Ursolic acid derivatives for pharmaceutical use: a patent review (2012-2016)

Introduction: Ursolic acid (UA), belongs to a group of pentacyclic triterpenoids and is known to possess some very interesting biological properties. Protocols have been developed in order to synthesize bioactive UA analogs which have resulted in numerous ursolic acid analogs being synthesized during the period 2012–2016. Ursolic acid and its analogues can be employed to treat various cancers, inflammatory diseases, diabetes, Parkinson’s disease, Alzheimer’s disease, hepatitis B, hepatitis C and AIDS to mention but a few.

Areas covered: This review covers patents on therapeutic activities of ursolic acid (UA) and its synthetic derivatives published during the four year period 2012–2016. A discussion about structure-activity relationships (SAR) of these analogs is also included.

Expert opinion: Ursolic acid and its synthetic derivatives demonstrated excellent anticancer, antidiabetic, antiarrhythmic, anti-hyperlipidemic, antimicrobial, anti-hypercholesterolemic, and anti-cardiovascular properties. Additionally, various ursolic acid analogues have been synthesized through modification at positions C₂-OH, C₃-OH and C_17-CO₂H. It is noteworthy that the C-17 amide and amino analogs of UA possessed better anticancer activity compared to the parent compound (UA). Most importantly, UA has the potential to conjugate with other anticancer drugs or be transformed into its halo derivatives since this will greatly facilitate scientists to get lead compounds in cancer drug discovery.     

Diabetes drugs and the incidence of solid cancers: a survey of the current evidence

Introduction: The evaluation of the relationship between the use of antidiabetic drug and the occurrence of cancer is extremely challenging, both from the clinical and pharmacoepidemiological standpoint. This narrative review described the current evidence supporting a relationship between the use of antidiabetic drugs and the incidence of solid cancers.

Areas covered: Data from pharmacoepidemiological studies on cancer incidence were presented for the main antidiabetic drugs and drug classes, including human insulin and insulin analogues, metformin, sulfonylureas, glinides, alpha-glucosidase inhibitors, thiazolidinediones, incretin mimetics, and sodium glucose co-transporter 2 inhibitors. The relationship between the use of antidiabetics and the incidence of solid cancer was described in strata by any cancer and by organ-specific cancer and by drug and by drug classes. Information supporting biological evidence and putative mechanisms were also provided.

Expert opinion: The history of exploration of the relationship between antidiabetic drugs and the risk of solid cancers has showed several issues. Unrecognized biases and misinterpretations of study results have had important consequences that delayed the identification of actual risk and benefits of the use of antidiabetic drugs associated with cancer occurrence or progression. The lesson learned from the past should address the future research in this area, since in the majority of cases findings are controversial and confirmatory studies are warranted.     

Current insights into anti-HIV drug discovery and development: a review of recent patent literature (2014–2017)

Introduction: To deal with the rapid emergence of drug resistance challenges, together with the difficulty to eradicate the virus, off-target effects and significant cumulative drug toxicities, it is still imperative to develop next-generation anti-HIV agents with novel chemical classes or new mechanisms of action.

Areas covered: We primarily focused on current strategies to discover novel anti-HIV agents. Moreover, examples of anti-HIV lead compounds were mainly selected from recently patented publications (reported between 2014 and 2017). In particular, ‘privileged structure’-focused substituents decorating approach, scaffold hopping, natural-product diversification and prodrug are focused on. Furthermore, exploitation of new compounds with unexplored mechanisms of action and medicinal chemistry strategies to deplete the HIV reservoir were also described. Perspectives that could inspire future anti-HIV drug discovery are delineated.

Expert opinion: Even if a large number of patents have been disclosed recently, additional HIV inhibitors are still required, especially novel chemical skeletons displaying a unexploited mechanism of action. Current medicinal chemistry strategies are inadequate, and appropriate and new methodologies and technologies should be exploited to identify novel anti-HIV drug candidates in a time- and cost- effective manner.     

Lapachol and lapachone analogs: a journey of two decades of patent research(1997-2016)

Introduction: Lapachol (1), β-lapachone (2) and α-lapachone (3) are three well-studied natural products isolated from Tabebuia impetiginosa having most interesting chemodiversity and demonstrating diverse biological effects.

Areas covered: The current review summarizes the recent and past discovery of chemotherapeutic agents based on the compounds 1–3. This review presents an overview of patents filed over the past two decades (1997 to 2016) mostly relating to the anticancer effects of these lapachol and lapachone analogues.

