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Pfizer, Inc. /ˈfaɪzər/ is an American multinational pharmaceutical corporation headquartered in New York City, and with its research headquarters in Groton, Connecticut, United States. It is one of the world's largest pharmaceutical companies by revenues.Pfizer develops and produces medicines and vaccines for a wide range of medical disciplines, including immunology, oncology, cardiology, diabetology/endocrinology, and neurology. Pfizer's products include the blockbuster drug Lipitor , used to lower LDL blood cholesterol; Lyrica ; Diflucan , an oral antifungal medication; Zithromax , an antibiotic; Viagra ; and Celebrex/Celebra , an anti-inflammatory drug.Pfizer was founded by cousins Charles Pfizer and Charles F. Erhart in New York City in 1849 as a manufacturer of fine chemicals. Pfizer's discovery of Terramycin in 1950 put it on a path towards becoming a research-based pharmaceutical company. Pfizer has made numerous acquisitions, including Warner–Lambert in 2000, Pharmacia in 2003 and Wyeth in 2009. The Wyeth acquisition was the largest of the three at US$68 billion. Pfizer is listed on the New York Stock Exchange, and its shares have been a component of the Dow Jones Industrial Average since April 2004.In September 2009, Pfizer pleaded guilty to the illegal marketing of the arthritis drug Bextra for uses unapproved by the U.S. Food and Drug Administration , and agreed to a $2.3 billion settlement, the largest health care fraud settlement at that time. Pfizer also paid the U.S. government $1.3 billion in criminal fines related to the "off-label" marketing of Bextra, the largest monetary penalty ever rendered for any crime. Called a repeat offender by prosecutors, this was Pfizer's fourth such settlement with the U.S. Department of Justice in the previous ten years. Wikipedia.

Antibody-drug conjugates (ADC) are an attractive approach for the treatment of acute myeloid leukemia and non-Hodgkin lymphomas, which in most cases, are inherently sensitive to cytotoxic agents. CD33 and CD22 are specific markers of myeloid leukemias and B-cell malignancies, respectively. These endocytic receptors are ideal for an ADC strategy because they can effectively carry the cytotoxic payload into the cell. Gemtuzumab ozogamicin (GO, Mylotarg) and inotuzumab ozogamicin consist of a derivative of calicheamicin (a potent DNA-binding cytotoxic antibiotic) linked to a humanized monoclonal IgG4 antibody directed against CD33 or CD22, respectively. Both of these ADCs have a target-mediated pharmacokinetic disposition. GO was the first drug to prove the ADC concept in the clinic, specifically in phase II studies that included substantial proportions of older patients with relapsed acute myeloid leukemia. In contrast, in phase III studies, it has thus far failed to show clinical benefit in first-line treatment in combination with standard chemotherapy. Inotuzumab ozogamicin has shown remarkable clinical activity in relapsed/refractory B-cell non-Hodgkin lymphoma, and it has started phase III evaluation. The safety profile of these ADCs includes reversible myelosuppression (especially neutropenia and thrombocytopenia), elevated hepatic transaminases, and hyperbilirubinemia. There have been postmarketing reports of hepatotoxicity, especially veno-occlusive disease, associated with GO. The incidence is ∼2%, but patients who undergo hematopoietic stem cell transplantation have an increased risk. As we steadily move toward the goal of personalized medicine, these kinds of agents will provide a unique opportunity to treat selected patient subpopulations based on the expression of their specific tumor targets. ©2011 AACR.

Dunn P.J.,Pfizer
Chemical Society Reviews | Year: 2012

Green Chemistry or Sustainable Chemistry is defined by the Environmental Protection Agency as "the design of chemical products that reduce or eliminate the use of hazardous substances" In recent years there is a greater societal expectation that chemists and chemical engineers should produce greener and more sustainable chemical processes and it is likely that this trend will continue to grow over the next few decades. This tutorial review gives information on solvents and solvent selection, basic environmental metrics collection and three industrial case histories. All three case histories involve enzymatic chemistry. Pregabalin (Lyrica®) is produced using a lipase based resolution and is extremely unusual in that all four manufacturing steps to make pregabalin are performed in water. Sitagliptin (Januvia®) uses a transaminase in the final chemical step. Finally a rosuvastatin (Crestor®) intermediate is produced using a deoxy ribose aldolase (DERA) enzyme in which two carbon-carbon bonds and two chiral centres are formed in the same process step. © 2012 The Royal Society of Chemistry.

Scott Obach R.,Pfizer
Pharmacological Reviews | Year: 2013

Metabolism represents the most prevalent mechanism for drug clearance. Many drugs are converted to metabolites that can retain the intrinsic affinity of the parent drug for the pharmacological target. Drug metabolism redox reactions such as heteroatom dealkylations, hydroxylations, heteroatom oxygenations, reductions, and dehydrogenations can yield active metabolites, and in rare cases even conjugation reactions can yield an active metabolite. To understand the contribution of an active metabolite to efficacy relative to the contribution of the parent drug, the target affinity, functional activity, plasma protein binding, membrane permeability, and pharmacokinetics of the active metabolite and parent drug must be known. Underlying pharmacokinetic principles and clearance concepts are used to describe the dispositional behavior of metabolites in vivo. A method to rapidly identify active metabolites in drug research is described. Finally, over 100 examples of drugs with active metabolites are discussed with regard to the importance of the metabolite(s) in efficacy and safety. © 2013 by The American Society for Pharmacology and Experimental Therapeutics.

Kalgutkar A.S.,Pfizer
Annual Review of Pharmacology and Toxicology | Year: 2015

Because of the inability to predict and quantify the risk of idiosyncratic adverse drug reactions (IADRs) and because reactive metabolites (RMs) are thought to be responsible for the pathogenesis of some IADRs, the potential for RM formation within new chemical entities is routinely examined with the ultimate goal of eliminating or reducing the liability through iterative design. Likewise, avoidance of structural alerts is almost a standard practice in drug design. However, the perceived safety concerns associated with the use of structural alerts and/or RM screening tools as standalone predictors of toxicity risks may be overexaggerated. Numerous marketed drugs form RMs but do not cause idiosyncratic toxicity. In this review article, we present a critique of the structural alert/RM concept as applied in drug discovery and evaluate the evidence linking structural alerts and RMs to observed toxic effects. Pragmatic risk mitigation strategies to aid the advancement of drug candidates that carry a RM liability are also discussed. ©2015 by Annual Reviews. All rights reserved.

Lovering F.,Pfizer
MedChemComm | Year: 2013

Toxicity plays a major role in attrition in the clinic and promiscuity has been linked to toxicity. A number of molecular descriptors have been identified that contribute to promiscuity including ionization and logP. In this study we report on the relationship between complexity, as measured by two descriptors [fraction sp3 (Fsp3) where Fsp3 = (number of sp3 hybridized carbons/total carbon count) and chiral carbon count], and promiscuity as well as Cyp450 inhibition. We find that increasing complexity reduces promiscuity and Cyp450 inhibition. As an understanding of key property descriptors has helped the pharmaceutical industry to address some of the deficiencies of compounds as pertains to bioavailability, awareness of the descriptors that impact promiscuity should allow us to better address toxicity in the clinic. © 2013 The Royal Society of Chemistry.

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