Drug discovery strategies and the preclinical development of D-amino-acid oxidase inhibitors as antipsychotic therapies

ABSTRACT

Introduction: D-amino-acid oxidase (DAAO) degrades D-serine, a co-agonist of the NMDA receptor whose dysfunction is involved in the positive, negative, and cognitive symptoms of schizophrenia. The inhibition of DAAO appears to be a viable strategy to increase D-serine level and to have therapeutic potential in schizophrenia.

Areas covered: This review describes the efforts to develop DAAO inhibitors and to optimize their in vitro and in vivo effects in preclinical settings. The structural evolution of DAAO inhibitors is presented from simple carboxylic acid derivatives via small, planar compounds with carboxylic acid mimetics to extended compounds whose binding is possible owing to DAAO flexibility. Inhibitory potency and pharmacokinetic properties are discussed in the context of compounds’ ability to increase D-serine level and to show efficacy in animal models of schizophrenia.

Expert opinion: The accumulated knowledge on the structural requirements of DAAO inhibitors and on their in vitro and in vivo effects provides appropriate basis to develop inhibitors with optimized potency, selectivity and pharmacokinetic profile including blood-brain penetration. In addition, the validation of DAAO inhibition therapy in alleviating the symptoms of schizophrenia requires further studies on the efficacy of DAAO inhibitors in behavioral assays of animals and on the species differences in D-serine metabolism.     

Therapeutic and cosmetic applications of mangiferin: a patent review

Introduction: Mangiferin, a natural C-glucoside xanthone [2-C-β-D-glucopyranosyl-1, 3, 6, 7-tetrahydroxyxanthone], is abundantly present in young leaves and stem bark of the mango tree. The xanthonoid structure of mangiferin with C-glycosyl linkage and polyhydroxy components contributes to its free radical-scavenging ability, leading to a potent antioxidant effect as well as multiple biological activities.

Areas covered: An extensive search was carried out to collect patent information on mangiferin and its derivatives using various patent databases spanning all priority years to date. The patents claiming therapeutic and cosmetic applications of mangiferin and its derivatives were analyzed in detail. The technology areas covered in this article include metabolic disorders, cosmeceuticals, multiple uses of the same compound, miscellaneous uses, infectious diseases, inflammation, cancer and autoimmune disorders, and neurological disorders.

Expert opinion: Mangiferin has the potential to modulate multiple molecular targets including nuclear factor-kappa B (NF-κB) signaling and cyclooxygenase-2 (COX-2) protein expression. Mangiferin exhibits antioxidant, antidiabetic, antihyperuricemic, antiviral, anticancer and antiinflammatory activities. The molecular structure of mangiferin fulfils the four Lipinski's requisites reported to favor high bioavailability by oral administration. There is no evidence of adverse side effects of mangiferin so far. Mangiferin could thus be a promising candidate for development of a multipotent drug.     

Two New Caffeoyl Conjugation from Erigeron Breviscapus

Abstract

Two new constituents with a novel basic skeleton were isolated from Erigeron breviscapus. On the basis of chemical and spectroscopic evidences, the structures of the new compounds were elucidated as 1R,3R-dihydroxy-4S,5R-dicaffeoyloxy cyclohexane carboxylic acid methyl ester (V), 1,4-dihydroxy-3R,5R-dicaffeoyloxy cyclohexane carboxylic acid methyl ester (VI).     

Farnesyl pyrophosphate synthase modulators: a patent review (2006 – 2010)

Introduction: Farnesyl pyrophosphate synthase (FPPS, also known as farnesyl diphosphate synthase (FDPS)) is one of the key enzymes involved in the mevalonate pathway and as such is widely expressed. FPPS modulators, specifically FPPS inhibitors, are useful in treating a number of diseases, including bone-related disorders characterized by excessive bone resorption, for example, osteoporosis, cancer metathesis to bone and infectious diseases caused by certain parasites.

Areas covered: This review covers structures and applications of novel FPPS modulators described in the patent literature from 2006 to 2010. Patents disclosing new formulations and uses of existing FPPS inhibitors are also reviewed. Thirty-three patents retrieved from the USPTO, EP and WIPO databases are examined with the goal of defining current trends in drug discovery related to FPPS inhibition, and its therapeutic effects.

Expert opinion: Bisphosphonates (BPs) continue to dominate in this area, although other types of modulators are making their appearance. Remarkable for their high bone mineral affinity, BPs are structural mimics of the dimethylallyl pyrophosphate substrate of FPPS, and constitute the major type of FPPS inhibitor currently used in the clinic for treatment of bone-related diseases. Lipophilic BPs and new classes of non-BP FPPS inhibitors (salicylic acid and quinoline derivatives) have been introduced as possible alternatives for treatment of soft tissue diseases, such as some cancers. Novel formulations, fluorescent diagnostic probes and new therapeutic applications of existing FPPS inhibitors are also areas of significant patent activity, demonstrating growing recognition of the versatility and underdeveloped potential of these drugs.     