Expert opinion: The large number of interesting patents published on the therapeutic potential of quinones 1–3 and their synthetic derivatives lends credence to the importance of these molecules. Moreover, these quinones demonstrated potent anticancer effects towards various cancer cell lines and chemical modification of these quinones have led to products displaying enhanced anticancer effects. It is noteworthy that the majority of patents published are on the anticancer effects of quinones 1–3 and their synthetic derivatives along with a limited number of additional biological effects. It is our opinion that in order to get lead compounds, there needs to be a greater focus on the elucidation of the precise mechanism of action of these compounds including SAR and in vivo studies.     

Medicinal plants and natural products in amelioration of arsenic toxicity: a short review

Context: Chronic arsenic toxicity (arsenicosis) is considered a serious public health menace worldwide, as there is no specific, safe, and efficacious therapeutic management of arsenicosis.

Objectives: To collate the studies on medicinal plants and natural products with arsenic toxicity ameliorative effect, active pre-clinically and/or clinically.

Methods: Literature survey was carried out by using Google, Scholar Google and Pub-Med. Only the scientific journal articles found on the internet for last two decades were considered. Minerals and semi-synthetic or synthetic analogs of natural products were excluded.

Results: Literature study revealed that 34 medicinal plants and 14 natural products exhibited significant protection from arsenic toxicity, mostly in preclinical trials and a few in clinical studies.

Conclusion: This research could lead to development of a potentially useful agent in clinical management of arsenicosis in humans.     

Cardiovascular safety of therapies for type 2 diabetes

Introduction: Dipeptidyl peptidase-4 (DPP4) inhibitors, glucagon-like peptide-1 (GLP-1) analogs and sodium-glucose cotransporter 2 (SGLT2) inhibitors are relatively new therapies for the treatment of type 2 diabetes mellitus. Given the high prevalence of cardiovascular complications in patients with type 2 diabetes and recent concerns questioning CV safety of newer antidiabetic medications, cardiovascular safety of these medications requires evaluation.

Areas covered: Cardiovascular effects of these drug classes from preclinical and clinical data as well as non-cardiovascular safety issues are delineated from literature searches covering the last decade and up to June 2016. Major clinical trials assessing the cardiovascular safety of GLP-1 agonists (ELIXA and LEADER), DPP-4 inhibitors (SAVOR-TIMI 53, EXAMINE, and TECOS) and SGLT2 inhibitors (EMPA-REG OUTCOME) are reviewed and interpreted.

Expert opinion: Based on review of the present evidence, these 3 classes of antihyperglycemic therapies have acceptably safe CV safety profiles for patients with type 2 diabetes. The latest evidence from LEADER and EMPA-REG OUTCOME trials indicate that liraglutide and empagliflozin have cardiovascular benefits that may prove to be of clinical importance in the management of type 2 DM.     

Acid-base and electrolyte disorders associated with the use of antidiabetic drugs

Introduction: The use of antidiabetic drugs is expected to substantially increase since diabetes mellitus incidence rises. Currently used antidiabetic drugs have a positive safety profile, but they are associated with certain acid-base and electrolyte abnormalities. The aim of the review is to present the current data regarding the antidiabetic drugs-associated acid-base and electrolyte abnormalities.

Areas covered: Sodium-glucose cotransporter 2 (SGLT2) inhibitors have been linked with the scarce, but serious, complication of euglycemic diabetic ketoacidosis, as well as with an increase in serum potassium, magnesium and phosphorus levels. Metformin use has been associated with the development of lactic acidosis, although many studies have doubt the direct link with this serious complication. Additionally, metformin in some studies has been linked with a decrease in serum magnesium levels. Insulin administration is associated with a reduction in serum potassium, magnesium and phosphorus concentration, along with reduced renal magnesium excretion. Pioglitazone is associated with an increase in serum magnesium levels. Current data regarding the pathophysiological mechanisms, precipitants, risk factors and presentation of the above abnormalities are discussed in the present review.

Expert opinion: Clinicians should choose appropriately between antidiabetic drugs based not only on their hypoglycemic efficacy and effects on cardiovascular risk but also based on the patient’s specific risk to develop acid-base or electrolyte derangements.     

Investigational and experimental GnRH analogs and associated neurotransmitters

Introduction: The GnRH agonistic analogs enable for desensitizing the hypothalamo-pituitary-gonadal axis in malignant and benign conditions where minimizing the production of sex hormones, or blocking ovulation is necessary. The possible indications are prostate cancer, benign prostate hyperplasia, breast cancer, endometriosis, precocious puberty, uterine leiomyomata, assisted reproduction (ART)/in vitro fertilization (IVF), PCOS, minimizing the gonadotoxic effect of chemotherapy in young women, and possibly ovarian cancer.

