7 research outputs found
Is adamantane a suitable substituent to pre-organize the acid orientation in E-selectin antagonists?
The selectins play a key role in the inflammatory process, that is, the recruitment of leukocytes from blood vessels into inflamed tissue. Because excessive infiltration of leukocytes can induce acute or chronic reactions, the control of leukocyte extravasation is of great pharmaceutical interest. All physiological ligands of the selectins contain the tetrasaccharide epitope sialyl Lewis(x), which therefore became the lead structure in selectin antagonist research. Previous studies indicated that an important factor for the affinity of sLe(x) is the fact that in solution its pharmacophores are already conformationally pre-organized in the bioactive orientation. In mimics where the GlcNAc- and the NeuNAc-moieties of sLe(x) were replaced by (R,R)-cyclohexane-1,2-diol and (S)-cyclohexyllactic acid, respectively, an optimized pre-organization of the pharmacophores could be realized, leading to antagonists with improved affinities. To further optimize the pre-organization of the carboxylic acid, a pharmacophore essential for binding, the replacement of NeuNAc by bulky (R)- and (S)-adamantyl-lactic acid was studied. Although antagonist (S)-7 showed a slightly reduced affinity, the expected beneficial effect of the (S)-configuration at C-2 of the lactate could be confirmed
Ligand channel in pharmacologically stabilized rhodopsin
In the degenerative eye disease retinitis pigmentosa (RP), protein misfolding leads to fatal consequences for cell metabolism and rod and cone cell survival. To stop disease progression, a therapeutic approach focuses on stabilizing inherited protein mutants of the G protein-coupled receptor (GPCR) rhodopsin using pharmacological chaperones (PC) that improve receptor folding and trafficking. In this study, we discovered stabilizing nonretinal small molecules by virtual and thermofluor screening and determined the crystal structure of pharmacologically stabilized opsin at 2.4 Ă
resolution using one of the stabilizing hits (S-RS1). Chemical modification of S-RS1 and further structural analysis revealed the core binding motif of this class of rhodopsin stabilizers bound at the orthosteric binding site. Furthermore, previously unobserved conformational changes are visible at the intradiscal side of the seven-transmembrane helix bundle. A hallmark of this conformation is an open channel connecting the ligand binding site with the membrane and the intradiscal lumen of rod outer segments. Sufficient in size, the passage permits the exchange of hydrophobic ligands such as retinal. The results broaden our understanding of rhodopsinâs conformational flexibility and enable therapeutic drug intervention against rhodopsin-related retinitis pigmentosa.ISSN:0027-8424ISSN:1091-649
Practical Synthesis of MDM2 Antagonist RG7388. Part 2: Development of the Cu(I) Catalyzed [3 + 2] Asymmetric Cycloaddition Process for the Manufacture of Idasanutlin
A concise catalytic
asymmetric synthesis of idasanutlin (<b>1</b>) was developed
in which the key pyrrolidine core, containing
four contiguous stereocenters, was constructed via a Ag/MeOBIPHEP
promoted [3 + 2] cycloaddition reaction. Further development of the
[3 + 2] cycloaddition reaction resulted in an improvement in diastereoselectivity
and enantioselectivity by changing the catalyst system to CuÂ(I)/BINAP.
While producing equivalent high quality API, the copperÂ(I) catalyzed
process not only increased the overall yield but also demonstrated
benefit with respect to cycle times, waste streams, and processability.
The optimized copperÂ(I) catalyzed process has been used to prepare
more than 1500 kg of idasanutlin (<b>1</b>)