDA) are a group of glutamate receptors and ion channel protein found in mammalian species. Cloning of NMDA receptor subunits leads to seven proteins, which are classified into three subunits: GluN1, GluN2, and GluN3. There are two obligatory GluN1 receptors (with a glycine binding site) and two variable GluN2 receptors (with a glutamate binding site), which are encoded by GRIN1 and one of four GRIN2 genes, respectively. In generally, the GluNR2 subunits expressed in different areas of the brain play a dominant role in the functional and pharmacological properties of the NMDA receptors. Furthermore, the GluN2B subunits mainly expressed in the forebrain have been implicated in the regulation of learning, memory processing, mood attention, emotion, and pain perception.