The provision of novel compounds for the healthcare industry via the Newcastle University based company NewChem
Submitting Institution
Newcastle UniversityUnit of Assessment
ChemistrySummary Impact Type
TechnologicalResearch Subject Area(s)
Chemical Sciences: Organic Chemistry
Summary of the impact
Newcastle research is the driving force behind NewChem, a Newcastle
University spin-out company which provides creative molecular design and
synthetic/analytical services for the pharmaceutical/chemical industry.
During 2008-2013, NewChem assisted Shire, a global pharmaceutical company,
in the quest for new drugs for treating a range of therapeutic
indications, including pain, cardiovascular disorders, ADHD and
Alzheimer's disease. Since 2008, NewChem has provided employment for >
60 FTE's and achieved sales exceeding £1 million per annum.
Underpinning research
The application of synthesis to the solution of problems in biology and
medicine has been the central tenet of Newcastle University research led
by Professor Golding (1983 to date — Professor of Organic
Chemistry) in the period 1993-present as exemplified by over 160
research papers. Post-1993, a portfolio of powerful synthetic
methodologies applicable to a range of therapeutic targets were developed
[P1 - P4]. This work included the accumulation of expertise in
selective isotopic labelling [P1], which was subsequently applied
to the synthesis of specifically labelled drug metabolites. Studies of
some of the most challenging problems in mechanistic enzymology [P1]
underpinned key innovations in drug design, most notably leading to the
development of the anticancer agent Rucaparib. These fundamental studies
created a unique research environment from which emerged seminal
discoveries relevant to the treatment of some of the most challenging
medical conditions including cancers, cardiovascular diseases, dementias,
attention deficit hyperactivity disorder (ADHD) and infections arising
from Clostridium difficile. This invaluable experience derived
from wide-ranging research achievements led to the creation of prodrugs
that are structurally fine-tuned to release their parent drug under either
chemical or enzymatic conditions.
Examples of Newcastle research in the context of drug development are:
- Knowledge derived from research requiring selective isotopic labelling
[P1] applied to the synthesis of labelled drugs for metabolism
studies.
- Fundamental research on the anagrelide metabolite 3-hydroxyanagrelide
leading to new anagrelide analogues (e.g. 3,3-dimethylanagrelide,
`Rafingrelide') resistant to metabolism [P2] One critical aspect
of this research was the application of X-ray crystallography at
Newcastle to the identification of a previously unrecognised isomer of
3-hydroxyanagrelide.
- Extensive experience of the synthesis of prodrugs [P3] enabling
an array of new prodrugs to be developed.
- Wide ranging nucleoside and nucleotide research [P4]
underpinning the synthesis of complex nucleotides for medical detection
devices.
- Diverse heterocyclic chemistry exemplified in > 50 research papers
since 1993 [e.g. P5, P6].
Key Researchers
Daniele Ciceri (2000 to 2001 — Research Associate)
Julian S Northen (2000 to 2001 — Research Associate)
Dr Tony Munter (1998 to 2000 — Research Associate)
Alex W White (1998 to 2000 — Research Associate)
References to the research
(Newcastle personnel are italicised)
[P1] *A J Pierik, D Ciceri, G Bröker, C H Edwards, W
McFarlane, J Winter, W Buckel, and B T Golding, Rotation of
the exo-methylene Group of (R)-3-methylitaconate catalyzed
by coenzyme B12-dependent 2-methyleneglutarate mutase from Eubacterium
barkeri, Journal of the American Chemical Society, 2002, 124,
14039-14048 (DOI: 10.1021/ja020340f).Detailed study of the mechanism of
a coenzyme B12-dependent enzyme. Shows the
value of selective isotopic labelling for uncovering complex enzyme
mechanisms.
[P2]*R B Scott, K M Downey, K P Healy, A P Henderson, C L
Robinson, W Clegg, R W Harrington, R Franklin, B T Golding,
Synthesis and stability of 3-hydroxyanagrelide, a biologically potent
metabolite of anagrelide, Heterocycles, 2012, 86, 1637-1646 (DOI:
10.3987/COM-12-S(N)115 ). First synthesis of 3-hydroxyanagrelide, the
key metabolite of anagrelide, and a study of its stability in pH 7.4
buffer. Research that laid the groundwork for the subsequent discovery
of Rafingrelide.
