Free Samples
BIOTECH7001 Drug Design And Development
.cms-body-content table{width:100%!important;} #subhidecontent{ position: relative;
overflow-x: auto;
width: 100%;}
BIOTECH7001 Drug Design And Development
0 Download9 Pages / 2,122 Words
Course Code: BIOTECH 7001
University: The University Of Adelaide
MyAssignmentHelp.com is not sponsored or endorsed by this college or university
Country: Australia
Question
Task:
Each student will be assigned a journal article from the available list. Each student must select a different paper. Using this article as the basis for your research, discuss the significance of the findings and their potential to address the target disease. You will specifically need to;
Explain what stage within the drug development pathway the published work
Describe any progress that has been made in the project area since publication.
Propose the next steps (or experimental results) that would be required to take the project to the next major milestone in the drug development pathway.
Answer
Introduction
The drug PF-4693627 has been under research as one of the next potential safe, potent and more bioavailable anti-inflammatory agent, with a mechanism of action different from the current textbook anti-inflammatory agents. This report presents the details of its development and assesses whether it’s up to the task or not. Current anti-inflammatory agents such as Nonsteroidal anti-inflammatory agents (NSAIDS) and corticosteroids have been used for this purpose for some time now. However, they pose many side effects. Corticosteroids have undesirable immunosuppressive side effects making patients susceptible to other opportunistic diseases. They can also cause osteoporosis, a bone disease. NSAIDs cause gastrointestinal disturbances, and more specifically, predispose to formation of ulcers and liver parenchymal destruction. The two classes of agents listed above inhibit inflammation by inhibiting the cyclooxygenase enzymes and phospholipase enzymes respectively. This displays an urgent need for a better and safer drug for inflammation.
The agents above pose the side effects because of blocking enzymes higher in the inflammatory pathway inhibiting the formation of compounds that are also required for normal body functions. For example, NSAIDs inhibit the formation of several prostaglandins, which are required for the production of substances such as Mucus that protects the stomach wall, leading to a predisposition to ulcers. Microsomal prostaglandin E synthase-1 (mpges-1) inhibitors present better safety compared to existing anti-inflammatory agents. This is because they are more specific, due to inhibition of formation of only one specific prostaglandin E2. Back in 2001, scientists reported the first ever mpges-1 synthetic inhibitor. Since then, many such compounds with different structures have been developed. However, only two inhibitors of this enzyme have gone into clinical trials though none is on the market yet. PF-4693627 is one the two agents.
More studies are being carried out since luckily these agents have anticancer activity too. This essay presents a discussion of the findings from the studies carried out on PF-4693627 and the significance of the same findings in addressing inflammation basing on the article: Arhancet, G. B.; et al. Bioorg. Med. Chem. Lett. (2012). An explanation of the stage of drug development the drug PF-4693627 had reached the time article was written is discussed. The progress that has been made with the drug since the publication and a proposition of the next steps or experimental results that are required to take the drug to the next stage of the drug development pathways are presented.
Method
In the article: Arhancet, G. B.; et al. Bioorg. Med. Chem. Lett. (2012), an array of benzoxazoles as inhibitors of microsomal prostaglandin E synthase 1 with excellent selectivity and potency, with unparalleled bioavailability are discussed. The benzoxazole chain has been cited in several patent literatures as being able to yield potent compounds with activity against a class of enzymes, which includes the mpges-1. Prostaglandin E2 is a vital mediator if inflammation, both acute and chronic. It also mediates fever and pain. It’s found among other places, the synovial fluid in patients with osteoarthritis and rheumatoid arthritis. Breakdown of prostaglandin E2 is initiated by breakdown of arachidonic acid by phospholipase A2 from membrane phospholipids. This is then converted to prostaglandin H2 by enzyme cyclooxygenase and by prostaglandin E synthase to prostaglandin E2.
There are three forms of prostaglandin E synthases (PGES): Microsomal pges-1, cytosolic pges, and microsomal pges-2. Both cytosolic pges and microsomal pges-2 are expressed constitutively expressed in many tissues hence their blockage would lead to a number of side effects depending on the tissues affected. Microsomal pges-1, referred in this report as mpges-1 is only upregulated during inflammation. Selective inhibition of this enzyme would, therefore, lead to inhibition of prostaglandin E2 production only under inflammatory conditions while sparing other constitutive mediators such as prostacyclin and thromboxane.
Initially, literature had described a series of selective and more potent mpges-1 inhibitors that were represented by 1. 1 was obtained by optimizing yet another compound, FLAP (5-lipoxygenase-activating protein) inhibitor lead. It had moderate human mpges-1 and rat mpges-1 inhibition. However, this couldn’t be reproduced in vivo, hence the shift to the benzoxazole scaffolds. In the article, the most potent inhibitors of mpges-1 were compounds designated by numbers 2 and 3. No efficacy and selectivity were reported in these compounds and were therefore abandoned. A prior study with a benzoxazole (designated by a number 5) done by High Throughput Screening (HTS) revealed modest enzyme assay activity but didn’t have potency the cell-based assay. Five had, at the fifth position, a chlorine atom and any attempts to replace it with methyl or hydrogen were futile and led to inactive analogs.
