Current Topics in Medicinal Chemistry - Volume 11, Issue 12, 2011

The term “metabolic syndrome” refers to a group of abnormalities, including glucose intolerance, hyperinsulinemia, hypercholesterolemia, hypertriglyceridemia, and hypertension, which collectively constitute the risk factors for cardiovascular disease. Originally coined in the late 1950s, metabolic syndrome has received much attention in recent years as the cardiovascular complications resulted from metabolic disorders has become a global health threat. Numerous studies have implicated obesity and insulin resistance as the two major etiological factors for metabolic disorders. Consequently, many pharmaceutical research and development efforts have been focused on developing agents to induce weight loss and improve glucose regulation. Although current therapeutic options for treating obesity and related metabolic disorders remain limited and ineffective, recent advances have identified a group of novel targets and discovered potential therapeutic agents which may offer long-term anti-obesity and antihyperglycemic effect with better safety profiles. This special issue describes molecular mechanisms underlying five emerging targets and the rationale that leads to the development of these promising molecules, which may become the next classes of anti-diabetic agents in the future. An effective strategy for weight control is to curb the food craving by blocking neuroendocrine system that stimulates food consumption. The cannabinoid-1 (CB1) receptor has been shown to play a role in the regulation of appetitive behavior and represent an attractive target for anti-obesity agent. Indeed, impressive therapeutic efficacy of CB1 antagonists has been demonstrated in animals and humans. However, the first approved CB1 antagonist, Rimonabant, was withdrawn from the market due to severe CNS side effects. Ever since, research interest in CB1 antagonist has focused on peripherally restricted CB1 antagonists in hope to preserve the sustained anti-obesity effect without any detrimental CNS side effects. The first review by Wu et al describes recent advances in the development of peripherally acting CB1 antagonists. The article focuses on how various synthetic approaches, including increasing polarity, water solubility and polar surface area, were used to restrict tissue distribution of these newly discovered agents. The authors also summarize the preclinical efficacy results on some of the promising agents. Besides CB1 receptor, pharmaceutical researchers also actively explore other neuroendocrine system for new alternatives to manage the metabolic disorders associated with obesity. In the second review, Plancher discusses recent advances in the biology and pharmacology of histamine H3 receptor, an emerging molecular target for cognitive and metabolic disorder. The review describes critical pharmacological experiments linking the H3 receptor agents and metabolic disease models as well as pharmacophore and homology models used in the design of H3 receptor agents. The article also summarizes the major hurdles and some of the contradictions seen in the H3R field, together with a brief overview of the ongoing clinical trials. Following the two anti-obesity agents, three potential anti-diabetic agents aiming at restoring metabolic homeostasis are discussed. The review from Chen and Jiaang focuses on current advances and therapeutic potential of agents targeting dipeptidyl peptidases-4 (DPP4). DPP4 is a serine protease involved in the degradation of incretin hormones, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). GLP-1 regulates glucose homeostasis by stimulating insulin secretion, inhibiting glucagon release, and delaying gastric emptying. Inhibitors of DPP4 prevent the degradation of GLP-1 and have been shown to provide therapeutic benefits for type 2 diabetes. The review summarizes important structural classes of DPP4 inhibitors, emphasizing mainly on their potency and selectivity over other related peptidases. Biological activity, selective inhibitors, and therapeutic potential for related peptidases are also discussed. The next review by Sun, Wang and Wang describes small molecule inhibitors for 11-beta hydroxysteroid dehydrogenase type 1 (11β- HSD1), an NADPH-dependent enzyme catalyzing the interconversion of inactive cortisone to active cortisol. 11β-HSD1 is responsible for hypercortisolism in adipose tissue and liver and has been implicated in the pathogenesis of abdominal obesity, metabolic syndrome and type 2 diabetes. The article summarizes recent progress in the discovery and development of small molecule inhibitors of 11β-HSD1. The article highlights the medicinal chemistry, SAR, in vivo pharmacodynamic effects, and efficacy of a few representative classes of inhibitors in models of diabetes. Furthermore, the authors also review the structural characteristics of each class of inhibitors by analyzing the inhibitor cocrystal structures of 11β-HSD1. The final review by Ho, Kulkarni and Lee focuses on the development of sodium-dependent glucose cotransporter 2 (SGLT2) inhibitors as potential antidiabetic therapeutics. SGLT2 is a high-capacity, low-affinity transporter responsible for approximately 90% of glucose reabsorption in the kidney. Genetic as well as pharmacological data indicate that elevating renal glucose excretion by suppressing SGLT2 can reduce plasma glucose levels, as well as decrease weight. The review summarizes a number of disclosed SGLT2 inhibitors, including their structure-activity relationships (SARs) studies, their selectivity against SGLT1, and the most updated phase III clinical data of SGLT2 inhibitor, dapapgliflozin. We would like to offer our deep appreciation to all the authors contributing to this issue; without whom this collection would not be possible. We would also like to express our sincere gratitude to Dr. Allen Reitz and Dr. Rhoda Weber Joseph for the invitation to be the Guest Editor to compile this issue, and the reviewers for being meticulous in their evaluation of the manuscript.