[P3] K Saravanan, H C Barlow, M Barton, A H Calvert, B T
Golding, D R Newell, J S Northen, N J Curtin, H D Thomas, R J Griffin,
Nucleoside transport inhibitors: structure-activity relationships for
pyrimido [5,4-d]pyrimidine derivatives that potentiate pemetrexed
cytotoxicity in the presence of f0611-acid glycoprotein, Journal of
Medicinal Chemistry, 2011, 54, 1847-1859 (DOI: 10.1021/jm101493z).
[P4] *Munter,T; Cottrell, L; Hill, S; Kronber, L;
Watson, WP; Golding, BT, Identification of adducts derived from
reactions of (1-chloroethenyl)oxirane with nucleosides and calf thymus
DNA, Chemical Research in Toxicology, 2002, 15, 1549-1560 (DOI:
10.1021/tx020070e).Research that unravelled the complex adduct
chemistry arising from the reactions of a chloroprene epoxide with
2¢-deoxyguanosine, 2¢-deoxyadenosine, 2¢-deoxycytidine, thymidine and
calf thymus DNA. First comprehensive study relevant to chloroprene
mutagenesis and has been much cited in subsequent work on chloroprene.
[P5] A W White, R Almassy, A H Calvert, N J Curtin, R J
Griffin, Z Hostomsky, K Maegley, D R Newell, S Srinivasan,
and B T Golding, Synthesis and biological properties of
benzimidazole inhibitors of the DNA repair enzyme
poly(ADP-ribose)polymerase (PARP), Journal of Medicinal Chemistry,
2000, 43, 4084-4097 (DOI: 10.1021/jm000950v).
[P6] J S Northen, F T Boyle, W Clegg, N J Curtin, A J
Edwards, R J Griffin, and B T Golding, Controlled stepwise
conversion of 2,4,6,8-tetrachloropyrimido[5,4-d]pyrimidine into
2,4,6,8-tetrasubstituted pyrimido[5,4-d]pyrimidines', Journal
of the Chemical Society Perkin Transactions 1, 2002, 108-115 (DOI:
10.1039/b102224p).
* = 3 papers that best indicate the quality of the
research
Selected grants
CEFIC-LRI: 2000 - 2003 "Molecular toxicology of industrially important
dienes and the relevance for human cancer". Awarded: £95,538
Commission of the European Communities: 2002 - 2005 "Reactions with
Cobalamins and their mimics: mechanisms, synthetic applications and
relevance to human health". Awarded: £146,923
Newchem Technologies
Limited: 2003 "Development of Processes for the Preparation of Pure
BCH24426 and its Isomer BCH29732" Awarded: £12,842
Details of the impact
The Newcastle University spin-out company NewChem Technologies, which was
founded in 2002, is primarily a drug development company working in
association with industrial partners. The company is the route by which
the academic research of Golding and his group is commercialised. In 2008,
as the result of steady growth, NewChem invested in new laboratories
within the School of Chemistry which are adjacent to Golding's research
group, thus enabling continuous and fruitful exchange of information and
expertise. In the period 2008-2013, NewChem has provided employment for
high quality chemists (>60 FTE) and has achieved annual sales of
greater than £1 million, thus making a significant contribution to
employment in the North East region [E1].
The impacts of Newcastle University research through the vehicle of
NewChem include contributions to the science of the drug anagrelide
(Xagrid), a core product of Shire, as well as development of prodrugs of
several therapeutic agents [e.g. galanthamine (Alzheimer's disease) ,
guanfacine (ADHD), meptazinol and oxycodone (pain) [E2, E3].
NewChem developed several customised release mechanisms for prodrugs that
aimed to resolve disadvantageous drug properties, e.g. poor intestinal
absorption, poor bioavailability due to extensive 1st pass
metabolism, high abuse potential, local GI toxicity, colonic delivery etc.
According to the Former Head of New Product Discovery (Small molecules) at
Shire: "The positive impact of that relationship [NewChem and
Shire] on the research output of Shire cannot be overstated and
singularly contributed to the development of over 40 patents on
potential new drug products" [E3].