Other attempts with other electron withdrawing groups such as trifluoromethyl making compound 17 and bromo (13) offered no significant benefit compared to the chloro analog designated as 12. When the chloro substituent was replaced with smaller, polar substitutes, for example, cyano forming compound 14, ethanesulfonyl-forming compound 15 or formation of compound 16 by substituting with carboxamide caused a right-shift in the mpges-1 inhibitory activity. Generally, experiments with the benzoxazole analogs were done by careful modification or substitution of the most active portion of the right hand of the first compound that was designated as five by High Throughput Screening. This led to the production of compound 12. Aryl and fluoroalkyl compounds were introduced at the C6 position on the benzoxazole ring. This led to compounds 23, 26 and 29 being discovered.
A myriad of other compounds were found by these modifications, tested via the guinea pig carrageenan stimulated air pouch as a model of inflammation. This model was chosen because up to date; there is no single mpges-1 inhibitor that has ever been published in literature as having activity on the rodent enzyme. Therefore, historical inflammatory models used in carrying out preclinical studies of NSAIDs and cyclooxygenase isoenzyme two inhibitors could not be utilized. They were also passed through studies with rats and finally their action determined in human fetal fibroblast cells. These compounds were designated by numbers as will be seen in the results section. Naproxen, a non-steroidal anti-inflammatory drug was used as the check drug or the reference drug to compare the enzyme activity and other features of the compounds such as efficacy, potency, and bioavailability.
Results
The following table shows the results of the pharmacokinetic properties that were obtained with different sample compounds. A 1 mg per kilogram intravenous dose of each compound was injected in Sprague Dawley rats. Bioavailability of the compounds was also determined by administering a 1mg per kilogram per oral dose in the same species of rats. Results for compound 26 (PF-4693627) have been highlighted.
Table 1
Compound
Clearance (ml/min/kg)
Volume of distribution (l/kg)
Half-life (h)
Mean residence time (MRT)
Bioavailability
(%F)
12
17
0.72
0.51
0.7
66
19
82
2.1
0.4
0.44
23
34
14
19.3
7.22
42
24
60
1.4
1.4
0.39
26
12
3.0
3.7
4.42
59
28
28
2.4
1.4
6.26
17
29
14
6.4
6.7
7.78
86
(table from Arhancet, G. B.; et al. Bioorg. Med. Chem. Lett. (2012), Table 3)
Prostaglandin E2 inhibition in the guinea pig carrageenan air pouch model for three compounds was also done and results were compared against Naproxen as shown in the table below.
Table 2
compound
Dose (mg/kg)
Plasma concentration
PGE2 (%) inhibition
Naproxen
10
153.9
60
23
10
1.6
66
26
10
1.2
63
29
10
0.51
52
(table from Arhancet, G. B.; et al. Bioorg. Med. Chem. Lett. (2012), Table 4)
Compound 26, more attractive to produce compared to others, was experimented with different enzymes to assess its selectivity against the respective enzymes and the results were as below.
Table 3
Compound
Human whole blood-(HWB-1483 ic50 (micrometers)
Fetal fibroblasts ic50
mpges-1
Prostaglandin D synthase
Thromboxane A synthase
5-lipoxygenase
mpges-1
Cyclooxygenase-2 (COX-2)
26
0.18
>50
>50
>50
0.006
>10
(table from Arhancet, G. B.; et al. Bioorg. Med. Chem. Lett. (2012), Table 5)
Discussion
The reference article describes the processes that happened to lead to the discovery of PF-4693627, referred to as compound 26. Many compounds were derived from the benzoxazole ring and tests done before compound 26 was chosen to be pursued. At the time the publication was being made, the compound PF-4693627 was undergoing pre-clinical trials. The published work, therefore, represents the preclinical trial stage of the development of compound 26 (PF-4693627).
Drug development takes various stages before it is fully allowed into the market. According to the Food and Drug Administration (FDA) and Chien, J. Y., Friedrich, S., Heathman, M. A., de Alwis, D. P., & Sinha, V. (2005), there are five stages which include: Discovery and development, Preclinical research, clinical research, Drug review by the organization and lastly, Post-market drug safety monitoring by the organization. The first stage of PF-4693627 was done by a realization that benzoxazole analogs have the enzyme prostaglandin E2 synthase inhibitory properties. Later, development of different analogs from the benzoxazole ring gave a wide variety of compounds were discovered that were recruited to preclinical research. The details of the preclinical research and the methods used are presented in the publication. Before PF-4693627 could be tested in people, it had to undergo the preclinical research to find out any potential toxicities.
