1.Design and x-ray crystal structures of high-potency nonsteroidal glucocorticoid agonists exploiting a novel binding site on the receptor.
Biggadike K1, Bledsoe RK, Coe DM, Cooper TW, House D, Iannone MA, Macdonald SJ, Madauss KP, McLay IM, Shipley TJ, Taylor SJ, Tran TB, Uings IJ, Weller V, Williams SP. Proc Natl Acad Sci U S A. 2009 Oct 27;106(43):18114-9. doi: 10.1073/pnas.0909125106. Epub 2009 Oct 12.
Crystallography and computer modeling have been used to exploit a previously unexplored channel in the glucocorticoid receptor (GR). Highly potent, nonsteroidal indazole amides showing excellent complementarity to the channel were designed with the assistance of the computational technique AlleGrow. The accuracy of the design process was demonstrated through crystallographic structural determination of the GR ligand-binding domain-agonist complex of the D-prolinamide derivative 11. The utility of the channel was further exemplified through the design of a potent phenylindazole in which structural motifs, seen to interact with the traditional GR ligand pocket, were abandoned and replaced by interactions within the new channel. Occupation of the channel was confirmed with a second GR crystal structure of this truncated D-alaninamide derivative 13. Compound 11 displays properties compatible with development as an intranasal solution formulation, whereas oral bioavailability has been demonstrated with a related truncated exemplar 14.
2.Dopamine receptor modulation by Pro-Leu-Gly-NH2 analogues possessing cyclic amino acid residues at the C-terminal position.
Johnson RL, Rajakumar G, Mishra RK. J Med Chem. 1986 Oct;29(10):2100-4.
The synthesis of several analogues of L-prolyl-L-leucylglycinamide (PLG) was carried out in which the glycinamide residue was replaced with the following cyclic amino acid residues: L- and D-prolinamide, (+)- and (-)-thiazolidine-2-carboxamide, L- and D-3,4-dehydroprolinamide, L-azetidine-2-carboxamide, L-piperidine-2-carboxamide, and L-thiazolidine-4-carboxamide to give PLG analogues 2-10, respectively. The ability of these analogues to enhance the binding of the dopamine agonist ADTN (2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene) to dopamine receptors was determined by using bovine brain tissue. All of the PLG analogues synthesized in this study enhanced the binding of ADTN to central dopamine receptors. The percent enhancement of ADTN binding produced by analogues 2,3, and 7-10 at various concentrations was comparable to the percent enhancement produced by PLG. The PLG analogues Pro-Leu-(+)-thiazolidine-2-carboxamide (4), Pro-Leu-(-)-thiazolidine-2-carboxamide (5), and Pro-Leu-L-3,4-dehydroprolinamide (6), however, produced significantly greater enhancement (2-3-fold) in ADTN binding than did PLG.
3.Enantioselective direct aldol reaction of α-keto esters catalyzed by (S(a))-binam-D-prolinamide under quasi solvent-free conditions.
Viózquez SF1, Bañón-Caballero A, Guillena G, Nájera C, Gómez-Bengoa E. Org Biomol Chem. 2012 May 28;10(20):4029-35. doi: 10.1039/c2ob25224d. Epub 2012 Apr 18.
(S(a))-Binam-D-prolinamide (20 mol%), instead of (S(a))-binam-L-prolinamide, in combination with chloroacetic acid (100 mol%) is an efficient organocatalyst for the direct aldol reaction between α-keto esters as electrophiles and alkyl and α-functionalised ketones, under quasi solvent-free conditions, providing access to highly functionalised chiral quaternary γ-keto α-hydroxyesters with up to 92% ee.
