Sigma receptor modulators: a patent review

Introduction: Sigma receptors are involved in several central nervous system (CNS) disorders, including mood disorders (depression and anxiety), psychosis, schizophrenia, movement disorders (i.e., Parkinson's disease) and memory deficits (i.e., Alzheimer's disease). Recently, the involvement of sigma receptors in neuropathic pain and cancer has also been observed.

Areas covered: This review aims at highlighting the research advancements published in the patent literature between 1986 and 2012, dividing patents according to both their time frame and applicants. The review especially focuses on the development of sigma receptor modulators and their application over the years with respect to CNS diseases, neuropathic pain and neurodegenerative pathologies. The literature was sought through Espacenet, Orbit, ISI Web and PubMed databases.

Expert opinion: In recent years, considerable progress in the knowledge of the biology and pharmacology of sigma receptors has encouraged research on the potential benefits of sigma modulators in a wide range of pathologies. So far, only few potent agonists and antagonists of sigma receptors are in clinical trial for acute and chronic neurodegenerative diseases (SA4503 and ANAVEX 2-73) or neuropathic pain (E-52862).     

Targeting glucose-dependent insulinotropic polypeptide receptor for neurodegenerative disorders

Introduction: Incretin hormones, glucose-dependent insulinotropic polypeptide (GIP), and glucagon-like peptide-1 (GLP-1) exert pleiotropic effects on endocrine pancreas and nervous system. Expression of GIP and GIP receptor (GIPR) in neurons, their roles in neurogenesis, synaptic plasticity, neurotransmission, and neuromodulation uniquely position GIPR for therapeutic applications in neurodegenerative disorders. GIP analogs acting as GIPR agonists attenuate neurobehavioral and neuropathological sequelae of neurodegenerative disorders in preclinical models, e.g. Alzheimer’s disease (AD), Parkinson’s disease (PD), and cerebrovascular disorders. Modulation of GIPR signaling offers an unprecedented approach for disease modification by arresting neuronal viability decline, enabling neuronal regeneration, and reducing neuroinflammation. Growth-promoting effects of GIP signaling and broad-based neuroprotection highlight the therapeutic potential of GIPR agonists.

Areas covered: This review focuses on the role of GIPR-mediated signaling in the central nervous system in neurophysiological and neuropathological conditions. In context of neurodegeneration, the article summarizes potential of targeting GIPR signaling for neurodegenerative conditions such as AD, PD, traumatic brain injury, and cerebrovascular disorders.

Expert opinion: GIPR represents a validated therapeutic target for neurodegenerative disorders. GIPR agonists impart symptomatic improvements, slowed neurodegeneration, and enhanced neuronal regenerative capacity in preclinical models. Modulation of GIPR signaling is potentially a viable therapeutic approach for disease modification in neurodegenerative disorders.     

Targeting GSK3 signaling as a potential therapy of neurodegenerative diseases and aging

ABSTRACT

Introduction: Glycogen synthase kinase 3 (GSK3) is at the center of cellular signaling and controls various aspects of brain functions, including development of the nervous system, neuronal plasticity and onset of neurodegenerative disorders.

Areas covered: In this review, recent efforts in elucidating the roles of GSK3 in neuronal plasticity and development of brain pathologies; Alzheimer’s and Parkinson’s disease, schizophrenia, and age-related neurodegeneration are described. The effect of microglia and astrocytes on development of the pathological states is also discussed.

Expert opinion: GSK3β and its signaling pathway partners hold great promise as therapeutic target(s) for a multitude of neurological disorders. Activity of the kinase is often elevated in brain disorders. However, due to the wide range of GSK3 cellular targets, global inhibition of the kinase leads to severe side-effects and GSK3 inhibitors rarely reach Phase-2 clinical trials. Thus, a selective modulation of a specific cellular pool of GSK3 or specific down- or upstream partners of the kinase might provide more efficient anti-neurodegenerative therapies.     

Solid lipid nanoparticles as a drug delivery system for the treatment of neurodegenerative diseases

ABSTRACT

Introduction: The failure of many molecules as CNS bioactive compounds is due to many restrictions: poor water solubility, intestinal absorption, in vivo stability, bioavailability, therapeutic effectiveness, side effects, plasma fluctuations, and difficulty crossing physiological barriers, like the brain blood barrier (BBB), to deliver the drug directly to the site of action.

