RSC Medicinal Chemistry Blog

Scientists have optimised a series of compounds that have the potential to treat diabetes and obesity.
The drug candidates work by inhibiting the enzyme diacylglycerol acetyl transferase 1, which is responsible for catalysing the production of triglycerides. Excessive levels of triglycerides contribute to metabolic syndrome, which increases risk of diabetes, heart disease and stroke. Previous drug inhibitors have been unsuccessful in clinical trials due to low solubility. The optimised compounds are highly soluble and exhibit excellent potency for their target.

Optimisation of biphenyl acetic acid inhibitors of diacylglycerol acetyl transferase 1 – the discovery of AZD2353
Michael J. Waring, Alan M. Birch, Susan Birtles, Linda K. Buckett, Roger J. Butlin, Leonie Campbell, Pablo Morentin Gutierrez, Paul D. Kemmitt, Andrew G. Leach, Philip A. MacFaul, Charles O’Donnell and Andrew V. Turnbull
Med. Chem. Commun., DOI: 10.1039/C2MD20190A

Take a look at the top 5 most downloaded MedChemComm articles in 2012 and blog your thoughts and comments below.

The developability of heteroaromatic and heteroaliphatic rings – do some have a better pedigree as potential drug molecules than others?
Timothy J. Ritchie, Simon J. F. Macdonald, Simon Peace, Stephen D. Pickett and Christopher N. Luscombe
Med. Chem. Commun., 2012,3, 1062-1069, DOI: 10.1039/C2MD20111A

Gd(III) chelates for MRI contrast agents: from high relaxivity to “smart”, from blood pool to blood–brain barrier permeable
Chang-Tong Yang and Kai-Hsiang Chuang
Med. Chem. Commun., 2012,3, 552-565, DOI: 10.1039/C2MD00279E

The use of phosphate bioisosteres in medicinal chemistry and chemical biology
Thomas S. Elliott, Aine Slowey, Yulin Ye and Stuart J. Conway
Med. Chem. Commun., 2012,3, 735-751, DOI: 10.1039/C2MD20079A

Inhibition of bromodomain-mediated protein–protein interactions as a novel therapeutic strategy
Silviya D. Furdas, Luca Carlino, Wolfgang Sippl and Manfred Jung
Med. Chem. Commun., 2012,3, 123-134, DOI: 10.1039/C1MD00201E

Development of second generation epigenetic agents
Philip Jones
Med. Chem. Commun., 2012,3, 135-161, DOI: 10.1039/C1MD00199J

Fancy submitting an article to MedChemComm? Then why not submit to us today or alternatively email us your suggestions.

During the Trojan war, Greeks built a huge wooden horse, hid men inside it and left it outside the city of Troy. The Trojans, claiming it as a victory trophy, brought it into their city. That night, the Greek force crept out of the horse, opened the gates for the rest of the Greek army and they destroyed the city of Troy

Marvin Miller at the University of Notre Dame and colleagues have synthesised analogues of iron scavenging compounds that contain a maleimide functional group for future drug conjugation. Miller explains that these compounds will be actively assimilated by the M. tuberculosis pathogen by the active iron transport system, but can also carry a lethal agent into the pathogen.

One of the challenges of synthesising drug conjugates is finding a suitable functional group to attach the drug to the conjugate. The maleimide functionalised mycobactin analogue synthesised by the team simplifies the synthetic route by reducing the need for protecting groups. Thiol-maleimide chemistry can then be used to attach the drug.

Derek Tan, an expert in rational drug design at the Memorial Sloan–Kettering Cancer Center, US, is enthusiastic about the work. He believes that the advantage of the maleimide functional group is that it can react with nucleophiles, which may already be present in a potential conjugate drug, as opposed to electrophiles, which generally need to be synthetically introduced into the conjugate drug. This maleimide–mycobactin analogue ‘will enable the future synthesis of a wider array of potential Trojan horse antibiotics’, says Tan.

Miller and co-workers found that the maleimide–mycobactin analogue displayed antibiotic activity against Mycobacterium tuberculosis, but it was inactive against a broad panel of Gram-positive and Gram-negative bacteria. ‘The use of siderophores [iron chelating compounds] to deliver antibiotics exclusively into a single type of bacteria (e.g., Mtb, P. aeruginosa, E. coli), could reduce the administration of broad-spectrum antibiotics, minimising exposure and therefore the development of drug resistance’ says Miller.

In the future, the team intends to use a rational approach for selecting drugs to attach to the maleimide–mycobactin analogue, starting with drugs that inhibit essential survival processes.

References
1. R E Juárez-Hernández, S G Franzblau and M J Miller, Org. Biomol. Chem., 2012, DOI: 10.1039/c2ob26077h

2. Chemistry World story by Alisa Becker

Antimalarial drugs with increased in vitro activity have been developed by scientists in Portugal and the US. These novel drugs, called primacins, are active against two stages of malarial infection and are more active against liver parasites than the current clinical use drug, primaquine.

Mosquito-borne malaria is a highly infectious and potentially fatal disease that affects millions of people every year. When humans are bitten by a malaria-infected mosquito, they undergo a clinically silent liver-stage infection when thousands of malaria parasites (merozoites) are released into the bloodstream. Drugs that are active against liver parasites are rare and currently, primaquine is the only drug in clinical use. However, its use is hampered by low oral bioavailability and high hemotoxicity, making it unsuitable for pregnant women, children and the elderly.

