Category Archives: Med Chem Strategy

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

MDM2-p53 protein-protein interaction inhibitors


The successful development of inhibitors of protein-protein interactions remains a formidable challenge for medicinal chemists. An excellent review highlights some successes in this field and ascribes the low tractability of these targets to: The large contact surfaces between proteins (~1,500–3,000 … Continue reading

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Drug discovery approaches to minimise drug induced liver injury in man


The recent literature has seen a flurry of papers describing the issue of, and potential approaches to minimising the incidence of, drug-induced liver injury (DILI) in the clinic.   It is well recognised that attrition throughout the development pipeline is often … Continue reading

Posted in Med Chem Strategy, Toxicology | Tagged , , , , , , , , , , , , , , , , | 3 Comments

More physicochemical musings & ChEMBL


Following on from his earlier papers (e.g. ADMET rules of thumb for candidate drug design), Gleeson’s most recent publication in Nature Reviews|Drug Discovery details a now familiar tale of physicochemical woe associated with the failure of many medicinal chemistry programmes to … Continue reading

Posted in Med Chem Strategy, Reviews, Software | 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

Discovery of MK-1220 (Hepatitis C NS3/4A protease inhibitor)


A recent letter in ACS Med.Chem.Lett. details the optimisation of a series of inhibitors of the Hepatitis C virus (HCV) NS3/4A protease, and is interesting in that it provides detailed pharmacokinetic data for a series of macrocyclic lactones, a class of therapeutic … Continue reading

Posted in Clinical Candidates, Enzyme Inhibitors, Med Chem Strategy | Tagged , , , , , , , , , , , , , , , , , , , , , , , , | 1 Comment

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