Area covered: Nanotechnology-based approaches with the employment of liposomes, micelles, dendrimers, and solid lipid nanoparticles (SLN) as drug delivery systems, are used to overcome the above reported limitations. Here, we focus on the delivery of drugs based on SLN formulation to treat neurodegenerative diseases. Notably, SLN have the ability to protect drugs from chemical and enzymatic degradation, direct the active compound towards the target site with a substantial reduction of toxicity for the adjacent tissues, and pass physiological barriers increasing bioavailability without resorting to high dosage forms.

Expert opinion: We believe that SLN could represent a suitable tool to pass the BBB and permit drugs to reach damaged areas of the CNS in patients affected by neurodegenerative pathologies, such as Alzheimer’s and Parkinson’s diseases.     

Inhibition of IKKβ by celastrol and its analogues – an in silico and in vitro approach

Context: Alzheimer’s disease (AD) is the most common form of dementia affecting the aged population and neuroinflammation is one of the most observed AD pathologies. NF-κB is the central regulator of inflammation and inhibitor κB kinase (IKK) is the converging point in NF-κB activation. Celastrol is a natural triterpene used as a treatment for inflammatory conditions.

Objective: This study determines the neuroprotective and inhibitory effect of celastrol on amyloid beta_1-42 (Aβ_1-42) induced cytotoxicity and IKKβ activity, respectively.

Materials and methods: Retinoic acid differentiated IMR-32 cells were treated with celastrol (1?μM) before treatment with Aβ_1-42 (IC₃₀ 10?μM) for 24?h. The cytotoxicity and IKK phosphorylation were measured by MTT and western blotting analysis, respectively. We screened 36 celastrol analogues for the IKKβ inhibition by molecular docking and evaluated their drug like properties to delineate the neuroprotective effects.

Results: Celastrol (1?μM) inhibited Aβ_1-42 (10?μM) induced IκBα phosphorylation and protected IMR-32 cells from cell death. Celastrol and 25 analogues showed strong binding affinity with IKKβ as evidenced by strong hydrogen-bonding interactions with critical active site residues. All the 25 analogues displayed strong anti-inflammatory properties but only 11 analogues showed drug-likeness. Collectively, molecule 15 has highest binding affinity, CNS activity and more drug likeness than parent compound celastrol.

Discussion and conclusion: The decreased expression of pIκBα in celastrol pretreated cells affirms the functional representation of inhibited IKKβ activity in these cells. The neuroprotective potentials of celastrol and its analogues may be related to IKK inhibition.     

Therapeutic potential of Panax ginseng and its constituents,ginsenosides and gintonin,in neurological and neurodegenerative disorders: a patent review

Introduction: Ginseng, Panax ginseng, has been used for various diseases and proven its great efficacy in managing central nervous system diseases.

Area covered: This article covers the therapeutic potential of patents on ginseng and its active constituents to develop therapies for neurodegenerative and neurological disorders, since 2010. The literature review was provided using multiple search engines including Google Patent, Espacenet and US Patent in the field of neurodegenerative diseases, Alzheimer’s disease, Parkinson’s disease, cognitive, and neurological disorders.

Expert opinion: The gathered data represented outstanding merits of ginseng in treatment of neurodegenerative and neurological disorders. These effects have been mediated by neurogenesis, anti-apoptotic and antioxidant properties, inhibition of mitochondrial dysfunction, receptor-operated Ca²⁺ channels, amyloid beta aggregation, and microglial activation as well as neurotransmitters modulation. However, these compounds have limited clinical application of for the prevention or treatment of neurodegenerative and neurological disorders. This might be due to incomplete data on their clinical pharmacokinetic and toxicity properties, and limited economic investments. There is an increasing trend in use of herbal medicines instead of chemical drugs, so it is time to make more attention to the application of ginseng, the grandfather of medicinal plants, from basic sciences to patients’ bed.     

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.     

Investigational drugs targeting 5-HT6 receptors for the treatment of Alzheimer’s disease

Introduction: There are significant efforts invested into the discovery and development of novel treatments for Alzheimer’s disease. While current discovery efforts and most scientific discussions seem to focus on disease-modifying therapy, there are several symptomatic therapy approaches that are being actively pursued. The goal of this review is to summarize the recent developments in the field of 5-HT6 receptor antagonists, a principle that has been extensively characterized preclinically and is now undergoing critical phases of clinical development.