Since Rimonabant was withdrawn in Europe in 2008 because of its substantial CNS risk factors including depression and anxiety, the development of anti-obesity drugs targeting CB1R in the brain has been suspended and/or terminated globally. Instead, developing peripherally restricted CB1R antagonists is actively pursued in the hope that not only could they eliminate any CNS adverse effects observed with Rimonabant, but also maintain therapeutic benefits in metabolic syndrome, including obesity, type 2 diabetes, and non-alcoholic fatty liver diseases. In this review, we summarized the most recent advances that have been made on this area, with particular emphasis on various synthetic approaches, whereby the increase in polarity, water solubility and polar surface area were centralized on, toward potential peripheralacting CB1 antagonists.

Since the histamine-3 receptor (H3R) was cloned in 1999, huge efforts have been made by most of the key players in the pharmaceutical industry as well as in smaller biotech companies to increase the knowledge on this peculiar receptor, with the ultimate goal of bringing new drugs to the market. This review gives a survey on the most valuable chemical tools discovered so far and the significant pharmacological experiments on metabolic disease models published to date. Pharmacology of H3R antagonists turns out to be very complex due to various functional activities, species selectivity, presence of H3R isoforms and the poorly understood dichotomy in efficacy between CNS and metabolic disease models. Adding an extra layer of complexity, researchers have to cope with some recurrent safety concerns, some of them being tightly linked to the nature of the H3R pharmacophore. Therefore this review also strives to summarize the major hurdles and some of the contradictions seen in the H3R field, together with a brief overview of the clinical trials currently running.

Dipeptidyl peptidase-IV (DPP-IV), a serine protease that specifically cleaves the N-terminal dipeptide with a preference for L-proline or L-alanine at the penultimate position, is involved in the degradation of incretin hormones, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). GLP-1 regulates glucose homeostasis by stimulating insulin secretion, inhibiting glucagon release, and delaying gastric emptying. Intravenous GLP-1 has been shown to increase insulin secretion in response to elevated glucose levels and offers therapeutic benefit for patients with type 2 diabetes. However, the therapeutic application of GLP-1 is severely compromised by its lack of oral activity and its rapid degradation by plasma DPP-IV. Consequently, small-molecule DPP-IV inhibitors that could extend the duration of action of GLP-1 and prolong its beneficial effects have been investigated as promising therapeutics for type 2 diabetes. This review summarizes important structural classes of DPP-IV inhibitors, focusing mainly on their inhibitory potency and selectivity for DPP-IV over other related peptidases such as DPP-II, DPP8, DPP9, and FAP. Because inhibition of DPP8 and/or DPP9 has been shown to cause severe toxicity in preclinical species, high selectivity is an important criterion in selecting DPP-IV inhibitors for clinical development. As of today, several DPP-IV inhibitors have completed phase III clinical studies for the treatment of type 2 diabetes. A brief overview of clinical efficacy data on these inhibitor drugs is provided here. In addition, biological activities of other related dipeptidyl peptidases (DPP-II, DPP8, DPP9, and FAP) will be summarized. Selective inhibitors for these peptidases and their therapeutic potential will be discussed.