Overview: Present Developments in Cardiotonic Agents

Summary

Novelty: Novel phenylsulphonamide substituted pyridine alkene and aminooxyalkane carboxylic acid derivatives are disclosed. These compounds are said to be thromboxane synthetase inhibitors which are potentially useful for treating asthma, atherosclerosis and allergic diseases.

Biology: TXA₂ inhibition was evaluated in vitro (IC₅₀ = 0.5–1 nM). Thromboxane receptor binding studies are also reported.

Chemistry: (EZ)-5-[[[3-pyridinyl-3(4-chlorophenylsulphonamido)phenyl]methylen]iminooxy]-pentane carboxylic acid is one of twenty-six exemplified compounds.

Structure:     

Bruton's tyrosine kinase as a molecular target in treatment of leukemias and lymphomas as well as inflammatory disorders and autoimmunity

Importance of the field: Bruton's tyrosine kinase (BTK) has emerged as a new anti-apoptotic molecular target for the treatment of B-lineage leukemias and lymphomas. Preclinical and early clinical results indicate that BTK inhibitors may be useful in the treatment of leukemias and lymphomas. BTK inhibitors may also be helpful in prevention and treatment of thromboembolic complications as well as inflammatory disorders.

Areas covered in this review: We provide a comprehensive review of the target diseases for which the use of BTK inhibitors may be helpful as well as the activity profiles of BTK inhibitors.

What the reader will gain: We review the currently available translational research, biomarker as well as patent literature regarding BTK molecular target and BTK inhibitors.

Take home message: BTK inhibitors may provide the foundation for therapeutic innovation against B-lineage leukemias/lymphomas, inflammatory disorders and autoimmunity.     

Patent Evaluation Anti-infectives: Novel derivatives of ′-D-neuraminic acid for the treatment of viral infection

This patent from Biota Scientific Management PTY Ltd. discloses compounds that are inhibitors of neuraminidases (from micro-organisms), in particular neuraminidases found on the surface of orthomyxoviruses and paramyxoviruses. Selective and potent inhibitors of viral neuraminidase are thought to prevent infection by viruses which require this enzyme for replication and infectivity.

The compounds disclosed in this patent comprise a new class of compounds consisting of 2,6-dideoxy-2,3-didehydro-6-thio derivatives of ′-D-neuraminic acid. These compounds are within the scope of compounds described and claimed but not exemplified, in a previous patent application [101]. The compounds disclosed in the earlier patent are analogues of 2-deoxy-2,3-dehydro-N-acetylneuraminic acid (DANA). One such analogue, 4-guanidino-2,4-dideoxy-2,3-didehydro-N-acetylneuraminic acid, is a selective and potent inhibitor of influenza A and B virus neuraminidase and has shown promise in clinical trials for the treatment of influenza virus infection.

The patent also describes methods for the preparation of 2,6-dideoxy-2,3-didehydro-6-thio derivatives of ′-D-neuraminic acid, the pharmaceutical formulations of these compounds, and their intended use as antiviral agents.     

Treatment options for deep vein thrombosis

Importance of the field: Anticoagulation is the main therapy for acute deep vein thrombosis (DVT) of the limbs. Over the last five decades, there has been little progress in the development of oral anticoagulant therapies. More recently, we have been experiencing a rapidly changing situation thanks to the development of new orally active anticoagulants.

Areas covered in this review: The aim of this review is to highlight main published data on direct thrombin and FXa inhibitors. The electronic database PubMed website and abstract proceedings were used to identify studies.

What the reader will gain: The main characteristics of these new classes of anticoagulant drugs, the development program of the most advanced molecules and the most recent published data on Phase III trials on DVT treatment for both the acute phase and the secondary prevention of the disease are reviewed.

Take home message: Oral administration, predictable anticoagulant responses, low potential for drug–drug interactions and first published clinical data render direct thrombin and factor Xa inhibitors good candidates to replace oral vitamin K antagonist and low molecular weight heparins for DVT treatment.     

NADPH oxidase inhibitors: a patent review

Introduction: NADPH oxidases, a family of multi-subunit enzyme complexes, catalyze the production of reactive oxygen species (ROS), which may contribute to the pathogenesis of a variety of diseases. In addition to the first NADPH oxidase found in phagocytes, four non-phagocytic NADPH oxidase isoforms have been identified, which all differ in their catalytic subunit (Nox1-5) and tissue distribution.

