Therapeutic applications for novel non-hypercalcemic vitamin D receptor ligands

Background: The active form of vitamin D₃, 1α,25-dihydroxyvitamin D₃ (1,25(OH)₂D₃), plays an important role in calcium homeostasis, cell differentiation, cell proliferation and immunity. A more complete understanding of the several physiological and pharmacological properties of 1,25(OH)₂D₃ indicates that the vitamin D receptor (VDR) is a promising drug target in the treatment of cancers, autoimmune diseases, infections and cardiovascular disease as well as bone and mineral disorders. The calcemic effect of 1,25(OH)₂D₃ and its derivatives has limited their clinical application. As a result, the development of non-calcemic VDR ligands is required to realize the potential of VDR-targeting therapy. Objective: In this review, we discuss the in vitro and in vivo pharmacological actions, including VDR interaction, regulation of cofactor recruitment, pharmacokinetics and cell type or tissue-selective action of VDR ligands with less-calcemic activity. Conclusion: Pharmacokinetic parameters and selective tissue accumulation are related to the therapeutic benefit of non-hypercalcemic vitamin D derivatives. Induction of distinct VDR conformations and cofactor recruitment may be associated with selective actions of non-secosteroidal VDR ligands. Derivatives of lithocholic acid, a newly identified endogenous VDR ligand, are less-calcemic VDR ligands.     

Retiferols – synthesis and biological activity of a conceptually novel class of vitamin D analogs

Introduction: The hypothesis that retiferols are a novel class of vitamin D analogs with therapeutic potential has been recently proved. The CD-ring of vitamin D, originated from a steroid precursor, is not necessary for biological activity. The retiferol, disubstituted at C-13, was bound to the ligand-binding domain (LBD) of vitamin D receptor (VDR) just like the vitamin D hormone [1,25-(OH)₂D₃]. This finding opens the way for retiferols as a novel class of vitamin D therapeutics.

Areas covered: This review presents the concept of retiferols and their structure evolution. Medicinal chemistry and therapeutic perspective of retiferols are reviewed showing how these vitamin D analogs became a source of potential therapeutics.

Expert opinion: Docking experiments and molecular modeling have shown that positioning of vitamin D analog at the LBD of VDR is not disturbed by deletion of a large portion of the vitamin D, exactly as hypothesized. Twenty years of structural modifications have shown that removal of the CD-ring fragment and regioselective methylation results in an almost complete loss of the undesired calcemic activity of retiferol while gaining the agonistic activity comparable to that of 1,25-(OH)₂D₃.     

Thyromimetics: a review of recent reports and patents (2004 – 2009)

Importance of the field: Thyroid hormones are produced by the thyroid gland and peripheral tissues, and control metabolic rate, including oxygen consumption, lipid metabolism and the cardiovascular system, mainly through binding to and activating thyroid hormone receptors (TRs). Abnormal elevation or lowering of circulating thyroid hormone induces various physiological disorders. As candidates for the treatment of such diseases, various thyromimetics, such as subtype- or tissue-selective TR agonists and antagonists, have been developed.

Areas covered in this review: This review focuses on recent reports and patents covering thyromimetics, especially those published in the last 6 years.

What the reader will gain: In this review, we classify thyromimetics based on structure. The structures of most thyromimetic compounds are based on those of endogenous thyroid hormones, which consist of a biaryl ether skeleton substituted with iodine, α-alanine moiety and hydroxyl group at two benzene rings. Many thyromimetics have been developed by replacement of the polar group, changing the bridging oxygen, or introduction of heterocycles. This review provides an overview of the structure–activity relationship.

Take home message: Some thyromimetics are subtype- or tissue-selective TR agonists and antagonists, and such compounds have the potential to become novel therapeutic agents, especially in the field of metabolic diseases.     

Protective effect of standardized extract of Myrtus communis L. (myrtle) on experimentally bleomycin-induced pulmonary fibrosis: biochemical and histopathological study

Context: Myrtle (Myrtus communis L) has been used widely in traditional medicine for different respiratory disorders. Idiopathic pulmonary fibrosis (IPF) is an inflammatory disease characterized by progressive loss of lung function with poor prognosis. The pathogenesis of disease has not been completely elucidated, but probably persistent epithelial damages are involved.