11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) catalyzes the interconversion of inactive cortisone to active cortisol in a NADPH dependent manner. Excess cortisol or 11β-HSD1 leads to insulin resistance and metabolic syndrome. Inhibition of 11β-HSD1 activity has been pursued vigorously by the pharmaceutical industry as a potential therapeutic strategy for the treatment of type 2 diabetes. As a result, a large number of chemical classes have been identified as potent and selective small molecule inhibitors for 11β-HSD1. Here we review the recent progress in the discovery and development of small molecule inhibitors of 11β-HSD1 by highlighting the medicinal chemistry, SAR, in vivo pharmacodynamic effects and efficacy of a few representative classes of inhibitors in models of diabetes. Furthermore, we also review the structural characteristics of each class of inhibitors by analyzing the inhibitor co-crystal structures of 11β- HSD1.

The kidney plays an important role in the regulation of plasma glucose. It is estimated that greater than 99% of the renal glucose filtered by kidney glomerulus is resorbed by sodium-dependent glucose co-transporters (SGLTs), and that SGLT2 located in the proximal renal tubule achieves the most of this assignment. Studies of SGLT2 inhibitors indicate that raising renal glucose excretion by inhibiting SGLT2 helps effectively normalize the plasma glucose levels in individuals with type 2 diabetes mellitus (T2DM). This review discusses the discovery of SGLT2 inhibitors and the related structure-activity relationship (SAR) studies. The clinical trial data of dapagliflozin is also involved.

γ-secretase is an aspartyl protease that cleaves a large number of substrates within the membrane environment. This multiprotein complex is responsible for the last cleavage step of the β-amyloid precursor protein (APP) that generates the amyloid-β peptide (Aβ), one of the primary components of amyloid plaques in Alzheimer's disease (AD). Over the last years, more than 90 type-I membrane proteins have been shown to be cleaved by γ-secretase. The mechanism and function of this cleavage event is not yet well understood. The -secretase cleavage of some substrates releases intracellular domains with critical signaling properties. In contrast, the cleavage of other substrates seems to have a mere degradative function. Knowledge about γ-secretase substrates and their function has clear implications for the development of new therapies for AD. Most γ-secretase inhibitors interfere with the cleavage of the Notch receptor, which is known to lead to adverse effects in animal models and in humans. Paradoxically, due to this effect, γ-secretase inhibitors are actively being investigated in cancer. An alternative approach is modulation of γ-secretase, in which small molecules allosterically attenuate the activity to reduce Aβ42, the most fibrillogenic species. Although tolerance and efficacy of some γ-secretase inhibitors in AD have shown to be poor in clinical trials, more selective compounds are on the road. As these compounds advance to clinical trials it is critical to understand the mechanism by which γ-secretase recognizes and cleaves this diverse set of substrates to predict possible adverse effects in humans. This knowledge will help to guide drug development in AD and cancer.

The use of homology models in docking-based drug discovery is already established, and provides an effective and computationally affordable alternative whenever experimental structures are not available. Recent methodological studies have confirmed and benchmarked the feasibility of using structural models in docking. However, more accurate methods are expected to be developed in the near future, especially for the model refinement stage. In this review, the latest developments in homology modeling in the context of structure-based virtual screening are presented, together with the recent success stories of homology modeling in actual docking-based drug discovery endeavours.

