作者: Gadwood, Robert ; Chinigo, Gary ; Lafuente, Maria José ; Gamo, Francisco Javier ; Clark, Robert D ; Ferrer, Santiago ; Le Roch, Karine G ; Lawless, Michael S ; Prudhomme, Jacques ; Woltosz, Walter S ; Morris, Denise N

Abstract:

There is a pressing need to improve the efficiency of drug development, and nowhere is that need more clear than in the case of neglected diseases like malaria. The peculiarities of pyrimidine metabolism in Plasmodium species make inhibition of dihydroorotate dehydrogenase (DHODH) an attractive target for antimalarial drug design. By applying a pair of complementary quantitative structure–activity relationships derived for inhibition of a truncated, soluble form of the enzyme from Plasmodium falciparum (s-PfDHODH) to data from a large-scale phenotypic screen against cultured parasites, we were able to identify a class of antimalarial leads that inhibit the enzyme and abolish parasite growth in blood culture. Novel analogs extending that class were designed and synthesized with a goal of improving potency as well as the general pharmacokinetic and toxicological profiles. Their synthesis also represented an opportunity to prospectively validate our in silico property predictions. The seven analogs synthesized exhibited physicochemical properties in good agreement with prediction, and five of them were more active against P. falciparum growing in blood culture than any of the compounds in the published lead series. The particular analogs prepared did not inhibit s-PfDHODH in vitro, but advanced biological assays indicated that other examples from the class did inhibit intact PfDHODH bound to the mitochondrial membrane. The new analogs, however, killed the parasites by acting through some other, unidentified mechanism 24–48 h before PfDHODH inhibition would be expected to do so.

2015-09-01·Antimicrobial agents and chemotherapy2区 · 医学

Novel Riboswitch-Binding Flavin Analog That Protects Mice against Clostridium difficile Infection without Inhibiting Cecal Flora

2区 · 医学

Article

作者: Blount, Kenneth F. ; Poel, Toni J. ; Plummer, Mark ; Schostarez, Heinrich J. ; Walker, Daniel P. ; O'Connell, Tim ; Wuts, Peter G. M. ; Chrusciel, R. Alan ; Aristoff, Paul ; Breaker, Ronald R. ; Megyola, Cynthia ; Stewart, Catherine A. ; Osterman, David ; Quinn, Cheryl

ABSTRACT:

Novel mechanisms of action and new chemical scaffolds are needed to rejuvenate antibacterial drug discovery, and riboswitch regulators of bacterial gene expression are a promising class of targets for the discovery of new leads. Herein, we report the characterization of 5-(3-(4-fluorophenyl)butyl)-7,8-dimethylpyrido[3,4-b]quinoxaline-1,3(2H,5H)-dione (5FDQD)—an analog of riboflavin that was designed to bind riboswitches that naturally recognize the essential coenzyme flavin mononucleotide (FMN) and regulate FMN and riboflavin homeostasis. In vitro , 5FDQD and FMN bind to and trigger the function of an FMN riboswitch with equipotent activity. MIC and time-kill studies demonstrated that 5FDQD has potent and rapidly bactericidal activity against Clostridium difficile . In C57BL/6 mice, 5FDQD completely prevented the onset of lethal antibiotic-induced C. difficile infection (CDI). Against a panel of bacteria representative of healthy bowel flora, the antibacterial selectivity of 5FDQD was superior to currently marketed CDI therapeutics, with very little activity against representative strains from the Bacteroides , Lactobacillus , Bifidobacterium , Actinomyces , and Prevotella genera. Accordingly, a single oral dose of 5FDQD caused less alteration of culturable cecal flora in mice than the comparators. Collectively, these data suggest that 5FDQD or closely related analogs could potentially provide a high rate of CDI cure with a low likelihood of infection recurrence. Future studies will seek to assess the role of FMN riboswitch binding to the mechanism of 5FDQD antibacterial action. In aggregate, our results indicate that riboswitch-binding antibacterial compounds can be discovered and optimized to exhibit activity profiles that merit preclinical and clinical development as potential antibacterial therapeutic agents.