Anagrelide (Xagrid or Agrylin®) which is used to treat the
myeloproliferative disorder called essential thrombocythemia (ET) has
annual peak sales of $97 million [E4]. Individuals with raised
platelet counts have a higher risk of adverse thrombotic and haemorrhagic
events. Previous investigations identified a metabolite
3-hydroxyanagrelide, derived from oxidation of anagrelide. Whilst
anagrelide and 3-hydroxyanagrelide are similarly potent against ET, the
metabolite is nearly 40-fold more potent against
phosphodiesterase-III (PDE-III), which causes severe cardiovascular
side-effects. Based on prior Newcastle research a synthetic route to
3-hydroxyanagrelide was devised [P2] which made this biologically
potent molecule reliably available for the first time and enabled a full
determination of its pharmacological profile. An analogue of anagrelide
was developed (3,3-dimethylanagrelide, `Rafingrelide') [E4], which
retains potency against ET, but has much reduced activity against PDE-III.
This compound "has completed phase 2 clinical testing...current
estimates of its market potential in the anti-thrombotic market exceed
$500 million" [E3 Former Head of New Product Discovery (Small
molecules) at Shire]. Phase 2 clinical trials represent an average of
$19,300 per patient investment into the drug [E6].
During 2008-2012, a major contribution has been made to the Shire drug
guanfacine which is used to treat attention deficit hyperactivity disorder
(ADHD) [E1]. Children with ADHD are deficient in normal social
skills and lack the ability to focus on tasks. Current sales for the
established ADHD drug Vyvanse approach $1030 million per annum [E4].
The alternative ADHD drug guanfacine has been converted into a novel
carbamate prodrug. Shire recently invested substantial effort via NewChem
in research for new prodrugs for alleviating pain. This has resulted in
the development of carbamate prodrugs of meptazinol and oxycodone, which
were produced by the synthetic methodologies analogous to those described
[P3]. NewChem studies for Shire have also created novel prodrugs of
the anti-Alzheimer drug galanthamine [E2]. Shire has requested that
the details of these prodrugs be kept confidential but we can disclose "that
three compounds (not to be named) that...[NewChem researchers] worked on
were nominated for IND [Investigational New Drug] studies (2009-2012)
and two of these went into man [phase 1 trials in humans]" [E5,
Senior Director Exploratory Projects, Shire]. Phase 1 trials represent on
average an investment per patient of $15700 (USD) [E6].
During 2012/2013 NewChem has provided invaluable assistance to two SMEs.
This assistance included the synthesis of key intermediates and products
that could not be sourced elsewhere. A key step in the synthesis of
complex nucleotides for the company QuantuMDX was accomplished based on
Golding's knowledge of protecting group chemistry arising from his
Newcastle research on nucleosides and nucleotides [P3]. QuantuMDx
have "...secured £1.4 million from the Technology Strategy Board
`biomedical catalyst fund' for developing a handheld device for rapid
tumour profiling...and ... a £3.5 million EU FP7 grant for
developing a handheld diagnostic test for Malaria..." [E7,
Chief Operating Officer, QuantuMDx Group Limited]. In another notable
achievement, Golding's Newcastle research has also assisted the company
Glythera in the synthesis of heterocyclic derivatives that are the basis
of therapeutic applications. "Based on the success of these studies
Glythera has...secured its second tranche of funding of £700,000 from its
investors" [E8, Chief Operating Officer, Glythera Ltd.].
In all of
the projects described above prior Newcastle research on prodrugs,
protecting groups, heterocyclic chemistry, nucleosides and reaction
mechanisms was critical to success.
Sources to corroborate the impact
[E1] Corroborating contact: Newchem Managing Director
[E2] Patents (searched and accessed on http://worldwide.espacenet.com/searchResults?compact=false&ST=singleline&query=Golding%2C+Bernard&locale=en_EP&DB=worldwide.espacenet.com)
[E3] Testimonial from the Former Head of New Product Discovery
(Small molecules) at Shire
[E4] Shire annual report 2012
[E5] Email from the Senior Director Exploratory Projects, Shire
[E6] Pellegrino, J. & Smith, R. 2009. Predictive Modeling in
Clinical Trial Enrollment. Acurian, Horsham, Pennsylvania, USA.
www.acurian.com
[E7] Testimonial from the Chief Operating Officer, QuantuMDx Group
Ltd.
[E8] Testimonial from the Chief Operating Officer, Glythera Ltd.