Objective: Evaluation of biochemical and histopathological effect of preventive and therapeutic doses of myrtle against bleomycin (BLM)-induced pulmonary fibrosis (PF) in animal model.

Materials and methods: Methanolic extract of M. communis was prepared by maceration method. Total flavonoid content was determined and experimentally PF was induced in rat with intratracheal instillation of a single dose of BLM (5?mg/kg) only on day 0. Myrtle antifibrotic effect was evaluated as preventive (50?mg/kg/day, intraperitoneal (i.p.) injection, from day 0–13) and therapeutic agent (50?mg/kg, i.p., from day 14–27) in comparison with methyl prednisolone (M-pred) (4?mg/kg, i.p. for 14 days).

Results: Parenchymal inflammation and fibrotic changes significantly were reduced by myrtle and M-pred. Significant decrease in hydroxyproline content and lipid peroxidation were observed in animals receiving myrtle extract while catalase activity was increased by myrtle. Improvement in inflammation and fibrosis was observed in myrtle group especially in the early phase of fibrosis (preventive regime).

Discussion and conclusion: Myrtle extract effectively inhibited the inflammation and fibrosis of lung parenchyma in both preventive and therapeutic methods. This effect might be due to the reduction of tissue inflammation and inhibition of oxidative stress. More studies are being carried out to find main mechanisms and separation of active compounds.     

Emerging small-molecule compounds for treatment of atopic dermatitis: a review

Introduction: Atopic dermatitis is a chronic, relapsing, pruritic inflammatory skin disease. Both skin barrier defects and abnormal immune reactions contribute to this complex disease. Current therapeutic guidelines recommend the use of moisturizers, good skin care and allergen avoidance as the first-line approach. In patients who do not respond well to these measures, topical corticosteroids, calcineurin inhibitors, and, in severe cases, systemic immunosuppressive agents are mostly used.

Areas covered: This review summarizes the patent applications for small-molecule compounds for the treatment of atopic dermatitis from 2009 to date. These substances include compounds targeting the skin barrier (filaggrin production promoters, filaggrin breakdown products and compounds improving stratum corneum lipid barrier including pseudoceramides), anti-inflammatory compounds (PDE4/7 inhibitors, CRTH2 inhibitors, chemokine receptor antagonists, inhibitors of chymase and other) and compounds specifically targeting itch (TRP agonists, opioid ligands, serotonin 7 and histamine 4 antagonists).

Expert opinion: Recent advances in understanding the pathogenic mechanisms of atopic dermatitis have created a strong rationale for the design of targeted therapeutics. Most emerging compounds target inflammation and/or pruritus, probably because of the broader therapeutic utility of such compounds. Specific skin barrier-corrective therapies are much fewer but bear strong potential to actually prevent inflammation.     

Pharmacological effects of berberine and its derivatives: a patent update

Introduction: A number of plant-derived agents are used in many therapeutic areas. Berberine, an important protoberberine alkaloid, is present in a number of medicinal plants that have been widely used in traditional Chinese medicine for hundreds of years. Modern research has shown that berberine and its derivatives display several pharmacological effects through various mechanisms.

Areas covered: This review discusses recent and mostly Chinese patents that report the synthesis of berberine, berberine derivatives and berberine salts, and methods of preparation for formulations (traditional Chinese medicine) containing herbal components rich in berberine, along with their applications. The review covers several therapeutic effects of berberine, its derivatives and pharmaceutical formulations against cancer, obesity, diabetes, inflammation, atherosclerosis, Alzheimer’s disease, rheumatoid arthritis and cardiovascular diseases. In addition, the mechanisms underlying the pharmacological effects are discussed.

Expert opinion: Modification of the functional groups of berberine has a significant effect on the pharmacological activity. However, studies on altering the atoms and size of the berberine skeleton are rare. Thus, it may be beneficial to initiate a drug development program focused on inserting heterocyclic rings of different sizes into berberine. Furthermore, structural modification to improve the safety, efficacy and selectivity is necessary to promote the use of berberine-based drugs in clinical settings.     