From the results presented above in table 1, the in vivo rat pharmacokinetic properties of PF-4693627, represented in the table by compound 26 reveals a very high bioavailability of the drug compared to other compounds and only beaten by compound 29 and 12. The compound has a discouraging short half-life of just 0.51 hours. Compound 26 is beaten by compound 29 regarding volume of distribution and half-life.
However, in table 2, the Guinea Pig carrageenan stimulated air pouch model experiment reveals compound 29 as having the lowest plasma concentration compared to the compounds 23,26 and Naproxen, the comparative drug at the same dose of 10mg per kilogram. This leaves compound 23 as the only competitor to PF-4693627. Compound 23 has the highest inhibitory activity against prostaglandin E2 synthase enzyme compared to the rest. However, compound 26 was chosen to proceed to clinical trials with the potential to become the next novel agent in the management of osteoarthritis and rheumatoid arthritis because of several reasons. The compound is highly selective, has high in vitro potency, good in vivo efficacy, excellent preclinical safety profile and excellent pharmacokinetic properties. It is also preferred to compound 23 and 29 because it is easier and therefore attractive to manufacture. If it goes through the next stage of clinical trials successfully, it may potentially become a relief for patients suffering from osteoarthritis and rheumatoid arthritis due to the cardiovascular and gastrointestinal side effects they experience from prolonged use of NSAIDs.
A lot of progress has been made in this area of microsomal prostaglandin E2 synthase inhibitors. Luz, J. G., Antonysamy, S., Kuklish, S. L., Condon, B., Lee, M. R., Allison, D., … & Russell, M. (2015) describes mpges-1 inhibitor crystal structure complexes as a basis for the design of more potent anti-inflammatory and analgesic therapeutics. Research in this project has expanded further as the same enzyme inhibitors have been discovered to have anti-cancer activities.
To take this project to the next level, that is; to take the drug PF-4693627 to the stage of drug review by the drug administrative organizations such as the Food and drug administration, there are several things it must achieve in the clinical trials which are currently undergoing. In the experiments on patients, the safety, effectiveness, and efficacy of the drug must be established. These are the three test it must pass for it to be reviewed and post-marketing surveillance done. The success rate of clinical trials according to BIO, Amplion and BioMedTracker’s 2006-2015 data is put at about 25% to 30%. PF-4693627 will have to be among the 30% to proceed to the next level. Results from the clinical studies should, therefore, reveal PF-4693627’s greater safety compared to existing anti-inflammatory agents, have better efficacy and be more effective.
The results obtained during the preclinical studies should be reproduced in the clinical trials for PF-4693627 to have any chance of seeing the drug market.
The ability of PF-4693627 to address inflammatory disorders is unquestionable. If it passes the clinical trials, this will be the most selective anti-inflammatory agent the world has ever discovered, only having effects during inflammation and having no effects during the normal body conditions. The drug achieves this by inhibiting only the microsomal form of the prostaglandin E2 synthase enzyme, whose substrate rises only under inflammatory conditions. It spares all the other prostaglandins and leukotrienes blocked by other agents such as corticosteroids and Non-Steroidal Anti-inflammatory agents. PF-4693627 is a perfect replacement for these agents and a dream come true for patients with incurable inflammatory disorders such as osteoarthritis.
PF-4693627, a mpges-1 inhibitor is a potential substitute for current ant-inflammatory agents. Having effectively passed the preclinical trials with greater safety, potency, bioavailability, and efficacy, it’s expected that clinical trials will be successful. It already showed the best safety profiles. Safety is the most significant setback of the current anti-inflammatory drugs with a myriad of side effects ranging from cardiovascular disorders to peptic ulcers. This drug will be a relief for patients who need long-term ant-inflammatory agents such as patients with osteoarthritis. The drug may also turn out to be useful in the treatment of cancer pain and inflammation.
Free Membership to World’s Largest Sample Bank
To View this & another 50000+ free samples. Please put
your valid email id.
Yes, alert me for offers and important updates
Submit
Download Sample Now
Earn back the money you have spent on the downloaded sample by uploading a unique assignment/study material/research material you have. After we assess the authenticity of the uploaded content, you will get 100% money back in your wallet within 7 days.
UploadUnique Document
DocumentUnder Evaluation
Get Moneyinto Your Wallet
Total 9 pages
PAY 6 USD TO DOWNLOAD
*The content must not be available online or in our existing Database to qualify as
unique.
Cite This Work
To export a reference to this article please select a referencing stye below:
APA
MLA
Harvard
OSCOLA
Vancouver
My Assignment Help. (2020). BIOTECH7001 Drug Design And Development. Retrieved from https://myassignmenthelp.com/free-samples/biotech-7001-drug-design-and-development/potential-treatment-of-inflammation.html.
