Blockbuster Drugs Research Articles

Noncovalent Immobilization of Molecular Electrocatalysts for Chemical Synthesis: Efficient Electrochemical Alcohol Oxidation with a Pyrene–TEMPO Conjugate

AbstractElectrocatalytic methods for organic synthesis could offer sustainable alternatives to traditional redox reactions, but strategies are needed to enhance the performance of molecular catalysts designed for this purpose. The synthesis of a pyrene‐tethered TEMPO derivative (TEMPO=2,2,6,6‐tetramethylpiperidinyl‐N‐oxyl) is described, which undergoes facile in situ noncovalent immobilization onto a carbon cloth electrode. Cyclic voltammetry and controlled potential electrolysis studies demonstrate that the immobilized catalyst exhibits much higher activity relative to 4‐acetamido–TEMPO, an electronically similar homogeneous catalyst. In preparative electrolysis experiments with a series of alcohol substrates and the immobilized catalyst, turnover numbers and frequencies approach 2 000 and 4 000 h−1, respectively. The synthetic utility of the method is further demonstrated in the oxidation of a sterically hindered hydroxymethylpyrimidine precursor to the blockbuster drug, rosuvastatin.

Engineering Streptomyces coelicolor Carbonyl Reductase for Efficient Atorvastatin Precursor Synthesis.

Streptomyces coelicolor CR1 (ScCR1) has been shown to be a promising biocatalyst for the synthesis of an atorvastatin precursor, ethyl-(S)-4-chloro-3-hydroxybutyrate [(S)-CHBE]. However, limitations of ScCR1 observed for practical application include low activity and poor stability. In this work, protein engineering was employed to improve the catalytic efficiency and stability of ScCR1. First, the crystal structure of ScCR1 complexed with NADH and cosubstrate 2-propanol was solved, and the specific activity of ScCR1 was increased from 38.8 U/mg to 168 U/mg (ScCR1I158V/P168S) by structure-guided engineering. Second, directed evolution was performed to improve the stability using ScCR1I158V/P168S as a template, affording a triple mutant, ScCR1A60T/I158V/P168S, whose thermostability (T5015, defined as the temperature at which 50% of initial enzyme activity is lost following a heat treatment for 15 min) and substrate tolerance (C5015, defined as the concentration at which 50% of initial enzyme activity is lost following incubation for 15 min) were 6.2°C and 4.7-fold higher than those of the wild-type enzyme. Interestingly, the specific activity of the triple mutant was further increased to 260 U/mg. Protein modeling and docking analysis shed light on the origin of the improved activity and stability. In the asymmetric reduction of ethyl-4-chloro-3-oxobutyrate (COBE) on a 300-ml scale, 100 g/liter COBE could be completely converted by only 2 g/liter of lyophilized ScCR1A60T/I158V/P168S within 9 h, affording an excellent enantiomeric excess (ee) of >99% and a space-time yield of 255 g liter-1 day-1 These results suggest high efficiency of the protein engineering strategy and good potential of the resulting variant for efficient synthesis of the atorvastatin precursor.IMPORTANCE Application of the carbonyl reductase ScCR1 in asymmetrically synthesizing (S)-CHBE, a key precursor for the blockbuster drug Lipitor, from COBE has been hindered by its low catalytic activity and poor thermostability and substrate tolerance. In this work, protein engineering was employed to improve the catalytic efficiency and stability of ScCR1. The catalytic efficiency, thermostability, and substrate tolerance of ScCR1 were significantly improved by structure-guided engineering and directed evolution. The engineered ScCR1 may serve as a promising biocatalyst for the biosynthesis of (S)-CHBE, and the protein engineering strategy adopted in this work would serve as a useful approach for future engineering of other reductases toward potential application in organic synthesis.