Areas covered: The aim of the current review is to summarize, giving a critical overview, of the investigational GnRH agonists, and shortly discuss the difference between the GnRH agonists, antagonists, Kisspeptin, and Neurokinin B analogs.

Expert opinion: The broad armamentarium of agonists may make it possible, in the future, to expand the indications and uses of these analogs, choosing and specifically tailoring the analog to the required effect, while minimizing side effects.     

The safety of DPP-4 inhibitor and SGLT2 inhibitor combination therapies

Introduction: Type 2 diabetes (T2D), a multifactorial and chronic disease, requires in an elevated percentage of patients the association of several antidiabetic drugs to achieve optimal glycemic control. Dipeptidyl peptidase-4 inhibitors (DPP-4i) and sodium–glucose cotransporter inhibitors (SGLT2i) are new classes of oral antidiabetic drugs developed over the last years.

Areas covered: This paper summarizes the safety of DPP-4i and SGLT2i combination therapies. Relevant studies were identified through searches in PubMed.

Expert opinion: DPP4i and SGLT2i are antidiabetic drugs that lower blood glucose without causing hypoglycaemia or weight increase. More importantly, cardiovascular trials have clearly demonstrated the cardiovascular safety of DPP4i and a reduction in cardiovascular events with SGLT2i (empagliflozin and canagliflozin). Therefore, the association of both therapeutic groups could be an attractive option to achieve optimal blood glucose control in T2D because of their complementary mechanism of action. Clinical trials evaluating the combination of SGLT2i and DPP4i show that the co-administration of these drugs in fixed-dose combinations in comparison to separate tablets does not carry additional safety concerns that each individual drug, but increases therapeutic effects. Therefore, this antidiabetic combination is a safe and effective therapy for patients with T2D.     

Novel benzopyran derivatives and their therapeutic applications: a patent review (2009–2016)

Introduction: The benzopyran derivatives present a wide variety of biological activity and behaviour. At the same time the benzopyran derivatives support their use as therapeutic agents for multiple diseases. Their structural characteristics correlated to physicochemical properties seem to define the extent of the biological activity.

Areas covered: This review summarizes new patents published on new benzopyran derivatives from 2009 to 2016.

Expert opinion: Many benzopyran derivatives have vivo/vitro biological responses. Their clinical evaluation will be critical to assess therapeutic utility. The compounds containing benzopyran moiety is well defined as lead compounds for design of new more promising molecules.     

Somatostatin analogs in the treatment of neuroendocrine tumors: current and emerging aspects

Introduction: Neuroendocrine tumors (NETs) harbor somatostatin receptors and there is a strong rationale for using somatostatin analogs (SSAs) for treatment of NETs.

Areas covered: This article discusses i) pharmacology of somatostatin and its analogs; ii) antisecretory and anti-proliferative effects of SSAs in NETs; iii) efficacy and safety of emerging therapeutic regimens with first generation SSAs administered at either high doses or in combination with antineoplastic drugs; iv) efficacy and safety of pasireotide and chimeric molecules; v) efficacy of radionuclide therapy of NETs using SSAs.

Expert opinion: SSAs are the first-line medical therapy for functioning and non-functioning well-differentiated NETs. In patients not responder to first generation SSAs, the increase of drug dose over the conventional regimens, the combination of SSAs with other biotherapies or molecular targeted therapies, the switch to pasireotide or the use of SSAs in radionuclide therapy may improve the therapeutic success.     

A patent review of two fruitful decades (1997-2016) of Isocoumarin research

Introduction: Isocoumarins comprise a six-membered oxygen heterocycle (α-pyranone) along with one aromatic ring and are known to possess interesting biological properties. During the last two decade (1997–2016), isocoumarin chemistry has attracted attention due to its biological and pharmaceutical effects viz., anticancer, anti-diabetic, antibacterial, antimalarial, and fungicidal effects.

Areas covered: This review covers the patents on the therapeutic activities of natural and synthetic isocoumarins over the last two decades (1997–2016). Moreover a number of international patents related to natural and synthetic isocoumarins along with their biological effects will be presented and discussed. Although a large number of patents have been published during the period of the review, the aim of this review is to focus on those important patents specifically related to microbial diseases, cancer, malaria, and diabetes.