Peptide nucleic acids (PNAs) are polyamidic oligonucleotide analogues which have been described for the first time almost twenty years ago and were immediately found to be excellent tool in binding DNA and RNA for diagnostics and gene regulation. Their use as therapeutic agents have been proposed since early studies and recent advancements in cellular delivery systems and in the so called anti-gene strategy make them good candidates for drug development. The search for new chemical modification of PNAs is a very active field of research and new structures are continuously proposed. This review focuses on the modification of the PNA backbone, and their possible use in medicinal chemistry with an update of this topics in view of emerging new trends and opening of new possibilities In particular two classes of structurally biased PNAs are described in details: i) PNAs with acyclic structures and their helical preference, which is regulated by stereochemistry and ii) cyclic PNAs with preorganized structures, whose performances depend both on stereochemistry and on conformational constraints. The properties of these compounds are discussed in terms of affinity for nucleic acids, and several examples of their use in cellular or animal systems are presented, with exciting new fields of research such as microRNA (miR) targeting and gene repair.

According to the β-amyloid (Aβ) hypothesis, compounds that inhibit or modulate γ secretase, the pivotal enzyme that generates Aβ, are potential therapeutics for Alzheimer's disease (AD). Studies in both transgenic and nontransgenic animal models of AD have indicated that γ secretase inhibitors, administered by the oral route, are able to lower brain Aβ concentrations. However, scanty data are available on the effects of these compounds on brain Aβ deposition after chronic administration. Behavioral studies are also scarce with only one study indicating positive cognitive effects of a peptidomimetic compound acutely administered (DAPT). γ-Secretase inhibitors may cause abnormalities in the gastrointestinal tract, thymus, spleen and skin in experimental animals and in man. These toxic effects are likely due to inhibition of Notch cleavage, a transmembrane receptor involved in regulating cell-fate decisions. Some non-steroidal anti-inflammatory drugs (NSAIDs) and other small organic molecules have been found to modulate γ secretase shifting its cleavage activity from longer to shorter β-amyloid species without affecting Notch cleavage. Long-term histopathological and behavioral animal studies are available with these NSAIDs (mainly ibuprofen) but it is unclear if the observed in vivo effects on Aβ brain pathology and learning depend on their activity on -secretase or on other biological targets. The most studied γ-secretase inhibitor, semagacestat (LY-450139), was shown to dose-dependently decrease the generation of Aβ in the cerebrospinal fluid of healthy humans. Unfortuantely, two large Phase 3 clinical trials of semagacestat in mild-to-moderate AD patients were prematurely interrupted because of the observation of detrimental effects on cognition and functionality in patients receiving the drug compared to those receiving placebo. These detrimental effects were mainly ascribed to the inhibition of Notch processing and to the accumulation of the neurotoxic precursor of Aβ (the carboxy-terminal fragment of APP, or CTFβ) resulting from the block of the γ-secretase cleavage activity on APP. Two large Phase 3 studies in mild AD patients with tarenflurbil (R-flurbiprofen), a putative γ-secretase modulator, were also completely negative. The failure of tarenflurbil was ascribed to low potency and brain penetration. New Notchsparing γ-secretase inhbitors and more potent, more brain penetrant γ-secretase modulators are being developed with the hope of overcoming the previous setbacks.

Aberrant angiogenesis has been observed in many solid tumors. The formation and metastases of tumors such as non-small cell lung cancer (NSCLC) and renal cell carcinoma (RCC) are very complex, often regulated by proangiogenic factors such as the vascular endothelial growth factor (VEGF) and other tyrosine kinases. The VEGFR, EGFR and mTOR pathways have played critical roles in controlling cell proliferation and angiogenesis. This paper reviews the mechanism and binding modes of recently approved tyrosine kinase inhibitors (TKIs), such as gefitinib, erlotinib, nilotinib, dasatinib, sunitinib, sorafenib, pazopanib, lapatinib, afinitor, and temsirolimus. We also cover the progresses of the recent development of tyrosine kinase inhibitors that are currently in the clinical trials at the phases I, II, and III, targeting the VEGFR, EGFR and/or mTOR pathways. Combination therapy intended to overcome drug resistance is also discussed. Recent TKI design based on the activation loop and the “DFG” conformation, is also discussed.