The Sanofi-Aventis Acquisition of Genzyme: Contingent Value Rights

This case is designed for MBA students in M&A or derivatives courses. In January 2011, Sanofi-Aventis was finalizing its offer terms for acquiring Genzyme. The M&A valuation disputes were about the market potential of alemtuzumab, a drug in Genzyme's pipeline, and how quickly Genzyme could resolve some of its manufacturing issues. To bridge the gap in their estimates, advisers had suggested an up-front cash payment and a contingent value right (CVR). Was a CVR the magical solution to bridging the valuation gap? Excerpt UVA-F-1715 Oct. 22, 2014 THE SANOFI-AVENTIS ACQUISITION OF GENZYME: CONTINGENT VALUE RIGHTS At the end of January 2011, Henri Termeer, the CEO of Genzyme, and Chris Viehbacher, the CEO of Sanofi-Aventis (Sanofi), were both attending the World Economic Forum, a gathering of chief executives, heads of state, and other influential figures at the ski resort in Davos, Switzerland. The advisers of the two firms had spent countless hours discussing merger deal alternatives, and the private meeting between the CEOs was expected to close these negotiations. Sanofi, a large French pharmaceutical company, had first expressed its interest in acquiring Genzyme in the summer of 2010. Termeer had led Genzyme for more than 25 years, overseeing its growth from an entrepreneurial venture to a top U.S. biotechnology firm. The main reasons Sanofi was attracted to Genzyme were its lucrative drug business that focused on hard-to-copy genetic diseases and its pipeline of drugs under development (Exhibit 1). Sanofi was fighting a looming drop in its revenues due to the patent expirations of several of its blockbuster drugs. The Genzyme acquisition would shift the focus of Sanofi's portfolio toward biopharma, an area in which the firm lagged behind its competitors. . . .

Docking-based structural splicing and reassembly strategy to develop novel deazapurine derivatives as potent B-RafV600E inhibitors.

The mutation of B-RafV600E is widespread in a variety of human cancers. Its inhibitors vemurafenib and dabrafenib have been launched as drugs for treating unresectable melanoma, demonstrating that B-RafV600E is an ideal drug target. This study focused on developing novel B-RafV600E inhibitors as drug leads against various cancers with B-RafV600E mutation. Using molecular modeling approaches, 200 blockbuster drugs were spliced to generate 283 fragments followed by molecular docking to identify potent fragments. Molecular structures of potential inhibitors of B-RafV600E were then obtained by fragment reassembly followed by docking to predict the bioactivity of the reassembled molecules. The structures with high predicted bioactivity were synthesized, followed by in vitro study to identify potent B-RafV600E inhibitors. A highly potent fragment binding to the hinge area of B-RafV600E was identified via a docking-based structural splicing approach. Using the fragment, 14 novel structures were designed by structural reassembly, two of which were predicted to be as strong as marketed B-RafV600E inhibitors. Biological evaluation revealed that compound 1m is a potent B-RafV600E inhibitor with an IC50 value of 0.05 μmol/L, which was lower than that of vemurafenib (0.13 μmol/L). Moreover, the selectivity of 1m against B-RafWT was enhanced compared with vemurafenib. In addition, 1m exhibits desirable solubility, bioavailability and metabolic stability in in vitro assays. Thus, a highly potent and selective B-RafV600E inhibitor was designed via a docking-based structural splicing and reassembly strategy and was validated by medicinal synthesis and biological evaluation.

A robust feeding strategy to maintain set-point glucose in mammalian fed-batch cultures when input parameters have a large error.

Industrial CHO cell cultures run under fed-batch conditions are required to be controlled in particular ranges of glucose, while glucose is constantly consumed and must be replenished by a feed. The most appropriate feeding rate is ideally stoichiometric and adaptive in nature to balance the dynamically changing rate of glucose consumption. However, high errors in biomass and glucose estimation as well as limited knowledge of the true metabolic state challenge the control strategy. In this contribution, we take these errors into account and simulate the output with uncertainty trajectories in silico in order to control glucose concentration. Other than many control strategies, which require parameter estimation, our assumptions are founded on two pillars: (i) first principles and (ii) prior knowledge about the variability of fed-batch CHO cell culture. The algorithm was exposed to an in-silico Design of Experiments (DoE), in which variations of parameters were changed simultaneously, such as clone-specific behavior, precision of equipment and desired control range used. The results demonstrate that our method achieved the target of holding the glucose concentration within an acceptable range. A robust and sufficient level of control could be demonstrated even with high errors for biomass or metabolic state estimation. In a time where blockbuster drugs are queuing up for time slots of their production, this transferable control strategy that is independent of tedious establishment runs may be a decisive advantage for rapid implementation during technology transfer and scale up and decrease in campaign change over time. © 2017 American Institute of Chemical Engineers Biotechnol. Prog., 33:317-336, 2017.