Vitamin D3 derivatives with adamantane or lactone ring side chains are cell type-selective vitamin D receptor modulators

The vitamin D receptor (VDR) mediates the biological actions of 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)], the active form of vitamin D, which regulates calcium homeostasis, immunity, cellular differentiation, and other physiological processes. We investigated the effects of three 1,25(OH)(2)D(3) derivatives on VDR function. AD47 has an adamantane ring and LAC67a and LAC67b have lactone ring substituents at the side chain position. These vitamin D derivatives bind to VDR but do not stabilize an active cofactor conformation. In a VDR transfection assay, AD47 and LAC67b act as partial agonists and all three compounds inhibit VDR activation by 1,25(OH)(2)D(3). The derivatives enhanced the heterodimerization of VDR with the retinoid X receptor, an effect unrelated to agonist/antagonist activity. AD47 and LAC67b weakly induced recruitment of the SRC-1 cofactor to VDR, and all three derivatives inhibited the recruitment of p160 family cofactors to VDR induced by 1,25(OH)(2)D(3). It is noteworthy that AD47 induced DRIP205 recruitment as effectively as 1,25(OH)(2)D(3), whereas LAC67a and LAC67b were not effective. We examined the expression of endogenous VDR target genes and the nuclear protein levels of VDR and cofactors in several cell lines, including cells derived from intestine, bone, and monocytes, and found that the vitamin D(3) derivatives act as cell type-selective VDR modulators. The data indicate that side chain modification is useful in the development of VDR antagonists and tissue-selective modulators. Further elucidation of the molecular mechanisms of action of selective VDR modulators will be essential for their clinical application.     

Imidazoline derivatives: a patent review (2006 – present)

Introduction: Recent decades have witnessed the growing interest in the development of imidazoline derivatives in drug discovery due to increased knowledge in pathogenesis of many diseases. Imidazoline structure has been one of the most sought-after scaffolds employed in developing various agents with different kinds of pharmacological activities. During 2006 – 2012, imidazoline structures have been found in numerous patented compounds for the treatment of neurodegenerative diseases and cancer.

Areas covered: This paper provides a general review of patented imidazoline derivatives from 2006 to 2012. Information from articles published in international peer-reviewed journals has also been included to give a more exhaustive overview.

Expert opinion: With the uncovering of the molecular mechanisms related to neurodegenerative diseases and cancer, the use of classical and novel imidazoline structures has been more frequently noted in recent (2006 – 2012) patented agents for the treatment of neurodegenerative diseases and cancer instead of agents for the treatment of cardiovascular disease noticed earlier.     

The multivalent activity of the tissue factor–thrombin pathway in thrombotic and non-thrombotic disorders as a target for therapeutic intervention

Importance of the field: Tissue factor (TF) is the key initiator of the coagulation cascade. The exposure of subendothelial TF after vessel injury to blood is a critical step in hemostasis and in the pathogenesis of arterial and venous thrombotic disorders. Moreover, an additional role for TF overexpression and subsequent generation of TF:FVIIa complex, FXa and thrombin have been recently emerged, contributing in non-thrombotic manifestations such as inflammation, cancer growth and fibrosis.

Areas covered in this review: The multivalent role of TF and the above mentioned proteases in disease is reviewed, with focus on their implication in non-thrombotic disorders, as suggested by clinical and experimental data. Moreover, potential therapeutic interventions using anticoagulation agents are discussed.

What the reader will gain: A better understanding of the pathogenic role of the TF–thrombin pathway in the pathogenesis of disease and the effect of anticoagulants in the treatment of such disorders.

Take home message: The TF-thrombin pathway, apart from the initiation of hemostasis and thrombosis, exert intracellular signaling activity through protease-activated receptors, participating in inflammation and tumor biology. Both low-molecular-weight heparins and recently developed anticoagulants rise as candidates for the modification of biological functions associated with disorders like sepsis, ischemia–reperfusion or cancer growth and metastasis.     