2015-03-24·Proceedings of the National Academy of Sciences of the United States of America1区 · 综合性期刊

Differentiation of antiinflammatory and antitumorigenic properties of stabilized enantiomers of thalidomide analogs

1区 · 综合性期刊

Article

作者: Judge, Thomas M. ; DeWitt, Sheila H. ; Van der Ploeg, Lex H. T. ; Czarnik, Anthony W. ; Jacques, Vincent

Therapeutics developed and sold as racemates can exhibit a limited therapeutic index because of side effects resulting from the undesired enantiomer (distomer) and/or its metabolites, which at times, forces researchers to abandon valuable scaffolds. Therefore, most chiral drugs are developed as single enantiomers. Unfortunately, the development of some chirally pure drug molecules is hampered by rapid in vivo racemization. The class of compounds known as immunomodulatory drugs derived from thalidomide is developed and sold as racemates because of racemization at the chiral center of the 3-aminoglutarimide moiety. Herein, we show that replacement of the exchangeable hydrogen at the chiral center with deuterium allows the stabilization and testing of individual enantiomers for two thalidomide analogs, including CC-122, a compound currently in human clinical trials for hematological cancers and solid tumors. Using "deuterium-enabled chiral switching" (DECS), in vitro antiinflammatory differences of up to 20-fold are observed between the deuterium-stabilized enantiomers. In vivo, the exposure is dramatically increased for each enantiomer while they retain similar pharmacokinetics. Furthermore, the single deuterated enantiomers related to CC-122 exhibit profoundly different in vivo responses in an NCI-H929 myeloma xenograft model. The (-)-deuterated enantiomer is antitumorigenic, whereas the (+)-deuterated enantiomer has little to no effect on tumor growth. The ability to stabilize and differentiate enantiomers by DECS opens up a vast window of opportunity to characterize the class effects of thalidomide analogs and improve on the therapeutic promise of other racemic compounds, including the development of safer therapeutics and the discovery of new mechanisms and clinical applications for existing therapeutics.

项与 Dipharma Francis Srl 相关的新闻（医药）

2024-05-07

·BioSpace

Successful FDA Inspection at Dipharma Facility in Kalamazoo, MI, USAThe Company expands its range of CGMP services to include small-scale commercial APIs

MILAN, Italy, May 07, 2024 (GLOBE NEWSWIRE) -- Dipharma Francis S.r.l. (Dipharma), a global Contract Development and Manufacturing Organization (CDMO) and leading manufacturer of New Chemical Entities (NCE), Generic Active Pharmaceutical Ingredients and Advanced Intermediates, proudly announced that Dipharma Inc., its US facility located in Kalamazoo, MI, has been inspected by the U.S. Food and Drug Administration (FDA) and has received the Establishment Inspection Report (EIR), satisfactorily closing the inspection process. The rigorous inspection took place in the second week of January this year. At the closing meeting the inspectors congratulated the Dipharma team members on the Current Good Manufacturing Practices (CGMP) Systems they created and their overall commitment to quality. Since 1970, Dipharma Group has achieved an unbroken positive record of inspections by the major international Regulatory Agencies, and this new achievement demonstrates the Company’s extensive experience in ensuring compliance with the highest global quality standards. With this accomplishment, Dipharma Inc. expands the range of services offered to its international clients to include commercial deliveries. Furthermore, it enhances the vertical integration of all Dipharma’s CGMP manufacturing processes, in all four facilities, from preclinical to commercial scale. "The successful closure of the FDA's Pre-Approval Inspection (PAI) marks a significant achievement for our US facility, Dipharma Inc.Congratulations to the whole team for this great accomplishment," stated Jorge Nogueira, Chief Executive Officer of Dipharma Francis. "This inspection, the first conducted by the FDA at our US facility, underscores the Dipharma Group's unwavering commitment to continuously improve our GMP Systems and uphold the highest quality standards. It reflects our dedication to ensuring that our products meet stringent quality benchmarks for patients worldwide." Dipharma Inc.’s Kalamazoo facility provides world-class CDMO services and API supplies for the Group’s pre-clinical and clinical customers. The facility has undergone significant expansion in recent years with the aim of supporting and growing its services to meet the growing demands of the U.S. market. Staffed by highly skilled employees, Dipharma Inc. is equipped with a world-class R&D laboratory and a state-of-the-art CGMP facility including a Kilolab with dedicated QC laboratory and warehouses. The latest significant investment, in 2023, added a second cutting-edge CGMP line, capable of running larger-scale reactions in the Kilolab in reactors of up to 105 L volume. With this investment, Dipharma Inc. more than triples its capacity to process projects for customers, both in the generics and CDMO arena, while enhancing operational safety and isolation technologies. About the Dipharma Francis group With revenues of €160 million, the Dipharma Group is a global CDMO and a leading manufacturer of APIs and Intermediates, with about 600 skilled and highly committed employees, 4 cGMP plants, located in the U.S.A. and Italy, plus sales offices in Italy, the U.S.A. and China. The fully equipped R&D Centers develop innovative chemical processes and crystalline forms for the most prominent pharmaceutical companies worldwide. As a third-generation family-owned company, Dipharma has a long history of stability, commitment, and financial solidity. Dipharma has the right size and variety of scale-up capabilities to act as a global player and manage processes efficiently, while offering flexibility and agility to promptly solve any challenge. Experience you can trust. For more information: Paola Clerici Communication Manager Dipharma Francis S.r.l. paola.clerici@dipharma.com A photo accompanying this announcement is available at Dipharma's researcher checking process parameters at the new cutting-edge CGMP Kilolab line Researcher checking process parameters at the new cutting-edge CGMP Kilolab line, located at Dipharma Inc., in Kalamazoo MI, USA