Expert opinion: Isocoumarin and its synthetic analogs display a wide range of important pharmaceutical properties. Furthermore, isocoumarins have the potential to conjugate with other anticancer drugs which will synergistically increase the delivery and thus anticancer effects. Moreover, in order to get lead compounds, scientists should focus on the synthesis of halo and functionalized heterocyclic ring containing derivatives of isocoumarins as more potent drugs.     

Safety and efficacy of teneligliptin in Japanese patients with type 2 diabetes mellitus: a pooled analysis of two Phase III clinical studies

Objective: To assess the safety and efficacy of long-term administration of teneligliptin alone and in combination with oral antidiabetic drugs in Japanese type 2 diabetes mellitus (T2DM) patients with insufficient glycemic control.

Methods: This post-hoc pooled analysis used data from two Phase III clinical studies involving 702 Japanese patients. We evaluated teneligliptin as monotherapy and combined with a sulfonylurea, glinide, biguanide, or α-glucosidase inhibitor. Safety measures included adverse events (AEs), adverse reactions and hypoglycemia. The main efficacy measure was the change in glycated hemoglobin (HbA_1c) from baseline.

Results: Incidences of AEs and adverse reactions were similar among the teneligliptin monotherapy group and all combination therapy groups except the combination with sulfonylurea. Hypoglycemia was more frequent in the sulfonylurea combination therapy group than in other groups. Teneligliptin administered once daily as monotherapy or combination therapy resulted in a decrease in HbA_1c, which was maintained for 52 weeks. Bodyweight showed no change or a slight increase at the end of 52 weeks in all groups.

Conclusions: This pooled analysis provides evidence for the safety and efficacy of long-term use of teneligliptin as monotherapy or combination therapy in Japanese T2DM patients.     

Assessing product adulteration of Eurycoma longifolia (Tongkat Ali) herbal medicinal product using DNA barcoding and HPLC analysis

Context: Eurycoma longifolia Jack (Simaroubaceae) commonly known as Tongkat Ali is one of the most important plants in Malaysia. The plant extracts (particularly roots) are widely used for the treatment of cough and fever besides having antimalarial, antidiabetic, anticancer and aphrodisiac activities.

Objectives: This study assesses the extent of adulteration of E. longifolia herbal medicinal products (HMPs) using DNA barcoding validated by HPLC analysis.

Materials and methods: Chloroplastic rbcL and nuclear ITS2 barcode regions were used in the present study. The sequences generated from E. longifolia HMPs were compared to sequences in the GenBank using MEGABLAST to verify their taxonomic identity. These results were verified by neighbor-joining tree analysis in which branches of unknown specimen are compared to the reference sequences established from this study and other retrieved from the GenBank. The HMPs were also analysed using HPLC analysis for the presence of eurycomanone bioactive marker.

Results: Identification using DNA barcoding revealed that 37% of the tested HMPs were authentic while 27% were adulterated with the ITS2 barcode region proven to be the ideal marker. The validation of the authenticity using HPLC analysis showed a situation in which a species which was identified as authentic was found not to contain the expected chemical compound.

Discussion and conclusions: DNA barcoding should be used as the first screening step for testing of HMPs raw materials. However, integration of DNA barcoding with HPLC analysis will help to provide detailed knowledge about the safety and efficacy of the HMPs.     

Pharmacokinetic drug evaluation of exenatide for the treatment of type 2 diabetes

Introduction: Glucagon-like peptide-1 (GLP-1) receptor analogs are a group of therapeutic agents which mimic endogenous GLP-1, exerting their effect by the stimulation of the GLP-1 receptor with a wide distribution. Its activation increases insulin releasing dependent on blood glucose levels, suppression of glucagon secretion and a reduction of hepatic glucose output. It delays gastric emptying and increases satiety. Exenatide is the synthetic version of exendin-4, a natural peptide with similar properties to human GLP-1. There are two pharmaceutical forms, for subcutaneous injection: twice daily and once weekly.

Clinical practice guidelines recommend them because of a high efficacy reducing hyperglycemia, low risk of hypoglycemia and a significative weight loss effect. Gastrointestinal adverse events are the most common beside injection site-related. Their cost is the main limitation to use.

Areas covered: We review the recent literature investigating the pharmacokinetics and pharmacodynamics and efficacy-safety studies of exenatide twice daily and once weekly in type 2 diabetes

Expert opinion: GLP-1 receptor analogs are now positioned as an effective and safe drug for the treatment of type 2 diabetes. Exenatide significally reduces HbA1c and fasting plasma glucose. Additionally, it produces moderate weight loss and decreases blood pressure. One weekly formulation may improve compliance while cost is still a limitation. EXSCEL trial has shown that, despite cardiovascular safety, exenatide do not exhibits cardiovascular benefits.     