“BIOTECH7001 Drug Design And Development.” My Assignment Help, 2020, https://myassignmenthelp.com/free-samples/biotech-7001-drug-design-and-development/potential-treatment-of-inflammation.html.
My Assignment Help (2020) BIOTECH7001 Drug Design And Development [Online]. Available from: https://myassignmenthelp.com/free-samples/biotech-7001-drug-design-and-development/potential-treatment-of-inflammation.html[Accessed 18 December 2021].
My Assignment Help. ‘BIOTECH7001 Drug Design And Development’ (My Assignment Help, 2020)
My Assignment Help. BIOTECH7001 Drug Design And Development [Internet]. My Assignment Help. 2020 [cited 18 December 2021]. Available from: https://myassignmenthelp.com/free-samples/biotech-7001-drug-design-and-development/potential-treatment-of-inflammation.html.
×
.close{position: absolute;right: 5px;z-index: 999;opacity: 1;color: #ff8b00;}
×
Thank you for your interest
The respective sample has been mail to your register email id
×
CONGRATS!
$20 Credited
successfully in your wallet.
* $5 to be used on order value more than $50. Valid for
only 1
month.
Account created successfully!
We have sent login details on your registered email.
User:
Password:
MyAssignmenthelp.com is a comprehensive solution for all assignment related woes. Expert writers, working with this portal, render tailor-made science assignment help in Canada. Not only chemistry assignment help and biology assignment help, but also capital budgeting assignment help is provided here. Subject matter experts at MyAssignmenthelp.com render assistance on 100+ subjects.
Latest Healthcare Samples
div#loaddata .card img {max-width: 100%;
}
5N1794 Safety And Health At Work
Download :
0 | Pages :
13
Course Code: 5N1794
University: University College Cork
MyAssignmentHelp.com is not sponsored or endorsed by this college or university
Country: Ireland
Answer:
Assignment 1
Answer to question 1
I have conducted a survey at my workplace maned Lady’s Hospice and Care Services to observe the working environment. The aim of the survey is to find if it is a safe, healthy, secured and fulfilling place to work. A visual survey was conducted to locate and record the safety signs in the workplace. The objective of the survey is to observe and list different types of signs, location, their prom…
Read
More
Tags:
Australia Maple Ridge Management Introduction to film studies University of New South Wales Masters in Business Administration
400837 Health And Socio Political Issues In Aged Care
Download :
0 | Pages :
14
Course Code: 400837
University: Western Sydney University
MyAssignmentHelp.com is not sponsored or endorsed by this college or university
Country: Australia
Answers:
Introduction
Palliative care services are designed to improve the life of patient with progressive disease. People receiving palliative care have illness that has no prospect of cure. As per the World Health Organisation, palliative care is a care given to patient suffering from life threatening illness to improve their quality of life by preventing and providing relief from sufferings by early recognition , assessment and trea…
Read
More
Tags:
Australia Minchinbury Management University of New South Wales
PUBH6304 Global Health
Download :
0 | Pages :
8
Course Code: PUBH6304
University: The University Of Newcastle
MyAssignmentHelp.com is not sponsored or endorsed by this college or university
Country: Australia
Answers:
Human Immunodeficiency Virus Infection and Acquired Immune Deficiency Syndrome (HIV/AIDS) is the spectrum of medical conditions caused due to human immunodeficiency virus (HIV) following which the patient suffers from a series medical complications due to suppression of the immune system of the body. With the progression of the disease, the patient is likely to suffer from a wide range of infections like tuberculosis and other opportu…
Read
More
Tags:
United States Newark Management University of New York Masters in Business Administration
CON 321 Health Related Research
Download :
0 | Pages :
3
Course Code: CON321
University: University Of Southern Maine
MyAssignmentHelp.com is not sponsored or endorsed by this college or university
Country: United States
Answer:
Introduction
Leadership in the hospital is the ability to influence the staff toward providing quality health care. Leadership involves influencing human behavior to create a positive working environment (Langlois, 2012). Good leadership enables healthy relationships among staffs in the hospital enhancing quality delivery of health care services. Leadership is responsible to building teams that have trust, respect, support and effecti…
Read
More
BL9412 Public Health
Download :
0 | Pages :
35
Course Code: BL9412
University: University Of The West Of England
MyAssignmentHelp.com is not sponsored or endorsed by this college or university
Country: United Kingdom
Answer:
Introduction
According to the researchers, it can be said that the management of the health care organizations has become a difficult task nowadays and the reason behind this is the occurrence of various issues in this sector (Hall et al., 2014). Therefore, the administrative employees of the organization should incorporate various revolutionized strategies for enriching the worth of care provided by the hospital to its clients and re…
Read
More
Tags:
Australia Ryde Management Information system strategy University of New South Wales (UNSW) Masters in Business Administration
Next