RSC Medicinal Chemistry Blog

Coronary heart disease has been shown to be related to low levels of high-density lipoprotein cholesterol (HDL-C) in blood plasma, and consequently methods of controlling HDL-C levels are sought to reduce the risk of heart disease.  Inhibition of the cholesteryl ester transfer protein (CETP) – the protein that transports cholesteryl esters from high-density lipoprotein (HDL) to low- and very low-density lipoproteins (LDLs and VLDLs) – has shown potential as a therapy.

Tarun Jha and a team from Jadavpur University have performed studies on a series of 2-arylbenzoxazoles to define the structural requirements of a good CETP inhibitor.  The 2D QSAR study using using PCR, PLS and MLR techniques and kNN-MFA 3D QSAR results have generated a pharmacophore that they hope will provide a good scaffold for the design of future potent CETP inhibitors.

Download the paper today to read the details of their findings – it’s free to access until the end of 2011:

Chemometric modeling and pharmacophore mapping in coronary heart disease: 2-arylbenzoxazoles as cholesteryl ester transfer protein inhibitors
Dhritiman Jana, Amit Kumar Halder, Nilanjan Adhikari, Milan Kumar Maiti, Chanchal Mondal and Tarun Jha
Med. Chem. Commun., 2011, Advance Article
DOI: 10.1039/C1MD00135C

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