'Forever Young'-Testosterone replacement therapy: a blockbuster drug despite flabby evidence and broken promises.

In the last decade, testosterone replacement therapy (TRT) has been increasingly prescribed to treat a controversial condition known as 'late-onset hypogonadism (LOH)'. This syndrome is diagnosed in men who, for no discernible reason other than older age, obesity or ill health have serum testosterone concentrations below the normal range for healthy young men and report one or more of the following symptoms: muscle weakness or wasting, mood, behaviour and cognition-related symptoms and sexual function or libido impairment. However, recent evidence has demonstrated that testosterone drugs do not substantially ameliorate these symptoms and, more worryingly, that their long-term use may be associated with severe adverse effects (i.e. increased risk of prostate cancer, stroke and myocardial infarction, worsening of benign prostatic hyperplasia symptoms and testicular atrophy). Nonetheless, testosterone drugs have exhibited extraordinary commercial success and their pharmaceutical sales are steadily rising. Behind this apparently unjustifiable trend there are deliberate, well designed direct and indirect pharmaceutical marketing initiatives that exploit the conviction rooted in contemporary society that testosterone can reverse the effects of ageing and ensure social accomplishment. Commercial mechanisms have laid the foundation for disease mongering of LOH and also have resulted a considerable expansion of the indications for treatment. This promotion model deserves particular attention since it is applicable to any drug with a purportedly favourable risk-benefit ratio not supported by evidence.

Update on Alzheimer's Disease Therapy and Prevention Strategies.

Alzheimer's disease (AD) is the primary cause of age-related dementia. Effective strategies to prevent and treat AD remain elusive despite major efforts to understand its basic biology and clinical pathophysiology. Significant investments in therapeutic drug discovery programs over the past two decades have yielded some important insights but no blockbuster drugs to alter the course of disease. Because significant memory loss and cognitive decline are associated with neuron death and loss of gray matter, especially in the frontal cortex and hippocampus, some focus in drug development has shifted to early prevention of cellular pathology. Although clinical trial design is challenging, due in part to a lack of robust biomarkers with predictive value, some optimism has come from the identification and study of inherited forms of early-onset AD and genetic risk factors that provide insights about molecular pathophysiology and potential drug targets. In addition, better understanding of the Aβ amyloid pathway and the tau pathway-leading to amyloid plaques and neurofibrillary tangles, respectively, which are histopathological hallmarks of AD-continues to drive significant drug research and development programs. The main focus of this review is to summarize the most recent basic biology, biochemistry, and pharmacology that serve as a foundation for more than 50 active advanced-phase clinical trials for AD prevention and therapy.

Drug manufacturing woes grow

Several companies are trying to overcome manufacturing roadblocks that stopped their new drugs from being approved by FDA in 2016. In responses to their applications, FDA cited problems found during preapproval plant inspections. Most problems were in Western facilities and centered on formulation, rather than active ingredient production. Only two companies—AstraZeneca and Opko Health—responded to the problems in time to refile in 2016. And Opko got an approval after its manufacturing partner, Catalent, fixed problems at its St. Petersburg, Fla., extended-release capsule plant. Ocular Therapeutix expects to refile this quarter, while Roche’s review is delayed until late March. Meanwhile, Sanofi and Regeneron Pharmaceuticals face a major setback for the potential blockbuster drug sarilumab, a monoclonal antibody targeting the interleukin-6 receptor. If approved, it will compete in the rheumatoid arthritis field against Abbvie’s Humira, the industry’s top-selling drug. During an October earnings call, Sanofi CEO Olivier Brandicourt said the company was

May Your Drug Price Be Ever Green

Presenting the first comprehensive study of evergreening, this article examines the extent to which evergreening behavior—which can be defined as artificially extending the protection cliff—may contribute to the problem. The author analyses all drugs on the market between 2005 and 2015, combing through 60,000 data points to examine every instance in which a company added a new patent or exclusivity. The results show a startling departure from the classic conceptualization of intellectual property protection for pharmaceuticals. Rather than creating new medicines, pharmaceutical companies are largely recycling and repurposing old ones. Specifically, 78% of the drugs associated with new patents were not new drugs, but existing ones, and extending protection is particularly pronounced among blockbuster drugs. Once companies start down the road of extending protection, they show a tendency to return to the well, with the majority adding more than one extension and 50% becoming serial offenders. The problem is growing across time.