2023-02-23

·Endpoints

Manufacturing roundup: Eli Lilly’s Mounjaro is moving past a shortage — report; Merck sells New Jersey facility

Eli Lilly’s diabetes drug Mounjaro now seems to be available once more. According to a report from Bloomberg, the pharma giant now has doses available and is shipping them “on an ongoing basis.” However, Bloomberg’s report does state that Eli Lilly is warning that due to demand, some pharmacies may still experience shipping delays. According to the FDA’s database on drug shortages, all dosage forms of Mounjaro are presently listed as being available. The FDA stated on its database that the reason for the shortage was the demand. Toward the end of last year, the US regulator had listed tirzepatide injections as being in shortage. A report from SVB securities last year also stated that Lilly plans to double its manufacturing capacity for the drug. Merck is selling one of its old locations in the Garden State. The pharma announced that it reached an agreement with Onyx Equities, LLC to sell its 108-acre campus in Kenilworth, NJ. Merck plans to vacate the property over the next several years while its new headquarters down in Rahway will be finishing an expansion. However, no details have been given on what the site will be. According to Merck’s website, the facility is one of Merck’s main R&D centers . “We believe Onyx Equities, LLC will foster long-term value, economic growth and sustainability within the community. We look forward to collaborating with Onyx Equities, LLC and their team members on a smooth transition,” said Shefali Shah, the global real estate lead at Merck, in a release . The Italian CDMO Dipharma has finished the second phase of expansion at its facility in Kalamazoo, MI. The expansion will add more manufacturing space along with a quality control lab and warehouse space. In an email to Endpoints News, Dipharma CEO Brian Eklov said the expansion is part of a recent investment to enlarge Dipharma’s offerings in Kalamazoo and “increase proximity” to its customers in the US. Dipharma first entered the US market in 2012 and acquired a Kalamazoo-based CRO, Kalexsyn, in 2018. Eklov also detailed to Endpoints that the second phase added 2000 square feet and that the total capital investment into the Kalamazoo site is north of $6 million for all expansion projects. PackGene, a contract research and manufacturing company in the AAV vector business, has broken ground on a new biomanufacturing facility in Houston. The 25,000-square-foot facility will be located outside of downtown Houston and will include laboratories, manufacturing space, a warehouse and offices. The expansion is planned to be finished by the end of the year and will have around 60 employees. The cost of the facility was not immediately available. “These capabilities will enable us to serve our U.S. customers better and, importantly, to help bring life-saving therapies to patients faster, more reliably, and more cost-effectively. With this, we are making great strides in advancing our mission of ‘making gene therapy affordable,” said PackGene CTO LiYing Yang in a release . Canadian contract manufacturer Dalton Pharma Services is planning to expand its sterile filling and pharma manufacturing space. In a release, the company said it is boosting its capacity with a new manufacturing line to fill vials, syringes and cartridges. The expansion will allow for more manufacturing room along with the ability to produce more active pharmaceutical ingredients and more storage space. However, the cost of the expansion was not disclosed “This major investment in the expansion of our sterile manufacturing capabilities enables us to meet the needs of our customers as their critical products advance to commercialization. It also represents a leap forward in both scale and technology for us, placing Dalton at the leading edge of sterile manufacturing capabilities,” said Peter Pekos, CEO of Dalton Pharma Services in a release . The life science consultancy company USP/Pharmatech is allying to offer its expertise and capabilities to drug makers who are looking to switch to continuous manufacturing. According to a release, Pharmatech Associates, along with Integra Contiguous Manufacturing Systems, will aim to provide training, compliance and regulatory needs for any company that is looking to switch from batch to pharmaceutical continuous manufacturing (PCM). “Given our expertise and experience with PCM, the alliance of USP, Pharmatech, and Integra will bridge the knowledge gap and lower the perceived barriers to adoption and implementation to allow drug sponsors and manufacturers to realize the benefits of PCM,” said Bikash Chatterjee, Pharmatech Associates CEO, in a release . However, details on the full range of offerings or any financial details on the offering were not immediately available. CDMO GenScript ProBio will be producing plasmid DNA for the biotech RVAC Medicines, and its Covid-19 vaccine candidate dubbed RVM-V001. The release stated that the partnership extends to other therapeutics in its pipeline, including an RSV and CDI candidate. The CDMO will also offer consultation services surrounding quality and regulatory issues. However, the financial details or the amount of plasmid that GenScript is manufacturing was not disclosed. “This collaboration will enable us to utilize our cutting-edge GMP plasmid manufacturing platform technology to support the development of mRNA-based Covid-19 vaccine and its therapeutic candidates,” said GenScript CEO Brian Min, in a release . The North Carolina-based CDMO Alcami has named Katie Schlipp as president of its laboratory operations. According to the release, Schlipp has over 25 years of experience heading up lab teams. She started with AAIPharma, which is now Alcami, as an assistant scientist at its location in Wilmington, NC, and has risen through the ranks since then. As president, she will be heading up Alcami’s lab network which is spread across four locations. “Katie’s proven track record of leading client-focused laboratory operations makes her the ideal choice to lead Alcami’s next phase of laboratory operations growth and expansion,” said Alcami CEO Patrick Walsh, in a release .