Areas covered: The article covers the current status of 5-HT6 receptor antagonists in clinical development. It also discusses the underlying mechanisms for the observed procognitive effects. The article is based on a search for investigational drugs using the key words ‘5-HT6?, ‘cognition’, ‘dementia’, ‘Alzheimer’s disease’, ‘Phase II’ and ‘Phase III’ in various databases and from conference abstracts.

Expert opinion: After some period of little or no development activities, the field of 5-HT6 receptor antagonists attracted a lot of attention with three companies (GSK, Pfizer and Lundbeck) confirming aggressive development plans and initiating pivotal Phase II and III studies. These studies will be critical to prove that 5-HT6 receptor antagonists have a symptomatic efficacy profile that can be differentiated from that of currently used agents (cholinesterase inhibitors and the NMDA-antagonist memantine). Furthermore, there are several sets of data that point at a disease-modifying potential of this class of agents and these effects are likely to receive critical exploration if the ongoing symptomatic trials bring 5-HT6 antagonists closer to clinical use.     

Neramexane: a moderate-affinity NMDA receptor channel blocker: new prospects and indications

N-methyl-D-aspartate (NMDA) receptor antagonists have a potentially wide range of therapeutic applications. Unfortunately, potent NMDA receptor channel blockers produce phencyclidine-like psychotropic symptoms in humans and rodents, and thereby produce numerous side effects. However, recent data indicate that moderate-affinity, voltage-dependent, open-channel blockers, such as memantine and neramexane (MRZ 2/579) are useful therapeutics as they prevent the pathological activation of NMDA receptors but allow their physiological activity and should prove to be useful therapeutics in a wide range of CNS disorders. Indeed, memantine was recently registered in both Europe and the USA for the treatment of moderate-to-severe Alzheimer’s disease (AD). Neramexane is under development as a potential neuroprotectant against various CNS disorders. Although the predicted therapeutic doses of neramexane were very well tolerated in male volunteers, unfortunately, recent Phase II/III clinical trials for moderate-to-severe AD delivered contradictory results. Neramexane also failed in a recent randomized controlled Phase II trial against drug abuse and depression. Although Phase Ib clinical trials for the indications of chronic pain showed positive results, Phase II results indicate no superiority to existing treatments. However, positive study results have been presented recently in a Phase IIb study on the treatment of tinnitus. A Phase III study for this indication is presently ongoing. Another promising application for neramexane as a neuroprotectant might be chronic neurodegeneration, such as Parkinson’s disease, Huntington’s disease, vascular dementia, frontal lobe dementia, Down’s syndrome and AD.     

The potential of targeting NMDA receptors outside the CNS

Introduction: NMDA receptor (NMDAR) is an ionotropic glutamate receptor with a high permeability to calcium and a unique feature of controlling numerous calcium-dependent processes. Apart from being widely distributed in the CNS, the presence of NMDAR and its potential significance in a variety of non-neuronal cells and tissues has become an interesting research topic.

Areas covered: The current review summarizes prevailing knowledge on the role of NMDARs in the kidney, bone and parathyroid gland, three main organs responsible for calcium homeostasis, as well as in the heart, an organ whose function is highly dependable on balanced intracellular calcium concentrations. The review also examines studies that have advanced our understanding of the therapeutic potential of NMDAR agonists and antagonists in renal, cardiovascular and bone pathologies.

Expert opinion: NMDARs have a preeminent role in many physiological and pathological processes outside the CNS. In certain organs and/or disease conditions, activating the NMDAR leads to beneficial effects for the target organ, whereas in other diseases cell signaling downstream of NMDAR activation can exacerbate their pathology. Therefore, targeting NMDARs therapeutically is rather intricate work, and surely requires more extensive investigation in order to properly tune up the diverse NMDAR’s actions translating them into beneficial cellular responses.     