Areas covered: This paper provides a comprehensive review of the patent literature on NADPH oxidase inhibitors, small molecule Nox inhibitors, peptides and siRNAs.

Expert opinion: Since each member of the NADPH oxidase family has great potential as a therapeutic target, several different compounds have been registered as NADPH oxidase inhibitors in the patent literature. As yet, none have gone through clinical trials, and some have not completed preclinical trials, including safety and specificity evaluation. Recently, small molecule pyrazolopyridine and triazolopyrimidine derivatives have been submitted as potent NADPH oxidase inhibitors and reported as first-in-class inhibitors for idiopathic pulmonary fibrosis and acute stroke, respectively. Further clinical efficacy and safety data are warranted to prove their actual clinical utility.     

Soluble epoxide hydrolase inhibitors: a patent review

Importance of the field: Soluble epoxide hydrolase (sEH) inhibitors have been shown to effectively increase the levels of epoxyeicosatrienoic acids and reduce the levels of dihydroxyeicosatrienoic acids, which may be translated to therapeutic potentials for multiple disease indications. It has been claimed that sEH inhibitors can be used to treat hypertension, diabetes, stroke, dyslipidemia, pain, immunological disorders, eye diseases, neurological diseases and other indications.

Areas covered in this review: A comprehensive synopsis of patent literature on sEH inhibitors is provided.

What the reader will gain: A total of more than 100 patent publications describing multiple classes of sEH inhibitors are analyzed. These include amides, ureas, thioamides, thioureas, carbamates, acyl hydrazones, chalcone oxdies, etc. In addition to selected in vitro and in vivo data of representative sEH inhibitors, a wide range of proposed applications of sEH inhibitors are also summarized.

Take home message: Several sEH inhibitors with potent in vitro and in vivo target inhibition appear promising, including one Phase II clinical candidate. The clinical evaluation will be critical to assess the proclaimed therapeutic utility of sEH inhibition.     

Analogs,formulations and derivatives of imatinib: a patent review

Introduction: The Bcr-Abl inhibitor imatinib was approved in 2001 for chronic myeloid leukemia therapy, and dramatically changed the lives of patients affected by this disease. Since it also inhibits platelet derived growth factor receptor (PDGFR) and c-Kit, imatinib is used for various other tumors caused by abnormalities of one or both these two enzymes.

Areas covered: This review presents an overview on imatinib formulations and derivatives, synthetic methodologies and therapeutic uses that have appeared in the patent literature since 2008.

Expert opinion: Innovative imatinib formulations, such as nanoparticles containing the drug, will improve its bioavailability. Moreover, oral solutions or high imatinib content tablets or capsules will improve patient compliance. Some solid formulations and innovative syntheses that have appeared in the last few years will reduce the cost of the drug, offering big advantages for poor countries. Some recently patented efficacious imatinib derivatives are in preclinical studies and could enter clinical trials in the next few years. Overall, Bcr-Abl inhibitors constitute a very appealing research field that can be expected to expand further.     

The emerging role of P-glycoprotein inhibitors in drug delivery: a patent review

Introduction: The ATP-binding cassette superfamily contains membrane transporter proteins that transport a wide range of diverse compounds across cellular membranes. The P-glycoprotein (P-gp) is an important member of this family and a multi-specific drug efflux transporter that plays a significant role in governing the bioavailability of many clinically active drugs. The inhibition of this efflux transporter by various P-gp inhibitors forms a distinctive approach in improving bioavailability and conquering drug resistance. Most P-gp inhibitors exhibit limitations associated with their safety and unwanted pharmacokinetic interactions, thereby restraining their clinical applicability.

Areas covered: This review explores the investigations on the feasibility and applicability of various classes of P-gp inhibitors as described in recent patents for enhanced drug delivery.

Expert opinion: Several candidates presently under development look promising as P-gp inhibitors, e.g., tariquidar and elacridar. Pharmaceutical excipients currently constitute the most promising class of P-gp inhibitors and are considered safe and pharmaceutically acceptable for use in formulations. In addition, lipid-based excipients and thiolated polymers play an active role in affecting P-gp-mediated transport not only by altering the membrane fluidity or ATPase activity but by down regulating P-gp expression. An additional overture such as the prodrug derivatization of P-gp substrates is a feasible approach to bypass P-gp-mediated efflux.     

Patent Evaluation: The Use of Aldose Reductase Inhibitors in the Treatment of Diabetes

Summary

Novelty: Novel biphenyl carboxylic acid derivatives are disclosed. These compounds are claimed to be aldose reductase inhibitors and are potentially useful for the treatment of diabetic complications such as cataract, retinal diseases, neuropathy, corneal and disorders diabetic ureitis.

