Case study of patents related to captopril,Squibb’s first blockbuster

Introduction: Arterial hypertension affects over one billion people around the world, making the prevention and treatment of this disease vital. Despite the efforts made to develop new antihypertensive drugs, few new therapies have become available. Angiotensin-converting enzyme (ACE) inhibitors have heralded major steps forward in the treatment of arterial hypertension and cardiovascular diseases since the first compound of this class, captopril, was approved for clinical use in 1981.

Areas covered: In this review, the authors investigated the patent documents that cite the priority patent for captopril, Squibb’s first blockbuster, or any other patent from its patent family. The documents were classified into the following: new compounds, new compositions, treatment, process (preparation of a compound), use of a compound, and process for the preparation of an intermediate. Therefore, the readers can identify potential innovations in the field.

Expert opinion: The pharmaceutical sector has attempted to provide significant technological developments on anti-hypertensive drugs based on the patenting of captopril, including the development of new compositions further comprising an ACE inhibitor and other antihypertensive agent, along with dual action compounds, novel molecules with dual activity. The target is to find a new agent with better blood pressure-lowering efficacy, improved safety and good tolerability pro?le.     

Physicians’ and pharmacies’ overview of patients’ medication. An analysis of fidelity coefficients

Background  

It is essential that pharmacies and prescribers have an overview of each patient’s medication in order to prevent drug interactions, unintentional co-prescribing, unnecessary polypharmacy and underprescribing. We have assessed this overview by measuring the ‘fidelity coefficient’, a measure of the extent to which a drug user has a preference for one prescriber or one pharmacy.     

Bibliometric analysis of scientific publications in the field of medicinal chemistry in Latin America, the People’s Republic of China, and India

This study was designed as a bibliometric analysis of scientific production on medicinal chemistry (MC) individually and collectively in ten countries from Latin America together with the People’s Republic of China (China), and India. The bibliometric analysis was performed using the Journal Citation Reports (JCR) Database of the Institute of Scientific Information. The number of indexed journals in the JCR of each country is associated with the Gross Domestic Product at Purchasing Power Parity (GDP-PPP). The journals with the greatest number of published articles from the ten Latin American countries, individually and collectively, together with India had an impact factor between 1.0 and 2.0, and China had an impact factor >2.0. China and India, in contrast to Latin America, have achieved diversification of their publications in all areas included. Latin American countries must adopt educational politics that allow it to be more competitive in the field of MC.     

Promoting global health—treatment and prevention of substance abuse and HIV in Asia

Journal of Neuroimmune Pharmacology -     

Alzheimer’s disease: Recent advances in diagnosis and overview of clinical research in newer treatments

Alzheimer’s disease (AD) is a progressive and fatal neurodegenerative disorder manifested by cognitive and memory deterioration, progressive impairment of activities of daily living, and a variety of neuropsychiatric symptoms and behavioral disturbances. This article discusses worldwide prevalence patterns, history, and summarizes hypotheses about the causes of AD. Currently available diagnostic methods, their effectiveness of, and problems with, different methods and recent advances are thoroughly discussed. Finally, current treatment strategies are discussed in light of the benefits and drawbacks of different therapeutic approaches along with ongoing drugs under development.     

Antibiotic and non-antibiotic tetracycline patents: 2002 – 2007

Background: Infectious diseases in all populations are increasing in frequency and severity as the problem of antibiotic resistance continues to emerge. As other antibiotics become ineffective, it is up to researchers worldwide to create new and more potent compounds to thwart such diseases. Objective: This review presents the recent efforts and patent portfolios of those groups actively engaged in tetracycline research. Methods: The tetracyclines, once studied thoroughly shortly after their discovery > 50 years ago, have been neglected as new sources of scaffolds suitable for producing more potent compounds until recently, where several companies and research institutions have described newer and more potent analogs via semisynthesis or by total synthesis. Furthermore, other useful therapeutic properties of the tetracyclines have also been discovered, primarily as observations from their use as clinical antibiotic agents, in the areas of inflammation, neurodegeneration and diseases characterized by tissue degradation. Results and conclusions: The recent patents pertaining to the synthesis and biological properties indicate that the tetracyclines are undergoing a renaissance as their activities are being revised against prokaryotic organisms and against mammalian disease states related to inflammation.     

