Changing the practice of medicine – Strategy and Approach of Novartis’ Biomedical R&D

This article focuses on Novartis’ innovative drug discovery research arm Novartis Institutes for BioMedical Research (NIBR) and summarizes its research strategies and recent success, thereby highlighting how the challenges facing the pharmaceutical industry today have been uniquely addressed by NIBR

Interaction of alpha- and beta-oligoarginine-acids and amides with anionic lipid vesicles: a mechanistic and thermodynamic study

Copyright © 2006 American Chemical SocietyThomas Hitz, Rico Iten, James Gardiner, Kenji Namoto, Peter Walde and Dieter Seebac

Trypsin inhibitors for the treatment of pancreatitis

Proline-based trypsin inhibitors occupying the S1-S2-S1’ region were identified by an HTS screening campaign. It was discovered that truncation of the P1’ moiety and appropriate extension into the S4 region led to highly potent trypsin inhibitors with excellent selectivity against related serine proteases and a favorable hERG profil

Interaction of Epothilone Analogs with the Paclitaxel Binding Site: Relationship between Binding Affinity, Microtubule Stabilization, and Cytotoxicity

12 páginas, 4 figuras, 3 tablas -- PAGS nros. 225-236The interactions of epothilone analogs with the paclitaxel binding site of microtubules were studied. The influence of chemical modifications in the C15 side chain and in C12 on binding affinity and microtubule elongation was characterized. Modifications favorable for binding affinity are (1) a thiomethyl group at C21 of the thiazole side chain, (2) a methyl group at C12 in S configuration, (3) a pyridine side chain with C15 in S configuration, and (4) a cyclopropyl moiety between C12 and C13. The same modification in different ligands has similar effect on affinity, allowing good structure-affinity characterization. The correlation between binding, microtubule stabilization, and cytotoxicity of the compounds has been determined, showing differential effects of the modifications. The binding constants correlate well with IC50 values, demonstrating that affinity measurements are a useful tool for drug designThis work was supported in part by grants BIO2001-1725 from MCyT to J.F.D., 07B/0026/2002 from Comunidad de Madrid to J.M.A., and the Avon Foundation with funds raised through the Avon Breast Cancer Crusade and NIH Prostate Cancer SPORE Grant CA-58236 to P.G. R.M.B. was supported by a MECD FPU predoctoral fellowship. K.C.N. acknowledges the Skaggs Institute for Chemical Biology, the National Institutes of Health, and Novartis for their financial supportPeer reviewe

In-cell selectivity profiling of serine protease inhibitors by activity-based proteomics.

Activity-based proteomics is a methodology that is used to quantify the catalytically active subfraction of enzymes present in complex mixtures such as lysates or living cells. To apply this approach for in-cell selectivity profiling of inhibitors of serine proteases, we designed a novel activity-based probe (ABP). This ABP consists of (i) a fluorophosphonate-reactive group, directing the probe toward serine hydrolases or proteases and (ii) an alkyne functionality that can be specifically detected at a later stage with an azide-functionalized reporter group through a Cu(I)-catalyzed coupling reaction ("click chemistry"). This novel ABP was shown to label the active site of several serine proteases with greater efficiency than a previously reported fluorophosphonate probe. More importantly, our probe was cell-permeable and achieved labeling of enzymes within living cells with efficiency similar to that observed for the corresponding lysate fraction. Several endogenous serine hydrolases whose activities were detected upon in-cell labeling were identified by two-dimensional gel and MS analyses. As a proof of principle, cell-permeable inhibitors of an endogenous serine protease (prolyl endopeptidase) were assessed for their potency and specificity in competing for the in situ labeling of the selected enzyme. Altogether these results open new perspectives for safety profiling studies in uncovering potential cellular "side effects" of drugs (unanticipated off-target inhibition or activation) that may be overlooked by standard selectivity profiling methods

Structure-based design and synthesis of macrocyclic human rhinovirus 3C protease inhibitors

The design and synthesis of macrocyclic inhibitors of human rhinovirus 3C protease is described. A macrocyclic linkage of the P1 and P3 residues, and the subsequent structure-based optimization of the macrocycle conformation and size led to the identification of a potent biochemical inhibitor 10 with sub-micromolar antiviral activity

Discovery of C-(1-aryl-cyclohexyl)-methylamines as selective, orally available inhibitors of dipeptidyl peptidase IV.

The successful launches of dipeptidyl peptidase IV (DPP IV) inhibitors as oral anti-diabetics warrant and spur the further quest for additional chemical entities in this promising class of therapeutics. Numerous pharmaceutical companies have pursued their proprietary candidates towards the clinic, resulting in a large body of published chemical structures associated with DPP IV. Herein, we report the discovery of a novel chemotype for DPPIV inhibition based on the C-(1-aryl-cyclohexyl)-methylamine scaffold and its optimization to compounds which selectively inhibit DPP IV at low-nM potency and exhibit an excellent oral phamacokinetic profile in the rat