Emerging chemical therapies targeting 5-hydroxytryptamine in the treatment of Alzheimer’s disease

Introduction: Alzheimer’s disease (AD) is a major neuropsychiatric disorder affecting more than 5 million Americans over age 65. By the year 2050, AD is expected to affect over 30 million. Characterized by neuronal cell death accompanied by the accumulation of neurofibrillary tangles and neuritic plaques, AD results in devastating clinical symptomatology with a lasting psychosocial and financial impact. Studies have shown that the current treatments for AD, cholinesterase inhibitors (ChEI’s) and NMDA receptor antagonists, have limited efficacy. The 5-HT-6 receptor antagonists Idalopirdine and Intepirdine have shown the most progress in current clinical trials and warrant consideration as emerging treatments for AD.

Areas covered: This review discusses 5-HT6 antagonists currently in clinical trials as potential treatments for AD symptomatology and how 5-HT6 physiology may play a positive role in alleviating AD symptom pathophysiology. A literature search using PubMed was conducted using the terms Idalopirdine, Intepirdine, 5-HT-6 antagonist, and AD as keywords. Clinicaltrials.gov and Alzforum were also used to obtain information on clinical trials.

Expert opinion: If current Phase-3 trials are positive, 5-HT6 antagonists such as Idalopirdine and Intepirdine may be considered as supplementary treatments to ChEI’s and NMDA receptor antagonists for the symptomatic treatment of AD.     

Pharmacokinetic drug evaluation of safinamide mesylate for the treatment of mid-to-late stage Parkinson’s disease

Introduction: Patients with Parkinson’s disease suffer from a heterogeneous expression of neurotransmitter deficits. They cause an individual variable expression of motor and non-motor symptoms. Thus, drugs with various mechanisms of actions are suitable to counteract these disease related neurotransmitter alterations.

Areas covered: This invited review suggests safinamide as an ideal compound for therapy of Parkinson’s disease, as its pharmacological profile includes reversible monoamine oxidase B inhibition, blockage of voltage-dependent sodium channels, modulation of calcium channels and abnormal glutamate release. Safinamide may provide benefits effects on non-motor symptoms in addition to the demonstrated amelioration of motor impairment in levodopa treated patients with Parkinson’s disease. Safinamide was well tolerated and safe when administered in dose of 50 or 100 mg daily in pivotal trials.

Expert opinion: Clinical handling, safety and tolerability of Safinamide are better than of dopamine agonists or levodopa. Safinamide supplements the existing armamentarium of drugs for Parkinson’s disease. Safinamide will help to reduce dosing of levodopa but also of dopamine agonists during long term treatment in patients with Parkinson’s disease.     

Protective effect of Convolvulus pluricaulis standardized extract and its fractions against 3-nitropropionic acid-induced neurotoxicity in rats

Abstract

Context: Convolvulus pluricaulis Chois. (Convolvulaceae), a well-known Ayurvedic “Medhya Rasayana” (nervine tonic), is extensively used for different central nervous system (CNS) disorders.

Objective: The objective of this study was to evaluate the protective effect of standardized hydro-methanol extract of C. pluricaulis (CPE) and its fractions, namely ethyl acetate (EAE), butanol (BE), and aqueous (AE), against 3-nitropropionic acid (3-NP) induced neurotoxicity in rats.

Materials and methods: The extract of the whole plant was standardized on the basis of scopoletin content (0.014%) using thin layer chromatography densitometric analysis. CPE (100 and 200?mg/kg) and its fractions, namely EAE (15 and 30?mg/kg), BE (25 and 50?mg/kg), and AE (50 and 100?mg/kg) were administered orally for 20?d. Their protective effect against 3-NP (10?mg/kg, i.p. for 14?d) was assessed by the effect on various behavioral parameters, namely body weight, locomotor activity, grip strength, gait pattern, and the effect on cognitive dysfunction. Biochemical parameters for oxidative damage were also assessed in the striatum and cortex regions of the brain.

Results: Administration of 3-NP induced HD-like symptoms that were indicated by reduced body weight, locomotor activity, memory, grip strength, and oxidative defense. CPE (200?mg/kg), EAE (30?mg/kg), and BE (50?mg/kg) significantly (p?<?0.001) attenuated 3-NP induced reduction in locomotor activity, grip strength, memory, body weight, and oxidative defense in comparison with 3-NP-treated animals on 10 and 15?d.

Conclusion: The present study suggested that CPE has a protective action against 3-NP-induced neurotoxicity and can be further explored for its efficacy against Huntington’s disease.     

