Category Archives: Enzyme Inhibitors

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

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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

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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

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TAK-733 & CH4987655 (Allosteric MEK Inhibitors)


The mitogen-activated protein kinase (MAPK) signalling cascade is one of the key pathways regulating cell proliferation and differentiation and aberrant activation of this pathway is implicated in a number of cancers. Targeting components of the cascade thus has the potential … Continue reading

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Halogen Bonding


Investigators at Roche recently published a communication describing a systematic study of halogen bonding effects in protein-ligand complexes of human Cathepsin L (hCatL).  They found that an inhibitor incorporating a 4-chlorophenyl moiety enhanced binding affinity by a factor of 13, … Continue reading

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Review: Gamma-secretase modulators


An excellent review titled ‘γ-Secretase Modulators as Potential Disease Modifying Anti-Alzheimer’s Drugs’ has recently published in J.Med.Chem. The review gives some background to the disease and to the generally, although not universally, accepted hypothesis that amyloid plays a key role … Continue reading

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Discovery of Rivaroxaban (Factor Xa Inhibitor)


The discovery of novel anticoagulants, and the search for novel orally active agents in particular, has been a long and difficult journey.  However, the recent (2008) launches of Bayer’s Factor Xa inhibitor (Rivaroxaban, BAY 59-7939) and Boehringer Ingelheim’s Thrombin inhibitor … Continue reading

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Discovery of LX2931 (Sphingosine 1-Phosphate Lyase Inhibitor) & Phase IIa Data


Fingolimod (FTY720, Gilenya), an immunosuppresive agent with activity purported to be mediated by binding of it’s phosphorylated derivative to the sphingosine-1-phosphate receptor 1 (S1P1), was approved earlier in the year as the first orally administered disease modifying therapy for the treatment … Continue reading

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Discovery of PF-04457845 (FAAH Inhibitor)


In this latest publication from the Pfizer labs, the authors describe their continuing efforts to identify urea-based, irreversible inhibitors of fatty acid amide hydrolase (FAAH).  Inhibition of FAAH and the concomitant elevation of endogenous levels of fatty acid amides has … Continue reading

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