PPARs as therapeutic targets in cardiovascular disease

Importance of the field: The role of peroxisome proliferator-activated receptors PPARα, PPARδ and PPARγ in cardiovascular disease is receiving widespread attention. As ligand-activated nuclear receptors, they play a role in regulation of lipid and glucose metabolism. This feature of the PPARs has been successfully exploited to treat systemic metabolic diseases, like hyperlipidemia and type-2 diabetes. Indirectly, their lipid lowering effect also leads to a reduction of the risk for cardiovascular diseases, primarily atherosclerosis.

Areas covered in this review: The pleiotropic effects of each of the PPAR isotypes on vascular and cardiac disease are discussed, with special emphasis on the molecular mechanism of action and on preclinical observations. The mechanism underlying the beneficial effect of PPARs is not confined to whole body metabolism, but also includes modulation of other vital processes, such as inflammation and cell fate (proliferation, differentiation, apoptosis).

What the reader will gain: A large body of preclinical studies indicates that, in addition to their effect on atherogenesis, PPAR ligands also impact on ischemic heart disease and the development of cardiac failure. It remains to be established to what extent these intriguing observations can be translated into clinical practice.

Take home message: The versatile mechanism of action extends the potential therapeutic profile of the PPARs enormously. Conversely, this versatility makes it harder to attain a specific therapeutic effect, without increasing the risk of undesirable side effects. The future challenge will be to design PPAR-based therapeutic strategies that minimize the detrimental side effects.     

2-Indolinone a versatile scaffold for treatment of cancer: a patent review (2008–2014)

Introduction: 2-Indolinone is a well-known aromatic heterocyclic organic compound. A lot of work has been done on this bicyclic structure by academic and company researchers to synthesize compounds directed to a plethora of molecular targets in order to discover new drug leads. This review presents up-to-date information in the field of cancer therapy research based on this small building block.

Areas covered: The present review gives an account of the recent patent literature (2008–2014) describing the discovery of 2-indolinone derivatives with selected therapeutic activities. In this period, a large amount of patents were published on this topic. We have limited the analysis to 37 patents on 2-indolinone derivatives having potential clinical application as chemotherapeutic agents. In this review, the therapeutic applications of 2-indolinone derivatives for the treatment of cancer reported in international patents have been discussed.

Expert opinion: 2-Indolinone is the scaffold of the compounds considered from a medicinal chemistry perspective. Many of them have been developed and marketed for therapeutic use. In cancer chemotherapy, progress has been made in designing selective 2-indolinone derivatives. Some of them show preclinical efficacy. However, 2-indolinone has not exhausted all of its potential in the development of new compounds for clinical applications and remains a great tool for future research.     

Pharmacological management of nonalcoholic fatty liver disease in type 2 diabetes

Introduction: The prevalence of nonalcoholic fatty liver disease (NAFLD) in patients with type 2 diabetes (T2D) is high and it is associated with poor prognosis. Hepatic steatosis results as a consequence of excessive hepatic lipid accumulation which correlates with insulin resistance and lipotoxicity, with subsequent oxidative stress, inflammation, apoptosis and fibrosis.

Areas covered: This article presents the main pathophysiologic mechanisms and currently available drugs evaluated for their therapeutic effects on NAFLD/nonalcoholic steatohepatitis (NASH) and drugs under development that target relevant pathogenetic pathways. However, to date there is no particular drug approved for treatment of NAFLD in patients with T2D.

Expert commentary: Early recognition and intervention are essential to ameliorate disease progression. Specific recommendations are still needed for NAFLD/NASH screening and diagnosis and therapeutic algorithm in patients with T2D. Lifestyle optimization with significant weight loss is a key intervention in patients with NAFLD and T2D. Pioglitazone, liraglutide, vitamin E, OCA and pentoxifylline have proven some histological improvements in NASH and omega 3-PUFAs were shown to decrease liver fat, but no specific recommendation can be made for treatment of NASH. Perhaps a combination of agents that target different pathogenic pathways are needed to better control disease progression, but more robust evidence for these agents is still needed.     

Patent Evaluation: Novel Rapamycin Derivatives

Summary

Novelty: Novel amide ester and carbamate derivatives of rapamycin, possessing immuno-suppressive activity, are disclosed. The compounds are potentially useful for the treatment of transplantation rejection, host vs graft disease, autoimmune disease, inflammation and as antitumour and antifungal agents.