The treatment of gastroparesis,constipation and small intestinal bacterial overgrowth syndrome in patients with Parkinson’s disease

Introduction: Parkinson’s disease (PD) affects the nerves of the entire gastrointestinal (GI) tract and may result in profound gastrointestinal (GI) dysfunction leading to poor patient outcomes. Common GI disturbances in patients with PD include gastroparesis (GP), constipation and small intestinal bacterial overgrowth syndrome (SIBO). In particular, GP is difficult to treat due to the limited options available and precautions, contraindications and adverse effects associated with the approved treatments. Moreover, some commonly used medications can worsen pre-existing PD.

Areas covered: Our review will focus on treatment options for GP and SIBO with motilin agonists, dopamine receptor antagonists, Ghrelin agonists muscarinic agonists, 5-HT₄ receptor agonists, antibiotics, probiotics and herbal formulation such as iberogast. Constipation occurs in the majority of patients with PD and fortunately many treatments are now available. Our review is based on original papers or reviews selected from PUBMED search and Cochrane reviews.

Expert opinion: Motility disorders of the GI tract are found frequently in patients with PD and treating the underlying GI disorders caused by PD with various prokinetics and laxatives is paramount in achieving improvements in patient’s motor function. Various prokinetics and laxatives are now available to provide some relief of the GI morbidity caused by PD leading even to better absorption of even the PD treatments.     

The bright side of psychoactive substances: cannabinoid-based drugs in motor diseases

Introduction: Psychoactive substances are associated with the idea of drugs with high addictive liability, affecting mental states, cognition, emotion and motor behavior. However these substances can modify synaptic transmission and help to disclose some mechanisms underlying alterations in brain processing and pathophysiology of motor disease. Hence, the ‘bright side’ of e cannabinoid-based drugs must be thoroughly examined to be identified within the latter framework.

Areas covered: We will analyze the preclinical and clinical evidence of cannabinoid-based drugs, discussing their therapeutic value in basal ganglia motor disorders such as Parkinson’s disease and Huntington disease.

Expert commentary: Despite the knowledge acquired in the last years, the therapeutic potential of cannabinoid-based drugs should be further tested by novel routes of investigation. This should be focused on the role of cannabinoid signaling system in mitochondrial function as well as on the physical and functional interaction with other key receptorial targets belonging to this network.     

Management of tics and Tourette's disorder: an update

Importance of the field: Tic disorders are fairly prevalent neuropsychiatric disorders. While a proportion of children may not present to the clinician's office for management of tic disorders, another proportion may present with severe symptoms that impair social and occupational functioning. A combination of psychosocial interventions and pharmacological approaches are required in these cases. While alpha-2 agonists and dopamine antagonists constitute the mainstay of pharmacological agents for tic disorders, advances in neurobiology and psychopharmacology have discovered newer avenues for treatment of tic disorders.

Areas covered in this review: Apart from reviewing evidence based literature and recent updates on alpha-2 agonists and dopamine antagonists in treating tic disorders, the review also includes novel treatment approaches such as glutamate modulators, nicotinic agents, antiandrogens and botulinum injection. In addition, a brief overview of electroconvulsive therapy (ECT), transcranial magnetic stimulation (TMS), deep brain stimulation (DBS) and habit reversal training is also provided.

What the reader will gain: A clear and concise review of the therapeutic options and advances in management of tic disorders.

Take home message: In addition to psychosocial interventions, alpha-2 agonists and dopamine antagonists constitute the mainstay of treatment approaches for treating tic disorders. Additional treatment options such as ropinirole, pramipexole and tetrabenazine may be useful if patients do not respond to the primary agents. Severe intractable cases might need a referral to specialist centers to consider the possibility of using ECT, TMS or DBS.     

The P2X7 receptor: a new therapeutic target in Alzheimer’s disease

Introduction: Alzheimer’s disease (AD) is a neurodegenerative illness with genetic risk as an etiological factor in a subset of cases. In AD with autosomal dominant inheritance, the extracellular β-amyloid (Aβ) aggregates and intracellular neurofibrillary tangles which consist of hyperphosphorylated tau, appear to be involved in the neuronal damage; however, other forms of AD may have a polygenetic causality. Microglial cells orchestrate pathophysiological events responsible for neuronal damage in AD. They surround Aβ aggregates and the stimulation of microglial P2X7 receptors (P2X7Rs) by high local concentrations of ATP which originates from damaged CNS cells, results in degeneration of nearby neurons.