Investigational parathyroid hormone receptor analogs for the treatment of osteoporosis

Introduction: Intermittent parathyroid hormone (PTH) administration, acting through multiple signaling pathways, exerts an osteoanabolic effect on the skeleton that surpasses the effect of other antiosteoporotic agents. However, its efficacy is limited by the coupling effect and relatively common adverse events. Thus, the development of more sophisticated PTH receptor analogs seems imperative.

Areas covered: In this review, the authors summarize the role of PTH signaling pathway in bone remodeling. The authors also summarize investigational analogs targeting this pathway, which may be potential treatments for osteoporosis.

Expert opinion: β-arrestins are multifunctional cytoplasmic molecules that are decisive for regulating intracellular PTH signaling. Recently, in preclinical studies, arrestin analogs have achieved the anabolic bone effect of PTH without an accompanying increase in bone resorption. However, it is not yet known whether these analogs have adverse effects and there are no clinical data for their efficacy to date. On the other hand, several molecules derived either from PTH and PTH-related protein (PTHrP) molecules have been developed. Alternative routes of PTH 1 – 34 delivery (oral, transdermal), the PTH analog ostabolin and the N-terminal PTHrP analogs PTHrP 1 – 36 and abaloparatide, have recently been or are currently being tested in clinical trials and are more likely to become available for use in the near future.     

Plants in our combating strategies against Mycobacterium tuberculosis: progress made and obstacles met

Context: Traditionally used plants for treating chest-related problems/tuberculosis (TB) have not been evaluated in detail and hence a thorough study is needed in this regard. This knowledge may find application in developing new anti-TB drugs.

Objective: This article elaborates on studying the activity of medicinal plants against different forms of Mycobacterium tuberculosis (Mtb) using different model strains, in vitro and ex vivo assays for studying the tuberculocidal activity and discusses the results from different studies on the activity against different forms of Mtb and human immunodeficiency virus-tuberculosis (HIV-TB) co-infection.

Methods: Scientific databases such as PubMed, Elsevier, Scopus, Google scholar, were used to retrieve the information from 86 research articles (published from 1994 to 2016) related to the topic of this review.

Results: Twenty-three plant species have been reported to possess active molecules against multi-drug resistant (MDR) isolates of Mtb. Seven plants were found to be active against intracellular Mtb and six against dormant bacilli. Seven plants were synergistically effective when combined with anti-TB drugs. Six studies suggest that the beneficial effects of plant extracts are due to their wide array of immuno-modulatory effects manifested by the higher expression of cytokines. Some studies have also shown the dual activity (anti-HIV and anti-TB) of plants.

Conclusion: We emphasize on identifying plants based on traditional uses and testing their extracts/phytomolecules against MDR strains, intracellular Mtb as well as against dormant Mtb. This will help in future to shorten the current therapeutic regimens for TB and also for treating HIV-TB co-infection.     

Clinacanthus nutans: a review on ethnomedicinal uses,chemical constituents and pharmacological properties

Context: Medicinal plants have attracted global attention for their hidden therapeutic potential. Clinacanthus nutans (Burm.f) Lindau (Acanthaceae) (CN) is endemic in Southeast Asia. CN contains phytochemicals common to medicinal plants, such as flavonoids. Traditionally, CN has been used for a broad range of human ailments including snake bites and cancer.

Objectives: This article compiles the ethnomedicinal uses of CN and its phytochemistry, and thus provides a phytochemical library of CN. It also discusses the known pharmacological and biological effects of CN to enable better investigation of CN.

Methods: This literature review was limited to articles and websites published in the English language. MEDLINE and Google Scholar databases were searched from December 2014 to September 2016 using the following keywords: "Clinacanthus nutans" and "Belalai gajah". The results were reviewed to identify relevant articles. Information from relevant selected studies was systematically analyzed from contemporary ethnopharmacological sources, evaluated against scientific literature, and extracted into tables.

Results: The literature search yielded 124 articles which were then further scrutinized revealing the promising biological activities of CN, including antimicrobial, antiproliferative, antitumorigenic and anti-inflammatory effects. Few articles discussed the mechanisms for these pharmacological activities. Furthermore, CN was beneficial in small-scale clinical trials for genital Herpes and aphthous stomatitis.

Conclusion: Despite the rich ethnomedicinal knowledge behind the traditional uses of CN, the current scientific evidence to support these claims remains scant. More research is still needed to validate these medicinal claims, beginning by increasing the understanding of the biological actions of this plant.