Statins library

Afifymax s thiolacyl library (Fig. 1.9) and Pharmacopeia s statine library (Fig. 1.10) are pharmacophore-based libraries however, their design is different. In the former library, a pool of advanced library intermediates are derivatized with the pharmacophore (thiolacylation) as the final step in library construction, while in the latter library the pharmacophore (statine) is derivatized with synthons as part of library construction. 

Fig. 7. Synthesis of the statine library B. Reagents anti conditions (a) TentaGel S-NH2 resin (0.3 mmol/g) distributed into seven reaction vessels (b) 3 Eq each Boc-Lys(Boc)-OH, HOBt, 5 Eq DIG, DCM (c) encode using three tags (d) 50% TFA/ DCM, 1 h (e) 5 Eq each 4-bromomethyl-3-nitrobenzoic acid, HOBt, 8 Eq DIG, DGM, 3 h (f) one of seven amines (Fig. 4) 10 Eq amine, THF, 8 h (g) pool and split into three reaction vessels (h) one of three Rg Boc-protected statines (Fig. 4) 4 Eq each statine, HATU, 8 Eq DIEA, DMF, 3 h (i) encoded using two tags (j) pool and split into 31 reaction vessels and encode using 5 tags (k) 50% TFA/DGM, 1 h (1) one of 31 Rc Fmoc-protected amino acids (Fig. 4) 4 Eq each amino acid, HATU, 8 Eq DIEA, DMF, 6 h (m) pool (n) 30% piperidine/DMF, 1 h (o) split into 20 reaction vessels (p) one of 20 Rj) acylation agents (Fig. 4) 4 Eq each of RDGO2H, HATU, 8 Eq DIEA, 6 h (q) hv (365 nm), MeOH, 50 G, 2.5 h.

Bergeron S, Chaplin D, Edwards JH, Ellis BS, Hill CL, Holt-Tiffin K, Knight JR, Mahoney T, Osborne AP, Ruecroft G (2006) Nitrilase-catalyzed desym-metrization of 3-hydroxyglutaronitrile preparation of a statin side-chain intermediate. Org Proc Res Dev 10 661-665 Burns M, Weaver J, Wong J (2005) Stereoselective enzymic bioconversion of aliphatic dinitriles into cyano carboxylic acids. WO 2005100580 DeSantis G, Zhu Z, Greenberg W, Wong K, Chaplin J, Hanson SR, Farwell B, Nicholson LW, Rand CL, Weiner DP, Robertson D, Burk MJ (2002) An enzyme library approach to biocatalysis development of nitrilases for enantioselective production of carboxylic acid derivatives. J Am Chem Soc 124 9024-9025... 

Fig. 1.10. Statine pharmacophore library targeting aspartic acid proteases (reprinted ( adapted or in part ) with permission from Journal of the American Chemical Society. Copyright 2001 American Chemical Society).

Another promising route was reported in patent and open hterature by both DSM and Diversa [13, 14]. This route employs a 2-deoxy-D-ribose 5-phosphate aldolase (DERA) that catalyzes a tandem aldol addition in which two equivalents of acetaldehyde (AA) are added in sequence to chloroacetaldehyde (CIAA) to produce a lactol derivative that is similar to the 3,5-dihydoxy side chain of synthetic statins (Figure 6.2e). Diversa screened environmental libraries for novel wild-type DERAs and identified an enzyme that was both tolerant to increased substrate concentrations and more active than DERA from E. coli in the target reaction [13]. 

Carroll CD, Patel H, Johnson TO, Guo T, Orlowski M, He ZM, Cavallaro CM, Guo J, Oskman A, Gluzman IY, Connelly J, Chelsky D, Goldberg DE, Dolle RE, Identification of potent inhibitors of Plasmodium falciparium plasmepsin II from an encoded statine combinatorial library, Bioorg. Med. Chem. Leu., 8 2315-2320, 1998. 

L. Banfi and co-workers utilized the Passerini three component reaction to prepare a 9600 member hit generation library of nor-statines. " ° These compounds are potential transition state mimetics for the inhibitors of aspartyl proteases. The authors produced the library by starting out from eight A/-Boc-a-aminoaldehydes, twenty isocyanides and sixty carboxylic acids. The key Passerini reaction occurred under mild conditions. This transformation was followed by removal of the Boc protecting group and acyl transfer. Three representative examples of the library are shown. 

Peters, B.J.M. (2010) Methodological approaches to the pharmacogenomics of statins http // dspace.library.uu.nl/handle/18741/ 191558... 

Library 1.11 Statine tetrapeptide Size >200 members Affiiiation Lily [22]... 

---