Author Archives: mcb

Improving Solubility using X-ray crystal structure data

A recent publication from AstraZeneca provides a really interesting overview of the approach that they took to optimise the solubility of a series of GPR119 agonists. The initial lead compound 2 was only poorly soluble but, by obtaining small molecule … Continue reading

Posted in GPCR ligands, Med Chem Strategy | Tagged , , , | 6 Comments

GPCR structure and modeling

A recently published letter from scientists at Boehringer Ingelheim nicely summarizes recent advances in our understanding of G protein-coupled receptor (GPCR) structure and function. X-ray structures of the inactive forms of bovine rhodopsin (2000), β2 adrenergic receptor (2007 – with antibody … Continue reading

Posted in Computational Methods, GPCR ligands | Tagged , , , , , , , , , , | 1 Comment

Review: Optimizing CNS access

Neurotherapeutic agents generally illicit their effects by acting on receptors in the central nervous system (CNS) and a short review in Expert Opin. Drug Discov. highlights the current best practices and recent developments in targeting molecules to the brain.  The … Continue reading

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Review: Bioisosteres in Drug Design

An excellent J.Med.Chem. perspective titled ‘Synopsis of Some Recent Tactical Applications of Bioisosteres in Drug Design‘ has just published (The article is based on a short course presented at an ACS Prospectives conference in 2009).  The author gives a brief … Continue reading

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Discovery of PF-04691502 (PI3K/mTOR dual inhibitor)

Rapamycin and it’s analogues (or rapalogues e.g. CCI-779) modulate the phosphatidylinositol 3-kinase (PI3K) signalling cascade by binding to an allosteric site on the mTORC1 complex (Mammalian target of rapamycin (mTOR), a class IV PI3K protein kinase, forms two functional complexes, … Continue reading

Posted in Clinical Candidates, Enzyme Inhibitors, Kinase Inhibitors, Kinases, Med Chem Strategy | Tagged , , , , , , , , , , , , , , , , , , , , , , , | Leave a comment

Synthesis: Sulfonylated Pyridines

Sulfonyl pyridines have utility both as constituents of bioactive molecules and as synthetic intermediates.  Typical methods for their preparation have suffered from the use of odiferous thiols, capricious oxidation steps, poor atom economy, and production of significant amounts of hazardous … Continue reading

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Enhancing solubility by disrupting crystal packing

Drug candidates can be classified, according to the BCS system, into four groups on the basis of their permeability and aqueous solubility.  Molecules with lower solubility tend to be more difficult to develop and are subject to closer scrutiny by … Continue reading

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Optimization of plasma protein binding (again…)

Following hot on the heels of the Pfizer paper we blogged recently, comes a very similar publication from scientists at Genentech/Depomed.  Titled ‘Do We Need to Optimize Plasma Protein and Tissue Binding in Drug Discovery?’, the authors highlight the apparent … Continue reading

Posted in Med Chem Strategy, Uncategorized | Tagged , , , , , , , | 1 Comment

Reducing bioactivation potential by chemical design

Continuing the theme of an earlier post, an excellent article in Current Topics in Medicinal Chemistry looks at the issue of adverse drug events associated with the formation of reactive intermediates.  The authors (from Novartis) give some background to drug-related … Continue reading

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Structure-based design of BACE inhibitors

In a recent post the difficulties of developing drug-like and CNS penetrant inhibitors of β-secretase (BACE-1 or ASP-2) were hinted at (a detailed account of the state of the art can be found in this book).  Many of the reported inhibitors … Continue reading

Posted in Computational Methods, Enzyme Inhibitors, Med Chem Strategy | Tagged , , , , , , , , , , , , , , | 1 Comment