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.     

Review of rivastigmine and its clinical applications in Alzheimer’s disease and related disorders

Rivastigmine (Exelon?, Novartis) is a novel intermediate-acting reversible and non-competitive carbamate acetylcholinesterase (AChE) that was recently introduced for the treatment of Alzheimer’s disease (AD). Preclinical studies have shown that rivastigmine has many similarities to other currently available cholinesterase inhibitors (ChEIs) and some important differences. The drug has been evaluated for this use in two well designed, published, adequately powered, Phase III, 26 week clinical trials that included a total of more than 1500 rivastigmine and 700 placebo recipients. Most of these patients had concomitant disorders that were being treated with numerous other drugs. These studies indicate that rivastigmine (6 - 12 mg/day) usually produces cognitive, global and functional changes that indicate significantly less deterioration than was observed with placebo in patients with mild-to-moderate AD, with higher doses producing more benefits. Rivastigmine is beneficial in all three domains (namely cognition, daily activities and behaviour) of AD. Data on long-term efficacy support continued benefits of rivastigmine beyond 6 months. Rivastigmine is generally well-tolerated with no requirement for routine electrocardiogram (ECG) or blood monitoring. Rivastigmine causes adverse events that are generally those expected from a ChEI and mainly involve gastrointestinal system. They are usually mild-to-moderate, of short duration and responsive to dosage reduction. They occur mostly during the dosage titration phase and decrease during the maintenance phase. Clinically significant drug-drug interactions are unlikely. The consistent efficacy in treating all three domains (cognition, daily functioning and behaviour) and good tolerability, particularly with slow titration, makes rivastigmine a good first-line ChEI therapy for the treatment of AD. Therapeutic dose range is 6 - 12 mg/day. Rivastigmine should be started at 1.5 mg b.i.d. with meals and increased at 2 - 4 week intervals to achieve the highest tolerated dose.     

Investigation of hallucinogenic and related β-carbolines

Certain β-carbolines are known to be hallucinogenic in humans, and several produce stimulus effects in animals similar to those of the classical hallucinogen 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM). Classical hallucinogens bind at 5-HT₂ serotonin receptors and these receptors are thought to play a role in their mechanism of action. In the present study, we examined the binding of 15 β-carbolines at rat 5-HT_2A and 5-HT_2C receptors. Affinities (K_i values) of the β-carbolines ranged from about 100 nM to greater than 10 000 nM depending upon the degree of saturation of the pyridyl ring, and upon the presence and location of methoxy substituents in the benzenoid ring. In a further study, six rats were trained to discriminate the hallucinogenic β-carboline harmaline (3.0 mg/kg, i.p.) from vehicle using a VI-15s schedule of reinforcement. This represents the first time a hallucinogenic β-carboline has been used as a training drug in a drug discrimination study. Administration of DOM to the harmaline-trained animals resulted in 76% harmaline-appropriate responding at 1.25 mg/kg DOM and disruption of behavior at a higher dose. Taken together, the results of the present investigation demonstrate that: (a) certain β-carbolines bind at 5-HT₂ receptors; (b) that harmaline serves as a training drug at 3.0 mg/kg in drug discrimination studies with rats as subjects; and that (c) there is some similarity between the stimulus effects produced by harmaline and DOM.     

Stereoselective and nonstereoselective pharmacokinetics of rabeprazole – an overview

1.?Proton pump inhibitors have been extensively used for the treatment of ailments due to increased gastric acid secretion such as peptic ulcers, gastroesophageal reflux disease, etc.

2.?There are several approved drugs in the proton pump inhibitor class with the latest entries representing single enantiomer drugs of the previously approved racemic drugs.

3.?Despite having a high degree of structural resemblance, rabeprazole, was shown to possess some unique differentiation from other drugs in the class. One of the key distinguishing features of rabeprazole was related to the lesser involvement of polymorphic metabolism in its pharmacokinetic disposition.