Short synthesis of polyfunctional sp3-rich threonine-derived morpholine scaffolds.

A convenient synthesis of novel complex morpholines was achieved by a two-step process involving a Petasis three-component coupling reaction of glycolaldehyde, organoboronic acid and different amines, followed by an acid- or base-mediated intramolecular cyclization. The use of threonine derivatives with glycolaldehyde in the Petasis reaction has been studied and successfully applied in the process, achieving morpholines with a higher fraction of sp3 carbon atoms compared to blockbuster drugs.

Experience of an academic institute in importing a novel preclinical drug into India.

The article throws light on the process of importing a novel preclinical drug into India based on the real-life experience from one of our studies. A novel drug “X” acting through a new mechanism of action was hypothesized by us to function as a neuroprotectant. It was decided to import this novel drug from a university located in Brazil. An official collaboration pact was exchanged between both the sides. In accordance with the Indian Drug and Cosmetics Act 1940, unauthorized import of drug into India is not permitted. Hence, we decided to apply for the import license from Government of India. During the process of registration, we realized that the CDSCO SUGAM portal did not have facilities for the application from academic institute. We further faced challenges in different steps of import such as registration of the institute, individual drug application, fee transaction through the bank for Form 12, and customs duty clearance in the New Delhi airport. The process of import of drug for the purpose of testing by academic institutes has not been regularized by the CDSCO, and we suggest the apex organization to make separate provision for the academic institutes. This will encourage more academic institutes in India to opt for global collaborative works. This narration will further help them in following the same footsteps without facing significant hurdles. If more research on novel chemical entities is carried out in various academic institutes of India, it would not be far that we discover a blockbuster drug making the whole world turn toward us.

Prospects and Challenges for the Commercialization of Biosimilars: Perspectives from the EU, Japan, and the US

With many blockbuster biologic drugs coming off patent in the next couple of years, biosimilars are making significant breakthroughs in cost-effective biologic therapies. The global market for biosimilars is expected to increase nearly 30 fold from $1.3 billion in 2013 to $35 billion by 2020. To promote biosimilar development and commercialization in the U.S., the Biosimilars Act was signed into law in 2010 to establish an abbreviated pathway by which the FDA could approve biosimilar versions of previously licensed biological products. Since its enactment, two biosimilars have been approved in the U.S. This Article will discuss key aspects of the U.S., the EU and Japanese approval pathways and will explore their likely impact on the commercialization of biosimilar medicines. Â

РОЛЬ ГІСТАМІНУ У ШЛУНКОВІЙ СЕКРЕЦІЇ В НОВОМУ: ВІД ВІДКРИТТЯ ДО КЛІНІЧНОГО ЗНАЧЕННЯ (НА ЧЕСТЬ 150 РІЧЧЯ З ДНЯ НАРОДЖЕННЯ ЛЕОНА ПОПЕЛЬСЬКОГО)

