Selective pyrrolidine inhibitors

Rummey et al. [223] searched replacements for the pyrrolidine present in their DPP-IV inhibitor searching a 10,000-molecule subset of small primary aliphatic amines extracted from the available chemical directory and visually inspected the top 500 of them. Four were selected for testing and two of them were novel hits. 

Similar strategies have been used for the synthesis (286) of the tetrahydro-pyrrolizidine 323 from 2,3 5,6-di-O-isopropylidene-D-g/yccroD-ta/o-hep-tono-1,4-lactone (322). These polyhydroxylated pyrrolidines and pyrrolizi-dines are potential specific inhibitors of glycosidases. The stereochemistry of the hydroxyl groups have a profound effect on the selectivity of the inhibition (286-288). 

A model for the structural relationship of /V-butyl-1 -deoxynojirimycin (131, Scheme 33) with ceramide, the substrate of ceramide glucosyltransferase, was suggested by Butters and coworkers. They conducted a comparative investigation on a range of 14 derivatives of 1-deoxynojirimycin substituted at the ring nitrogen and/or C-l, as well as 5 pyrrolidine-type inhibitors selected by superpositioning of the iminoalditol with a portion of the ceramide structure.364... 

Wannamaker W, et al. (S)-l-((S)-2- (l-(4-amino-3-chloro-phe-nyl)-methanoyl)-amino -3,3-dimethyl-butanoy l)-pyrrolidine-2-carboxylic acid ((2R,3S)-2-ethoxy-5-oxo-tetrahydro-furan-3-yl)-amide (VX—765), an orally available selective interleukin (IL)-converting enzyme/caspase-1 inhibitor, exhibits potent antiinflammatory activities by inhibiting the release of IL-lbeta and IL-18. J. Pharmacol. Exp. Ther. 2007 321 509-516. 

Ismail, M.A.H., Ahoul-Enein, M.N., Ahouzid, K.A.M., El Ella, D.A.A., and Ismail, N.S.M. (2009) ACE inhibitors hypothesis generation for selective design, synthesis and biological evaluation of 3-mercapto-2-mefhyl-propanoyl-pyrrolidine-3-imine derivatives as antihypertensive agents. Bioorganic ei Medicinal Chemistry, 17, 3739-3746. 

J.K. Xu, S. Zhu, B. Thomberry, N.A. Weber, A.E. (25,35)-3-Amino-4-(3,3-difluoro-pyrrolidin-l-yl)-A,A-dimetbyl-4-oxo-2-(4-[l,2,4]triazolo[l,5-fl]-pyridin-6-ylpbenyl)bu-tanamide a selective a-amino amide dipeptidyl peptidase IV inhibitor for tbe treatment of type 2 diabetes. J. Med. Chem. 2006, 49, 3614-3627. 

Nordhoff S, Cerezo-Galvez S, Deppe H, Hill O, Lopez-Canet M, Rummey C, Thiemann M, Matassa VG, Edwards PJ, Feurer A (2009) Discovery of beta-homophenylalanine based pyrrolidin-2-ylmethyl amides and sulfonamides as highly potent and selective inhibitors of dipeptidyl peptidase IV. Bioorg Med Chem Lett 19 4201-4203... 

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