Novartis compounds

Jacoby E,Schuffenhauer A, Popov M, etal. (2005) Key aspects of the Novartis compound collection enhancement project for the compilation of a comprehensive chemogenomics drug discovery screening collection. Curr. Top. Med. Cfcem. 5 397-411. 

Schopfer U, Engeloch C, Stanek J, et al. (2005) The Novartis compound archive — From concept to reality. Comb. Chem. High Throughput Screen. 8 513-519. 

Figure 12.3 Target Hit Rates (THR) for marketed drugs and Novartis compounds. A TH R of >20% is considered to be promiscuous (black), 5-20% medium promiscuous (hatched) and 0-5% selective (white). 65% of the Marketed Drug set of 293 compounds, including antipsychotics and withdrawn drugs, were selective, whereas only 13% were promiscuous.

The combined VS hit list is summarized in Fig. 4. In addition to the sets described in Subheading 2.2, the virtual hit lists includes 650 compounds from previous lead-finding activities on MDM2 (hit finding and hit-to-lead optimization assays). After elimination of duplicates, the hit list includes 46,511 unique compounds which were available at the Novartis compound archive via HTCP. 

A high-throughput binding screen of the Novartis compound file identified a potent hit, 5, which the authors hypothesized had a dose structural similarity to the Schering CCR5 antagonist, SCH-C. Crossover compounds were prepared and... 

The Schultz group at Calibr screened 70 000 compounds from the Novartis compound collection initially for inhibition of biofilm formation in M. smegma-tis [58] and discovered a series of compoimds (TCAl, 12) that inhibits the same enzyme as BTZ043. This series of compoimds binds at the same site of the DprEl enzyme as does PBTZ169, although they are noncovalent inhibitors as... 

Novartis AG has filed a patent application on novel naphthalene derivatives as potent cannabinoid agonists, especially at the CBi receptor [208]. One compound was specifically claimed, the naphthalene derivative (319), which exhibited CBi binding with a if value of 15 nM. This compound was also active in an in vivo model of neuropathic pain, reversing hyperalgesia... 

In addition, Novartis filed a patent application on a series of quinazolines as cannabinoid agonists [209]. Compound (320) is one of the two compounds specifically claimed and exhibited CBi and CB2 binding with if values of 34 and 11 nM, respectively. It was shown to be a full agonist at the CBi receptor with an EC50 of 132nM (no functional data for the CB2 receptor). Compound (320) was also active in the neuropathic pain model described above with an ED50 of 0.5mg/kg after oral dosing. 

In the context of Pmp-containing tripeptide derivatives, the 3-indol-l-yl-pro-pyl analogue turned out to exhibit high affinity. Substituting the indol 5-posi-tion with methyl or hydroxyl resulted in compounds 41 and 42 with subnanomolar IC50 values (Scheme 7). These have been the first compounds of SH2 domain antagonists with subnanomolar affinity reported. These systematic studies enabled Novartis to push further analogues into in vivo studies [148,... 

Furet et al. described the discovery of a novel, potent and selective kinase CK2 inhibitor by a high-throughput docking protocol [250]. A large subset of the Novartis corporate database with 400 000 compounds was flexibly docked using DOCK 4.01 [93, 117]... 

Chapter 1 contributed from the Novartis Molecular and Library Informatics group focuses on small molecules for chemogenomics based drug discovery and summarizes the main compound categories and selection methods of relevance for the compilation of a comprehensive discovery screening collection. 

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