Biology: The disclosed compounds were evaluated for inhibition of aldose reductase and for suppression of sorbitol accumulation in lens and sciatic nerves. The specified compound provided 63% inhibition of aldose reductase at a concentration of 0.1γ. At 2.5γ, sorbitol accumulation (lens) was inhibited by 85%.

Chemistry: 2,2′-Dimethoxy-5,5′-bis(3-carboxypropyl)biphenyl is one of three specifically claimed compounds.

Structure:      

Discovery and development of heat shock protein 90 inhibitors as anticancer agents: a review of patented potent geldanamycin derivatives

Introduction: There has been research on anticancer strategies which focus on disrupting a single malignant protein. One of the strategies is the inhibition of one protein, heat shock protein 90 (Hsp90). There are many reasons why Hsp90 protein is targeted by anticancer agents: maintenance of cellular homeostasis in organisms involves Hsp90 and its client proteins; moreover, Hsp90 complex is involved in regulating several signal transduction pathways and plays an important role in the maturation of lots of tumor-promoting client proteins. Geldanamycin (GM), the first benzoquinone ansamycin, has shown anticancer activity by binding to Hsp90. Currently, several GM derivatives such as 17-AAG, 17-(2-dimethylaminoethyl)amino-17-demethoxygeldanamycin, IPI-493, and IPI-504 are being progressively developed toward clinical application.

Areas covered: Several research groups have studied GM and its derivatives to develop novel and potent Hsp90 inhibitors for the treatment of cancer. The crystal structure of Hsp90 was utilized to undergo structural optimization of GM derivatives. A wide variety of structural modifications were performed and some of the derivatives are now in clinical studies. The aim of this review was to summarize and analyze the structure-activity relationships of GM derivatives and the focus is on patented novel and pharmaceutically efficacious derivatives published from 1971 to 2012.

Expert opinion: Hsp90 inhibitors offer an effective therapeutic approach for treatment of cancer. To date, the clinical results of 17-AAG, IPI-493, and IPI-504 suggest that these GM derivatives could be used either alone or in combination with other marketed medications for the treatment of cancer patients. As there are not any marketed Hsp90 inhibitors, inhibiting Hsp90 chaperone function remains as a promising strategy that still requires further research.     

Osteoclast differentiation inhibitors: a patent review (2008 – 2012)

Introduction: Mononuclear macrophage/monocyte-lineage hematopoietic precursors differentiate into multinucleated osteoclasts. Abnormally increased numbers and/or overactivation of osteoclasts can lead to bone loss. Therefore, pharmaceutical inhibition of osteoclast differentiation is one therapeutic strategy for mitigating the occurrence of bone loss-associated disorders and related fractures.

Areas covered: This review surveys the patents and patent applications from 2008 to 2012 that are related to inventions of therapeutics and/or methods for inhibiting osteoclast differentiation.

Expert opinion: Over the past 20 years, the identification and validation of signaling molecules involved in osteoclast differentiation has led to a better understanding of the molecular mechanism, and to the development of new therapeutic agents for treating bone loss-associated disorders. Since 2008, 34 WO patents or patent applications have been filed that relate to inventions of therapeutics and/or methods for chemical-based, natural product-based, or biological-based inhibitors of osteoclast differentiation. Here, analysis of these patents and patent applications is presented, and summarize the disclosed osteoclast differentiation-inhibiting target molecules. This report can support further advances in the development of anti-osteoclastogenic therapeutics for bone loss-associated disorders, including osteoporosis, rheumatoid arthritis, Paget's disease, periodontal disease, osteosarcoma, and cancer bone metastasis.     

Discovery methodology for the development of direct factor VIIa inhibitors

Introduction: Heparin and warfarin have historically been the only antithrombotics available. Recently, however, newer anticoagulants have been developed. Factor VIIa (fVIIa) inhibitors represent one of the new and potentially exciting classes of anticoagulants currently under development. Indeed, several methodologies have been used to develop fVIIa inhibitors.

Areas covered: The authors highlight some of the methologies applied for the discovery of fVIIa inhibitors including phage display, isolation of endogenous peptides from hematophagous animals and the use of the 1,5-benzothiazepine molecular scaffolds and screens of large chemical libraries previously used to identify other serine protease inhibitors. Although these screens were intended to identify thrombin and factor Xa inhibitors, the compounds often had concomitant fVIIa activity. The authors also discuss the utilization of medical chemistry techniques for the discovery of these compounds.