Professor of Lviv National Medical University (formerly known as Jan Kazimierz Lemberg University), Ukraine, Leon Popielski was the fi rst to recognize that histamine stimulated gastric acid secretion 100 years ago, at 1916. He produced over one hundred publications and founded Lviv’s experimental gastroenterology school (Koskowski, 1931), and strong pharmacology tradition. He is less well known today than he deserves to be. Popielski began his scientifi c career at the Military Medical Academy in St Petersburg, then dominated by I. Pavlov. In 1901, he published work indicating the existence of a peripheral ‘refl ex center’ controlling gastric secretion (Popielski, 1901). His fi ndings contradicted the prevailing ‘nervism’ theory of Pavlov, who had supervised Popielski’s PhD thesis. Perhaps not surprisingly this caused friction between them. Pavlov then started a process to verify Popielski’s results, which was later described in Boris Babkin’s memoirs. The results were confi rmed thereby establishing the idea that processes other than conditional-refl exes, and in particular peripheral mechanisms, also controlled gastric secretion. Popielski’s work on histamine was carried out in Lviv during the World War I period, although published only later. He clearly showed that histamine was a strong stimulant of gastric acid secretion. His PhD student W. Koskowski subsequently introduced the histamine test for gastric secretion in patients, which in a somewhat modifi ed form, was used clinically for many decades in Poland at 1930’s. In the 1960’s and early 1970’s, Professor Sir James Black, at what was then Smith, Kline and French, brilliantly extended Popielski’s model of the role of histamine in gastric secretion through the development and use of a new class of antisecretory drug – the H2 receptor antagonists (Black et al., 1972). These proved the essential role of histamine in stimulating acid secretion. An early example, cimetidine, became the fi rst truly blockbuster drug, and revolutionised the treatment of peptic ulcer disease. At 21st century the novel gastric acid blockers – inhibitors of proton pump (PPI) were included in standard protocols for treatment several acid-related diseases. Long-term gastric acid suppression has been associated with different complications in gastric mucosa. Moreover, the roles of gastric acid inhibition in extragastral damage manifestation and several groups have reported abnormal proliferation in gastrointestinal tract during long-term treatment by IPP or H2 receptor antagonists. In the past 10 years due to these side effects, there is a need to study dual actions of histamine on gastrointestinal mucosa. Progress of scientifi c thought allowed to identify numerous histamine receptors (H1-H4) and their multifunctional meaning, and in that way to facilitate appearing of new medicine, which have totally changed treatment tactic of gastroenterological and neurogical diseases. Popielski’s work provides a clear example of how basic physiological research can be translated into the clinic for patient benefi t. Scientifi c portrait of L. Popielski doesn’t limit in his scientifi c and studying publications, he is an author of numerous publications, dedicated to the healthy way of life. Intellectual courage, belief in the reliability of obtained results and incredible assiduity of L. Popielski, deserve to be respected nowadays.

Invalidation of Atorvastatin Patent Highlights Complex Chinese Patent Law

Pfizer's atorvastatin (Lipitor) is a blockbuster drug for the treatment of cardiovascular diseases. In China, a critical polymorph patent of this drug has been recently invalidated by the Supreme People's Court for insufficiency of disclosure. Here, we discuss the particularities in patent litigation in China worth attention from the community.

Cardioprotective role of peroxisome proliferator-activated receptor-γ agonist, rosiglitazone in a unique murine model of diabetic cardiopathy

AimsRosiglitazone (RSZ), a PPARγ agonist was potent efficacious insulin sensitizing blockbuster drug for treatment of Type 2 diabetes mellitus (T2DM) but the benefit of PPARγ activation in congestive heart failure (CHF) was controversial. The present work was planned to study the role of RSZ in diabetic cardiopathy. Main methodsZucker fa/fa rats, the genetic model of T2DM were subjected to constriction of suprarenal abdominal aorta so that they represent a combined model of diabetes and cardiopathy. The development cardiopathy was assessed biochemically (plasma BNP and aldosterone levels), using echocardiography and expression angiotensin II receptor type 1a gene in heart and Endothelin-1 gene in aorta. Rats were treated with RSZ and in combination with amiloride for four weeks and were assessed to evaluate the effect of RSZ or amiloride or its combination on antidiabetic activity, adverse or toxic effects and congestive heart failure status. Key findingsRSZ shows its anti-diabetic effect from 0.3mg/kg dose onwards and at 3mg/kg dose levels it caused beneficial effects (reduction of blood pressure) on cardiovascular system and at highest (30mg/kg) dose it starts showing adverse effects like body weight gain, edema, left ventricular hypertrophy. However, when highest dose of RSZ animals were treated with amiloride (ENaC inhibitor) at 2mg/kg the reversal of the adverse effects was evident, indicating the combination of RSZ and amiloride is beneficial in diabetic cardiopathy model. SignificanceRSZ and amiloride combination appeared promising treatment in diabetic patients with cardiopathy without any side effect.

A Chromogenic and Fluorogenic Peptide Substrate for the Highly Sensitive Detection of Proteases in Biological Matrices.