4.?The review was aimed to provide pharmacokinetic data of rabeprazole from several clinical studies including drug–drug interaction studies where rabeprazole was either a perpetrator drug or victim drug.

5.?Additional perspectives on therapy considerations due to the unique metabolic disposition of rabeprazole including the possible issues related to chirality were provided.     

Emerging approaches to the treatment of uveitis: patents of 2000 – 2004

The treatment of non-infectious uveitis is often a challenging experience for both the patient and the treating physician. The use of traditional forms of treatment is restricted by limited effectiveness and considerable side effects. This review examines the current trends in therapy and the emerging new classes of therapeutic agents used in the treatment of non-infectious uveitis. It then examines some of the newer approaches apparent from recent patenting over the past four years and assesses their likely future significance.     

Impact of HIV and chronic kidney disease comorbidities on hepatitis C treatment choices,drug–drug interactions and hepatitis C cure

International Journal of Clinical Pharmacy - Background Human immunodeficiency virus (HIV) co-infection and chronic kidney disease add challenges to hepatitis C virus treatment. Objective To...     

Therapeutic modulation of retinoid X receptors – SAR and therapeutic potential of RXR ligands and recent patents

Introduction: Retinoid X receptor (RXR) agonists have a limited role in cancer therapy with bexarotene and alitretinoin as approved drugs but their use is limited by adverse effects. Several evidence from in vitro, in vivo, and small clinical studies points to various further potential applications of RXR ligands in neurodegenerative and inflammatory diseases.

Areas covered: The authors review known RXR ligand classes with their key structure–activity relationships and recent reports on pharmacological effects of RXR modulation. Based on these aspects, the authors evaluate recent patents claiming novel RXR ligands or their use.

Expert opinion: While the use of RXR modulators has been claimed in several novel and promising indications, little progress has been made in the development of innovative rexinoids with improved (subtype-)selectivity. Next-generation RXR modulators that selectively target the RXR subtypes for individual indications may be required to exhaustively exploit the therapeutic potential of RXRs.     

An overview of late-stage functionalization in today’s drug discovery

ABSTRACT

Introduction: Late-stage functionalization (LSF) can introduce important chemical groups in the very last steps of the synthesis. LSF has the potential to speed up the preparation of novel chemical entities and diverse chemical libraries and have a major impact on drug discovery. Functional group tolerance and mild conditions allows access to new molecules not easily accessible by conventional approaches without the need for laborious de novo chemical synthesis.

Areas Covered: A historical overview of late-stage functionalization and its applicability to drug discovery is provided. Pioneering methodologies that laid the foundations for the field are briefly covered and archetypal examples of their application to drug discovery are discussed. Novel methodologies reported in the past few years mainly stemming from the recent renaissances of photoredox catalysis and radical chemistry are reviewed and their application to drug discovery considered.

Expert opinion: It is envisioned that late-stage functionalization will improve the efficiency and efficacy of drug discovery. There is evidence of the widespread uptake of LSF by the medicinal chemistry community and it is expected that the recent and continuing endeavors of many academic laboratories and pharmaceutical companies will soon have an impact on drug development.     

Strategies for TGF-β modulation: a review of recent patents

Background: TGF-β has been identified as a key factor in the progression of various diseases, in particular cancer and fibrosis. The signaling of TGF-β can be modulated through three distinct strategies: using antisense nucleotides that block TGF-β mRNA (trabedersen (AP 12009)), using monoclonal antibodies to block TGF-β isoforms (lerdelimumab, metelimumab) or using small molecule inhibitors of the TGF-β receptor 1 (TGF-βR1 or ALK-5). Objective: This review focuses on small molecules and summarizes the most recent TGF-βR1 inhibitors reported in the patent literature. Methods: We searched and analyzed the patent literature claiming chemical matter for TGF-βR1 inhibition from the 1^st of January 2005 to the 1^st of January 2009. Results/conclusions: The inhibition of TGF-β has recently been clinically validated with antisense nucleotide trabedersen. Small molecules inhibitors of TGF-βR1 that are now in Phase I clinical trials and in preclinical stage are, therefore, of high interest and could provide a more versatile route to TGF-β modulation through oral dosing while maintaining the same therapeutic benefits.