疫苗

2023-02-10

·GlobeNewswire-Health Care

Dipharma completes second phase of CGMP expansion at its Kalamazoo site

The Company continues to strengthen its capabilities in the North American marketMILAN, Italy, Feb. 10, 2023 (GLOBE NEWSWIRE) -- Dipharma Francis S.r.l. (Dipharma), a global CDMO and leading manufacturer of Active Pharmaceutical Ingredients and advanced Intermediates, announced today the completion of the second phase of expansion of its American site, Dipharma Inc., located in Kalamazoo, MI. (US). The new investment provides additional CGMP, Quality Control laboratory and warehouse spaces, increasing the capability of the American site to support and expand its CDMO services. The state-of-the-art QC laboratory is designed and equipped according to the latest pharmaceutical quality standards, with full 21CFR Part 11 compliance for Electronic Data Integrity, and the new warehouses are fully-climate controlled and allow enhanced material storage with increased material segregation. This expansion follows the 2020 opening of the dedicated CGMP Kilolab and QC laboratory. The third phase of the project is ongoing and will expand the current Kilolab by adding a second CGMP line. The new line will be capable of running larger-scale reactions, up to 85 L while also expanding our cryogenic reaction and solid isolation capabilities. The third phase is expected to be completed by the 2nd quarter of 2023. “Expanding and upgrading our US operations enhances Dipharma’s CDMO portfolio, allowing us to offer a wider and more customized set of solutions designed to meet the most stringent customer requirements," said Jorge Nogueira, Chief Executive Officer of Dipharma Francis S.r.l. "These activities compliment strategic investments underway at our Italian facilities, including doubling our pilot plant capacity and others with the aim to further strengthen Dipharma’s capacity and support the growing demand from our worldwide partners at all phases of development.” About the Dipharma Francis group With revenues over €137 million, the Dipharma Group is a global CDMO and a leading manufacturer of APIs and advanced Intermediates for Generic and Contract Manufacturing markets, with more than 500 skilled and highly committed employees and 4 CGMP plants, located in the U.S.A. and Italy. The fully equipped R&D Centers develop innovative chemical processes and crystalline forms for the most prominent pharmaceutical companies worldwide. As a third-generation family-owned company, Dipharma has a long history of stability, commitment, and financial solidity. Since 1970, Dipharma has managed to achieve a positive unbroken record of inspections by the main Regulatory Agencies and its CGMP manufacturing sites are equipped to supply quantities from laboratory to industrial scale. Dipharma has the right size and variety of scale-up capabilities to act as a global player and manage processes efficiently, while offering flexibility and agility to promptly solve any challenge. Experience you can trust. For more information: Paola Clerici Communication ManagerDipharma Francis S.r.l.paola.clerici@dipharma.comwww.dipharma.com A photo accompanying this announcement is available at https://www.globenewswire.com/NewsRoom/AttachmentNg/d9d0b11a-f917-43b5-9a42-0647fdce7e72 https://www.globenewswire.com/NewsRoom/AttachmentNg/1856e4d9-72ce-4437-83ed-85ce5b775a53 https://www.globenewswire.com/NewsRoom/AttachmentNg/897d51c8-558e-47d3-9dd6-8bd8c161c95d https://www.globenewswire.com/NewsRoom/AttachmentNg/f7e6176c-453a-4324-8d2a-0d83a581ad33

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