The synthesis and application of a novel type of chromogenic and fluorogenic substrate for protease detection is described. The outstanding performance of the tripeptide substrates is exemplified by specific fluorescence detection of thrombin and factor Xa at only 500 fM concentration. The substrate is also applicable to the sensitive detection of the thrombin inhibitor dabigatran in human plasma and whole blood samples, highlighting its potential for a point-of-care test for instant monitoring the blood levels of this blockbuster anticoagulant drug in specific clinical situations.

Enhanced enzymatic synthesis of the enantiopure intermediate for the blockbuster drug intermediate abacavir through a two-step enzymatic cascade reaction

A very efficient enzymatic two-step cascade reaction was devised (E>200) for the resolution of activated γ-lactams (±)-1 and (±)-2. The N-hydroxymethyl group worked as a traceless activating group, when the reactions were performed with H2O (0.5equiv) in the presence of benzylamine (1equiv) in i-Pr2O at 60°C. The ring-opened enantiomerically pure γ-amino acids (1S,4R)-6 (ee=99%, intermediate of abacavir) and (1S,3R)-8 (ee=99%) and unreacted lactams (1S,4R)-1 and (1R,4S)-2 (ee⩾96%) were obtained in good yields (⩾43%). Treatment of (1S,4R)-1 and (1R,4S)-2 with 18% HCl or NH4OH resulted in (1R,4S)-6·HCl and (1S,3R)-8·HCl or (1S,4R)-3 and (1R,4S)-4 quantitatively, with ee⩾96%.

Niacin: Time to Believe Outcomes Over Surrogate Outcomes

Long-acting niacin, a blockbuster drug for many years, emerged during an era in which the simple assumption was that favorably modifying patients’ lipid profiles was tantamount to lowering their risks for cardiovascular disease. The implicit assumption in the medical community and among regulators was that improving lipid profiles would improve outcomes even as the mechanism of the drug action was not clear. This approach holds sway today as evidenced by the recent approval of the PCSK9 inhibitor drugs before the completion of the definitive phase 3 outcome trials.1,2 The evidence suggests that the way in which a risk factor is modified matters for whether it produces a benefit.3 Long-acting niacin is a particularly interesting case because it was included in one of the earliest outcome trials, the Coronary Drug Project, initiated in 1966, although the results were equivocal.4 With 5 to 8 years of follow-up, niacin failed to improve mortality, the primary end point. The 5-year rates of death were 21.2% for niacin and 20.9% for placebo. Death rates because of coronary heart disease were also close and not significantly different: 15.9% for niacin and 16.2% for placebo. The niacin group did have a lower risk of nonfatal myocardial infarction, one of the secondary end points. It should also be noted that because …

Asymmetric Synthesis of Methylphenidate and Quinolizidinones by Addition of Aldehydes to Piperidine-Based Conjugated N-Acyl­iminium Ions

The synergistic effect of Lewis acids and MacMillan organocatalyst allows the α-regioselective and enantioselective α-amidoalkylation of piperidine derivatives with enolizable aldehydes. The potentiality of the synthetic method is illustrated by a short asymmetric synthesis of the eutomer of the blockbuster drug Ritalin and by a concise formal synthesis of 1-alkyl-4-substituted quinolizidine alkaloids.

Subcutaneously Administered Self-Cleaving Hydrogel-Octreotide Conjugates Provide Very Long-Acting Octreotide.

We developed a long-acting drug-delivery system that supports subcutaneous administration of the peptidic somatostatin agonist octreotide-a blockbuster drug used to treat acromegaly and neuroendocrine tumors. The current once-a-month polymer-encapsulated octreotide, Sandostatin LAR, requires a painful intragluteal injection through a large needle by a health-care professional. To overcome such shortcomings, Tetra-PEG hydrogel microspheres were covalently attached to the α-amine of d-Phe(1) or the ε-amine of Lys(5) of octreotide by a self-cleaving β-eliminative linker; upon subcutaneous injection in the rat using a small-bore needle, octreotide was slowly released. The released drug from the ε-octreotide conjugate showed a remarkably long serum half-life that exceeded two months. The α-octreotide conjugate had a half-life of ∼2 weeks, and showed an excellent correlation of in vitro and in vivo drug release. Pharmacokinetic models indicate these microspheres should support once-weekly to once-monthly self-administered subcutaneous dosing in humans. The hydrogel-octreotide conjugate shows the favorable pharmacokinetics of Sandostatin LAR without its drawbacks.