Areas covered: We discuss the pathogenesis of Alzheimer’s disease, the role of P2X7 receptors and their potential as therapeutic targets. We also address the fundamental hurdles in the development of new therapeutic strategies for Alzheimer’s disease.

Expert opinion: There are many difficulties associated with the development of efficient pharmacological strategies for AD; the lack of good animal and cellular models for this illness is a key obstacle. None of the pharmacological strategies developed so far have led to an improvement of the treatment of AD. Hence, the consideration of blood-brain barrier-permeable P2X7R antagonists as possible therapeutic agents in AD is a must.     

Cannabinoid-1 receptor (CB1R) blockers as medicines: beyond obesity and cardiometabolic disorders to substance abuse/drug addiction with CB1R neutral antagonists

Introduction : Addiction to chemical substances with abuse potential presents medical needs largely unsolved by extant therapeutic strategies. Signal transmission through the cannabinoid-1 receptor (CB1R) in the central nervous system (CNS) modulates neurotransmitters/neuronal pathways contributing to the rewarding properties and hedonic effects of certain nondrug stimuli (e.g., food) and many prototypical addictive drugs, promoting excessive intake and its pathological consequences. Typical CB1R antagonists/inverse agonists reduce the rewarding effects and normalize behavioral phenotypes associated with food and abused drugs, but carry an unacceptable adverse-event profile that may reflect, at least partly, their intrinsic ability to alter basal homeostatic CB1R signaling in the CNS and elicit a negative efficacy response. Alternatively, peripherally biased CB1R inverse agonists with limited CNS permeability and putative CB1R neutral antagonists expressing modest (if any) inverse-agonist efficacy are garnering attention for treating obesity and related cardiometabolic complications with a potentially enhanced benefit-to-risk profile.

Areas covered : This mini-review calls attention to the proposition that CB1R neutral antagonists offer attractive opportunities for pharmacotherapeutic exploitation in the substance abuse/drug addiction space, whereas the restricted CNS accessibility of peripherally biased CB1R inverse agonists circumscribes their therapeutic utility for this indication.

Expert opinion : The unique preclinical pharmacology, efficacy profiles, and reduced adverse-event risk of CB1R neutral antagonists make them worthy of translational study for their potential therapeutic application beyond obesity/cardiometabolic disease to include substance-abuse/drug-addiction disorders.     

MAO inhibitors and their wider applications: a patent review

Introduction: Monoamine oxidase (MAO) inhibitors, after the initial ‘golden age’, are currently used as third-line antidepressants (selective MAO-A inhibitors) or clinically enrolled as co-adjuvants for neurodegenerative diseases (selective MAO-B inhibitors). However, the research within this field is always increasing due to their pivotal role in modulating synaptic functions and monoamines metabolism.

Areas covered: In this paper, MAO inhibitors (2015–2017) are disclosed ordering all the patents according to their chemical scaffold. Structure-activity relationships (SARs) are extrapolated for the most investigated chemotypes (coumarins, pyrazole/oxazepinones, (hetero)arylamides). 108 Compounds are divided into two main groups: newly synthesized molecules and naturally-occurring metabolites. Finally, new therapeutic options are outlined to ensure a more complete view on the potential of these inhibitors.

Expert opinion: New proposed MAO inhibitors are endowed with a marked isoform selectivity, with innovative therapeutic potential toward other targets (gliomas, inflammation, muscle dystrophies, migraine, chronic pain, pseudobulbar affect), and with a promising ability to address multi-faceted pathologies such as Alzheimer’s disease. The increasing number of patents is analyzed collecting data from 2002 to 2017.     

Patent Evaluation: Benzanilide derivatives as 5-HT1D antagonists

Summary

Novelty: Novel benzanilide derivatives are claimed to be 5-HT₁₀ antagonists. They are potentially useful for the treatment of depression, Parkinson's disease and a variety of CNS disorders including anxiety, panic and memory disorders.

Biology: No biological data are disclosed.

Chemistry: A total of forty-six final compounds and fifty-one intermediates are disclosed. Syntheses are given in all cases. Yields, mps and some ¹H nmr data are given. Twenty-five compounds are specifically claimed including 4′-cyano-N4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2′-methyl-[1,1′-biphenyl]-4-carboxamide.