The new primacins, developed by Paula Gomes from the University of Porto, Portugal, and co-workers combine primaquine with cinnamic acids, which are also known for their antimalarial activity. ‘This ‘‘covalent bitherapy’’ involves linking two molecules with individual intrinsic activity into a single agent, thus packaging dual activity into a single hybrid molecule,’ explains Gomes. ‘So far, none of the antimalarials reported in the literature combine these two antimalarial pharmacophores. Moreover, the chemistry underlying their preparation is simple and cheap, which is our constant concern when dealing with development of antimalarials, as malaria is mainly endemic to low income countries.’

Larry Walker, a professor in pharmacology at the University of Mississippi, US, agrees that the work is promising, but says that further experiments and animal testing are necessary. ‘What is new here is the finding that, using this liver stage parasite culture model, which is fairly new and very useful, they can show improved potency of these derivatives. This is really the most important feature of this study,’ he says. ‘However, it is important to keep in perspective what still needs to be done to have a real advance for this drug class. What is needed is to show that it improves activity in animal models; and more importantly, shows reduced hematological toxicity compared to primaquine.’

Gomes agrees that in vivo tests are the way forward: ‘The next step consists of establishing how active our compounds are in vivo, how are they absorbed, distributed, metabolised and eliminated,’ she says. ‘If the compounds are confirmed to be highly active in vivo, we’ll then step forward into the so-called pre-clinical assays.’

REFERENCES

1. Chemistry World story by Emma Eley

2. B Pérez et al, MedChemComm, 2012, DOI: 10.1039/c2md20113e

Insulin could be administered topically rather than by needles in the future

Scientists in Japan have developed a way to administer insulin to patients through the skin. Such a method avoids one of the problems associated with injections and oral administration in which a drug’s concentration is reduced as it passes through the digestive system. It would also be a more pleasant experience for patients.

Masahiro Goto from Kyushu University in Fukuoka and SO Pharmaceutical Corporation in Kobe, and colleagues, prepared a capsule loaded with insulin that is able to penetrate the skin with its cargo.

The team made their capsule by surrounding insulin molecules with proteins and coating the protein molecules with a hydrophobic surfactant to form protein–surfactant complexes. Then, they added oligo-arginine peptides as protein transduction domains and dispersed the complexes in oil – isopropyl myristate – which is known to have a permeation-enhancing effect. ‘The main function of this new system is to promote protein penetration through the hydrophobic stratum corneum [outermost layer of the skin],’ explains Goto.

The team tested their delivery vehicle on pig skin and found that the solid-in-oil dispersion delivered six times more insulin into the skin than an aqueous solution. The peptides further enhanced the concentration of insulin delivered through the skin.

‘Transcutaneous protein delivery is a difficult problem, the solution of which could enhance the quality of life for patients in need of protein therapeutics,’ says Paschalis Alexandridis from the chemical and biological engineering department at the University of Buffalo, US, whose work includes pharmaceutical formulations. He adds that Goto’s work demonstrates the versatility of solid-in-oil nanodispersions as a platform for enhanced transdermal delivery of protein therapeutics and vaccines.

Goto and his team say that in theory such dispersion could be used for any drug that is soluble in water and can form a water-in-oil emulsion. They hope to be able to produce a transdermal vaccine in the future.

Original story from Chemistry World, written by Jennifer Newton

The 2011 Journal Citation Reports ® (Thomson Reuters, 2012) have just been released, which showed:

Organic & Biomolecular Chemistry: 3.696

MedChemComm: 2.8         (Partial IF only, based on five issues)

Natural Product Reports: 9.79

The Cambridge Editorial Office would like to thank everyone involved for their hard work and dedication to all three journals over the years. In particular, we would like to thank all of our Associate Editors, Editorial and Advisory Board members, authors and referees, without whom none of this would have been possible.

With another successful year in the bag, we hope you will join us in making this year even better…

Read more about the 2011 Impact Factors from across RSC Publishing on the RSC Publishing Blog.

MedChemComm Editor Richard Kelly will be visiting several North East universities next week as part of the RSC US Roadshows 2012.

Week 4 sees the Royal Society of Chemistry visiting four universities in Pennsylvania and New York:

May 7th – University of Pittsburgh

May 8th – Pennsylvania State University

May 10th – University of Pennsylvania

May 11th – Columbia University

Read more about the US roadshows 2012:

Starting in mid April 2012, RSC Publishing has been touring the United States of America to share more than 170 years experience of publishing in the chemical sciences. Sixteen universities across the country are hosting these one-day events, which are open to all members of the hosting institute.

Attendees have the opportunity to explore RSC’s apps on mobile devices and meet informally with RSC editors. Lunchtime discussion groups explore reading habits and opportunities in the 21st century and an afternoon seminar give an insight into the world of scholarly publishing, with tips on how to get published in high impact journals. A demonstration of ChemSpider, and a guest lecture from an RSC associate editor or board member are available at many of the roadshows.

Follow the RSC Roadshows on Twitter – just look for #RSC2012.