Case Study I Indoloquinolizinones 221 Origin of the Indoloquinolizinone Lead

In the early stages of this project, leads were identified by focused screening of a limited set of compounds that were either identified by molecular modeling or were members of a collection of compounds designed to exemplify a diverse set of molecular scaffolds. Initially, compounds were assayed by detection of the displacement of ZipA185.328 from the immobilized C-terminal 16 amino acid fragment of the FtsZ protein by surface plasmon resonance (SPR) 18 . Later on, as a new assay became...

Case 4 Ras Farnesyl Transferase Inhibitors

Saha et al.51 at Johnson & Johnson reported the solid-phase synthesis of triazole-based Ras farnesyl transferase inhibitors. Farnesyl transferase (FTase) is a zinc metalloenzyme that catalyzes the binding of a farnesyl group to the thiol of a cysteine residue of several proteins involved in cell signaling. The Ras oncogene protein contains a tetrapeptide sequence known as the CAAX motif that, upon farnesylation, promotes Ras translocation to the internal cell membrane. It has been determined...

Case 7 Tissue Factor Factor VIIa TFVIIa Complex Inhibitors

Parlow et al.46 at Pharmacia Corporation reported the structure-base design and polymer-assisted solution-phase synthesis of pyrazinones as selective small-molecule inhibitors of the tissue factor factor VIIa (TF VIIa) complex. The coagulation cascade involves several proteins that are activated at certain points in the coagulation pathway and form active complexes that, in turn, proteolytically activate other targets, ultimately generating the formation of thrombin (IIa) and a fibrin clot....

References

M ller, and A. Alanine. Hit and lead generation beyond high-throughput screening. Nature Rev. Drug Discov., 2003, 2, 369. 2. S.J. Shuttleworth, R.V. Connors, J. Fu, J. Liu, M.E. Lizarzaburu, W. Qiu, R. Sharma, M. Wa ska, and A.J. Zhang. Design and synthesis of protein superfamily-targeted chemical libraries for lead identification and optimization. Curr. Med. Chem., 2005, 12, 1239-1281. 3. D. Obrecht and J.-M. Villalgordo. Solid-supported combinatorial and parallel...

Antifungals

Kundu et al.10 at the Central Drug Research Institute in India published a classic study of using a positional scanning combinatorial chemistry peptide approach for the optimization of hexapeptides as antifungal agents. Screening a peptide collection against Candida albicans (Ca) and Cryptococcus neoformansa (Cn), the hexapeptide His-D-Trp-D-Phe-Phe-D-Phe-Lys-NH2 (compound 8) was identified as a hit with IC50 29.6 pM and MIC 6.81 pM, respectively. For this study it was decided to keep the...

Z

Having improved cellular potency in this series, the authors then proceeded to change the amide functionality of 366 into its carboxylic acid analog 367. Although 367 lost some activity in the SRC1 assay EC50 125 nM , this carboxylic acid analog exhibited improved potency in cells EC50 190 nM . Further in vivo testing in mice indicated that 367 possesses an acceptable pharmacokinetic profile with a t1 2 2 hr, Cmai 12.7 g mL, and F 70 when administered at 10 mg kg. Moreover, 367 was also found...

Case 4 HRV 3CP Inhibitors

A Reich et al.42 at Pfizer Global R amp D-La Jolla Agouron Pharmaceuticals reported a study on the structure-based design of benzamide-based inhibitors of the human rhinovirus 3C protease HRV 3CP , particularly the HRV-14 3CP serotype. To design non-peptide inhibitors, the authors used the crystal structure of HRV-14 3CP co-crystallized with a peptide aldehyde. Analysis of the crystal structure led the authors to propose that 3-formylbenzamide would provide a scaffold where the aldehyde would...

Scheme

8.3.6 Generation of Library from Scaffold ii The second library based on lupeol involved the generation of compounds by derivatizing II with a variety of isocyanates, amino acids aromatic acids, and aromatic aldehydes and led to the synthesis of structurally diverse derivatives 6, 7, and 8 Scheme 8.5 . A library of 48 compounds was generated in parallel format using automation with 8 compounds represented by 6, 32 compounds represented by 7, and 8 compounds represented by 8. SCHEME 8.5 Reagents...

Case Study

8.3.1 Lead Optimization Studies with a Natural Product Lupeol Natural products play an important role in drug discovery, and many approved therapeutics as well as drug candidates have been derived from natural sources. They also represent promising scaffolds for diversification by using combinatorial techniques, as they have been selected by nature for their ability to undergo transformations in a three-dimensional space. Library construction around such scaffolds thus has the potential for...

Nh

207 R4 CH3, IC50 1000 nM Akt-1 amp Akt-2 209 R4 isobutyl5 IC50 gt 20,000 nM Akt-1 IC50 325 nM Akt-2 Library 3 Dual Akt-1 Akt-2 inhibitor Library 3 Dual Akt-1 Akt-2 inhibitor 210 IC50 58 nM Akt-1 IC50 210 nM Akt-2 210 IC50 58 nM Akt-1 IC50 210 nM Akt-2 sCHEME 1.23 Akt targeted library 2 and library 3.