RSC Medicinal Chemistry Blog

Chronic obstructive pulmonary disease (COPD) is caused by emphysema and chronic bronchitis that damages the airways of the lungs leading to significantly reduced air flow and is predicted to be the third largest cause of death by 2030. Symptomatic relief is given by prescribing up to three different drugs for concurrent use, but the complexity of combining three different drugs that operate via three distinct mechanisms into a single device for inhalation dosing, such that patient compliance is high, is considerable.

Lyn Jones et al. from Pfizer have sought to facilitate the triple therapy concept by pursuing a strategy to incorporate muscarinic antagonism and β₂ agonism into a single molecule, such that combination with an inhaled corticosteroid could be achieved in a single dry powder inhaler device.

Compound 15 combined high metabolic clearance, low synthetic complexity, low oral bioavailability, desirable material properties and an impressive therapeutic index over haemodynamic effects, and these characteristics led to its nomination as a clinical candidate (PF-4348235).

This molecule has great potential to ease the medicines burden for COPD sufferers, so read about it now in MedChemComm.

This HOT article is free to access.

Optimized glucuronidation of dual pharmacology β-2 agonists/M3 antagonists for the treatment of COPD
Laura Hilton, Rachel Osborne, Amy S. Kenyon, Helen Baldock, Mark E. Bunnage, Jane Burrows, Nick Clarke, Michele Coghlan, David Entwistle, David Fairman, Neil Feeder, Kim James, Rhys M. Jones, Nadia Laouar, Graham Lunn, Stuart Marshall, Sandra D. Newman, Sheena Patel, Matthew D. Selby, Fiona Spence, Emilio F. Stuart, Susan Summerhill, Michael A. Trevethick, Karen N. Wright, Michael Yeadon, David A. Price and Lyn H. Jones
Med. Chem. Commun., 2011, Advance Article

DOI: 10.1039/C1MD00140J

Malaria is a parasitic disease caused by Plasmodium spp. which still ravages many parts of the world, responsible for killing an estimated 781,000 people each year according to the World Health Organisation’s 2010 World Malaria Report. Treatment is frequently associated with the development of resistance and so new drug leads are always needed.

Dr Paul O’Neill and colleagues from the University of Liverpool and the London and Liverpool Schools of Tropical Medicine have developed a new series of tetraoxane analogues and screened them for their in vitro and in vivo antimalarial activity. All of the compounds synthesized showed remarkable in vitro activity in the low nanomolar range (0.2–3.7 nM) and several demonstrated promising oral activity in the P. berghei ANKA mouse model of malaria.

A preliminary study suggests that members of this series have improved metabolic stability compared with the parent compound RKA182 and these data coupled with the excellent activity profiles, low ClogP and high aqueous solubilities (e.g. >40mg/ml) make this series an exciting development in the struggle against malaria. Watch out for future studies on these compounds!

This HOT article is free to access, so read it today in MedChemComm

Second generation analogues of RKA182: synthetic tetraoxanes with outstanding in vitro and in vivo antimalarial activities
Francesc Marti, James Chadwick, Richard K. Amewu, Hollie Burrell-Saward, Abhishek Srivastava, Stephen A. Ward, Raman Sharma, Neil Berry and Paul M. O’Neill
Med. Chem. Commun., 2011, Advance Article
DOI: 10.1039/C1MD00102G

Lipinski’s rule of five is probably one of the first principles taught to a medicinal chemist, as it defines the chemical space likely to yield a successful oral drug. However, in recent years some drugs have moved beyond traditional rule of five space in order to access alternative or challenging targets.

In this HOT paper David S. Millan and colleagues at Pfizer R&D explore the influence of intramolecular hydrogen bonding on the membrane permeability and bioavailability of some of these drugs.  By determining the propensity of molecules to form intramolecular  hydrogen bonds they are able to revise previous assumptions about where certain molecules sit in chemical space.  They find that when hydrogen bonding is taken into account these drugs sit much closer to rule of five space – thereby explaining the successful absorption of drugs that otherwise violate rule of five principles.

To read more on this interesting new tool for predicting intramolecular hydrogen bonding, download the article which is currently free to access:

Intramolecular hydrogen bonding to improve membrane permeability and absorption in beyond rule of five chemical space
Alexander Alex, David S. Millan, Manuel Perez, Florian Wakenhut and Gavin A. Whitlock
Med. Chem. Commun., 2011, Advance Article
DOI: 10.1039/C1MD00093D

The majority of therapeutics clinically available for cancer treatment are platinum-based and work via a DNA alkylation mechanism that leads to cell apoptosis.  But a number of cancers are resistant to apoptosis and not treatable with platinum-based drugs.

In this paper Peter Sadler (University of Warwick), Steve Shnyder (University of Bradford) and teams have developed an organometallic half-sandwich osmium complex that displays significant anti-cancer activity with negligible toxicity in vivo. Osmium is also a platinum group metal but has a completely different mode of action and appears to operate via redox mechanisms – making these complexes candidates for further investigation and potentially clinical trials.

Read more about this exciting find here – the article is currently free to access:

Anti-colorectal cancer activity of an organometallic osmium arene azopyridine complex
Steve D. Shnyder, Ying Fu, Abraha Habtemariam, Sabine H. van Rijt, Patricia A. Cooper, Paul M. Loadman and Peter J. Sadler
Med. Chem. Commun., 2011, Advance Article
DOI: 10.1039/C1MD00075F

There are a vast number biologically active natural products out there with the potential to cure any number of rather nasty diseases.  But searching for them and identifying their therapeutic targets can seem like a bewilderingly large task.  In this interesting paper Weidong Zhang and colleagues from several institutes in Shanghai have combined knowledge from traditional Chinese medicine with computational chemical biology to rapidly identify novel targets for natural products derived from plants.