Biology: The immunosuppressive effects of the representative compounds were evaluated by the comitogen-induced thymocyte proliferation procedure (LAF). An in vivo popliteal lymph node (PLN) test procedure was used for testing host vs graft disease. Another in vivo procedure designed to determine the survival time of pinch skin graft from male DBB/2 donors transplanted to male BALB/C recipients is also described.

Chemistry: Rapamycin 42-ester with 4-(dimethylamino)-4-oxobutanoic acid is one of four specifically claimed compounds in US5118677; rapamycin 42-ester with (4-fluorophenyl) carbamic acid is one of fourteen specifically claimed compounds in US5118678.     

Vitamin D receptor as a drug discovery target

1alpha, 25-dihydroxyvitamin D3 [1,25 (OH)(2)D(3)], the active metabolite of vitamin D3, is known for the maintenance of normal skeleton architecture and mineral homeostasis. Apart form these traditional calcemic actions, 1,25 (OH)(3)D(1) and its synthetic analogs are increasingly recognized for their potent anti-proliferative, prodifferentiative and immunomodulatory activities. The calcemic and non-calcemic actions of 1,25 (OH)(2)D(3) and its synthetic analogs are mediated through vitamin D receptor (VDR), which belongs to the superfamily of steroid/thyroid hormone nuclear receptors. Physiological and pharmacological actions of 1,25 (OH)(2)D(3) in various systems, along with the detection of VDR in target cells, have indicated potential applications of VDR ligands in inflammation, dermatological indications, osteoporosis, cancers and autoimmune diseases. VDR ligands have shown therapeutic potential in limited clinical trials as well as in animal models of these diseases. As a result, a VDR ligand, calcipotriol is in clinic for psoriasis and another, OCT, [2-oxa-1,25 (OH)(2)D(3)] is being developed as a topical agent for the same indication. Further, 1alpha,-hydroxyvitamin D3 (alphacalcidol), a prodrug of 1,25 (OH)(2)D(3) is in clinic and a synthetic VDR ligand, ED-71, is under consideration for approval in Japan for the treatment of osteoporosis. Interestingly, VDR ligands have shown not only preventive but also potent therapeutic anabolic activities in animal models of osteoporosis. However, the wide spread use of VDR ligands in above-mentioned indications is hampered by their major side effect, namely hypercalcemia. In view of this associated toxicity, synthetic VDR ligands with reduced calcemic potential have been synthesized with the ultimate aim of improving their therapeutic efficacy. This review presents recent advances in VDR biology, novel VDR ligands and therapeutic applications of VDR ligands.     

DHA derivatives of fish oil as dietary supplements: a nutrition-based drug discovery approach for therapies to prevent metabolic cardiotoxicity

Introduction: During the early 1970s, Danish physicians Jorn Dyerberg and colleagues observed that Greenland Eskimos consuming fatty fishes exhibited low incidences of heart disease. Fish oil is now one of the most commonly consumed dietary supplements. In 2004, concentrated fish oil was approved as a drug by the FDA for the treatment of hyperlipidemia. Fish oil contains two major omega-3 fatty acids: eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). With advancements in lipid concentration and purification techniques, EPA- or DHA-enriched products are now commercially available, and the availability of these components in isolation allows their individual effects to be examined. Newly synthesized derivatives and endogenously discovered metabolites of DHA exhibit therapeutic utility for obesity, metabolic syndrome and cardiovascular disease.

Areas covered: This review summarizes our current knowledge on the distinct effects of EPA and DHA to prevent metabolic syndrome and reduce cardiotoxicity risk. Since EPA is an integral component of fish oil, we will briefly review EPA effects, but our main theme will be to summarize effects of the DHA derivatives that are available today. We focus on using nutrition-based drug discovery to explore the potential of DHA derivatives for the treatment of obesity, metabolic syndrome and cardiovascular diseases.

Expert opinion: The safety and efficacy evaluation of DHA derivatives will provide novel biomolecules for the drug discovery arsenal. Novel nutritional-based drug discoveries of DHA derivatives or metabolites may provide realistic and alternative strategies for the treatment of metabolic and cardiovascular disease.