Expert opinion: FVIIa inhibitors represent a viable option for the development of new anticoagulants. There are theoretical advantages that fVIIa inhibitors may possess over existing anticoagulants and highly specific inhibitors that possess oral bioavailability and low bleeding risk may succeed.     

Selective JAK1 inhibitor and selective Tyk2 inhibitor patents

Introduction: The JAK family comprises of the four non-receptor tyrosine kinases JAK1, JAK2, JAK3 and Tyk2, which play key, but differing, roles in cytokine receptor signal transduction. A non-selective JAK inhibitor, ruxolitinib, has recently been approved to treat myelofibrosis whereas tofacitinib is poised for approval to treat rheumatoid arthritis. Selective inhibition of JAK3, JAK1 or Tyk2 provides the opportunity to achieve clinical efficacy in the treatment of inflammatory diseases while reducing the risk of dose-limiting effects attributable to JAK2 inhibition.

Areas covered: This review considers the small number of published patent filings that claim either selective JAK1 or selective Tyk2 inhibitors. These are considered in the context of the considerably larger number of disclosures and patent filings claiming selective JAK2 or JAK3 inhibitors.

Expert opinion: The recent disclosure of the clinical efficacy of a selective JAK1 inhibitor (GLPG-0634) in rheumatoid arthritis and detailed disclosure of the some potent and highly selective JAK1 inhibitors provide a clear stimulus for further activity in this area. The availability of a selective Tyk2 inhibitor will provide the opportunity for better understanding of the physiological role of this kinase. Recent patent applications indicate that Tyk2 selectivity is achievable and Tyk2 inhibitors have potential in the treatment of multiple sclerosis.     

Kinesin spindle protein inhibitors in cancer: a patent review (2008 – present)

Introduction: Inhibition of kinesin spindle protein (KSP) has emerged as a novel and validated therapeutic strategy against cancers. A lot of new KSP inhibitors have been identified in recent years and some of them have entered clinical trials. This may provide more selections in future cancer therapy.

Areas covered: In the present review, the authors will describe the most recent classes of KSP inhibitors by reviewing about 96 literatures in which 24 patent applications were included from 2008 to now.

Expert opinion: Many new KSP inhibitors have been discovered that act either by binding in an allosteric site of KSP or by ATP competitive inhibition. There are several ATP non-competitive KSP inhibitors entering clinical investigation. Although they were both well tolerated and showed acceptable pharmacokinetic profiles, limited clinical response was always the problem. Mutation of the binding pocket was also a hindrance in the development of these allosteric inhibitors. The appearance of ATP competitive KSP inhibitors was considered to be able to overcome mutation-mediated resistance to the allosteric inhibitors, which could be a new approach for the development of novel KSP inhibitors.     

Therapeutic uses of furin and its inhibitors: a patent review

Introduction: Since the discovery of furin, numerous reports have studied its role in health and diseases, including cancer, inflammatory and infectious diseases. This interest has led to the development of both large protein- and peptide-based inhibitors aiming to control furin activity to treat these disorders. The most recent advances include the development of potent peptidomimetic furin inhibitors, considerably expanding the field of therapeutic applications.

Area covered: In this review, the use of furin or its inhibitors for therapeutic conditions is described through the patent literature since 1994. Only compounds with biological efficacy or augmented properties demonstrated within the patent literature or the associated publications concerning their claimed uses are discussed.

Expert opinion: Considering the diseases that may benefit from furin inhibition, several patents detail the use of the restricted number of furin inhibitors. However, there have been recent reports of new scaffolds, and even the use of furin itself, as a therapeutic agent. Despite considerable evidence of in vivo efficacy, limited confirmation from clinical trials supports or refutes the further use of these compounds in a therapeutic context. The most advanced application is the use of furin knockdown in the generation of an autologous cancer vaccine, which has initiated clinical trials.     

Transglutaminase inhibitors: a patent review

Introduction: Transglutaminases (TGases) are a class of enzymes that play multifunctional roles. Their protein-crosslinking activity has been linked to fibrosis and Huntington’s disease, their glutamine deamidation activity has been related to celiac disease and their GTP-binding activity has been implicated in cancer. All of these physiological disorders have prompted the development of inhibitors, which has accelerated dramatically over the past decade.

Areas covered: This review presents an overview of TGase inhibitors published in the patent literature, from the first compounds developed in the late 1980’s, to the current date. This article is focussed on the chemical structure of new inhibitors and their probable mechanism of action.

Expert opinion: Comparison of effective TGase inhibitors reveals common structural features that may guide future design. Many of these elements are embodied in the first TGase inhibitor to recently enter into clinical trials.