The authors selected Bacopa monnieri (L.) Wettst (BMW) and Daphne odora Thunb. var. marginata (DOT) – which are used in traditional medicine for the treatment of diabetes and inflammation – and screened 19 compounds isolated from the plants against a potential drug target database using a reverse docking approach.  Based on these results and the clinical indication of the plants the DPP-IV protein (a therapeutic target for type II diabetes) was chosen for experimental validation.  When tested in vitro, 5 of the 19 compounds showed moderate inhibition of DPP-IV.  Then, from these five compounds analogues from an in-house library were screened, almost half of which again showed the ability to moderately inhibit the protein.

The authors emphasise that further work must be done to identify the synergistic pathways that result in the overall efficacy of traditional Chinese medicinal treatments, but this paper does demonstrate how it is possible to use natural products derived from clinically effective, but poorly understood, traditional treatments as a starting point for rapidly and successfully identifying new therapeutic targets.

Fast and effective identification of the bioactive compounds and their targets from medicinal plants via computational chemical biology approach
Shoude Zhang, Weiqiang Lu, Xiaofeng Liu, Yanyan Diao, Fang Bai, Liyan Wang, Lei Shan, Jin Huang, Honglin Li and Weidong Zhang
Med. Chem. Commun., 2011, Advance Article
DOI: 10.1039/C0MD00245C

Senile plaques (SPs) and neurofibrillary tangles (NFTs) are two pathological hallmarks for Alzheimer’s disease. Unfortunately, there is no an effective and simple diagnostic method to detect them.

In this paper, Masahiro Ono, Hideo Saji and colleagues at Kyoto University, have developed a series of radioiodinated phenyldiazenyl benzothiazole (PBD) derivatives as probes for the imaging of NFTs in the brain. Imaging agents need to be able to both penetrate the blood-brain barrier after an intravenous injections and be rapidly washed out from the normal brain. Unfortunately, even though these radioiodinated PDB derivatives displayed high affinity for tau aggregates and good brain uptake, the persistent radioactivity in the brain made them unsuitable for imaging NFTs in vivo.

If you want to find out more about these ‘inspiring’  imaging agents, you can download the article for free.

Phenyldiazenyl benzothiazole derivatives as probes for in vivo imaging of neurofibrillary tangles in Alzheimer’s disease brains
Kenji Matsumura, Masahiro Ono, Shun Hayashi, Hiroyuki Kimura, Yoko Okamoto, Masafumi Ihara, Ryosuke Takahashi, Hiroshi Mori and Hideo Saji
Med. Chem. Commun., 2011, Advance Article
DOI: 10.1039/C1MD00034A

Finding ligands to selectively bind to nicotinic acetylcholine receptor family of ligand gated ion channels is challenging due to the diversity of receptor subtypes, but ligands for the α7 subtype in particular could lead to new therapies for brain disorders such as schizophrenia and Alzheimer’s disease.

To screen for potential ligands Jeroen Kool (Leiden/Amsterdam Center for Drug Research) and colleagues recently developed an online fluorescence enhancement assay for the water-soluble acetylcholine binding protein (AChBP) – a model protein for the binding domain of α7 nicotinic acetylcholine receptors.  Using the related proteins Ls and Ac-AChBP  they sifted through in-house fragment libraries, discovering that Ls-AChBP is a better template for fragment screening and accurate, rapid hit exploration is possible using single point injections in the 96-well format.  They also produced an optimised hit with mM affinity for the α7 nicotinic acetylcholine receptor.

The authors hope that this technology will find applicability elsewhere – as it only requires a water-soluble protein and a good fluorescence enhancement tracer ligand.

Why not download the article and see for yourself – it’s currently free to access:

Online parallel fragment screening and rapid hit exploration for nicotinic acetylcholine receptors
Gerdien E. de Kloe, Jeroen Kool, Rene van Elk, Jacqueline E. van Muijlwijk-Koezen, August B. Smit, Henk Lingeman, Hubertus Irth, Wilfried M. A. Niessen and Iwan J. P. de Esch
Med. Chem. Commun., 2011, Advance Article
DOI: 10.1039/C1MD00031D

Finding ligands capable of stabilising G-quadruplex DNA structures has been a hot topic in medicinal chemistry for a number of years now, due to their potential as anti-cancer treatments.  But despite intensive research G-quadruplex ligands are yet to appear on the drug market-due to various problems with toxicity and efficacy-requiring the investigation of new, effective compounds.

Adam Le Gresley and colleagues from Kingston University have therefore investigated 8 anthracene-9-monoacrylamides and anthracen-9,10-bisacrylamides, which fit the criteria that has been identified for successful G-quadruplex binding.  They were surprised that neither the synthesis nor biological evaluation of their chosen diacrylamides had previously been reported, and so characterise them fully here.  They found that one class of ligand tested possesses anti-cancer activity, based on promotion of quadruplex DNA formation observed in solution by NMR, coupled with ‘compelling’ fluorescence data and initial biological testing. The group are now undertaking further investigations to better understand the activity of the diacrylamides.

Read more about this new class of potential G-quadruplex ligands – the paper is currently free to access:

Diacrylamides as selective G-quadruplex ligands in in vitro and in vivo assays
Adam Le Gresley, Ammara Abdullah, Deepak Chawla, Pratchi Desai, Uttam Ghosh, Uma Gollapalli, Munazza Kiran, Shehri Lafon and Alex Sinclair
Med. Chem. Commun., 2011, Advance Article
DOI: 10.1039/C1MD00020A