Drug design and discovery最新文献

Strong hydrogen-bonding forces between the Thr26 and Thr26' of the protease stabilize the internal cage of the dimeric triad of the aspartyl HIV-1 protease (Asp25Thr26Gly27 and Asp25' Thr26'Gly27', respectively). The interaction of reversible inhibitors of HIV-1 protease is based on (i) strong hydrogen-bonding forces between the main chain (--CONH--) oxygen atoms of Gly27 and/or Gly27' and hydrogen-bond donating moieties of a drug, and (ii) hydrogen bonds between the oxygen of the catalytic Asp25 and/or Asp25' carboxylates and aliphatic hydroxyl groups of a drug. The free entry of natural substrates into the active-site cavity is sterically hindered by inhibitors, so that the catalytic Asp carboxylates cannot interact with natural substrates. Irreversible inhibitors interact with the nucleophilic carboxylate moiety of Asp25 of HIV-1 protease by covalent bonding.

Quantitative structure-activity relationship (QSAR) study of human factor Xa inhibitor N2-aroylanthranilamides, recently reported by Yee et al. (J. Med. Chem., 43, 873-882), has been performed using principal component factor analysis as the preprocessing step. The study reveals that presence of electron-donating R2 substituent at the para position (with respect to the amide linkage) is conducive to the binding affinity, whereas a meta R2 substituent decreases the affinity. Again, electron-donating R1 substituents with less bulk and optimum hydrophilic-lipophilic balance (particularly, methyl and methoxy groups) favor the activity. The study further suggests that electron-withdrawing R3 substituents are detrimental for the activity, whereas bulkier R4 substituents (particularly NHSO2Me group) increase the activity.

Imidazole and oxazole derivatives 1 to 4 were designed and prepared as dipeptide mimetics to replace the Ser-Leu dipeptide sequence of Ro-25-9980 (Ac-(Cha)-RAMA-S-L-NH2), a peptidic inhibitor of antigen binding to major histocompatibility complex (MHC) class II DR molecules linked to rheumatoid arthritis (RA). The most potent analog in binding assays (IC50 = 30 nM in DRB1*0401 binding; 1.6 times as potent as Ro 25-9980) was 16, Ac-(Cha)RAMA-(S)S-psi(oxazole)-L-NH2. The SAR of peptide hybrids 10 to 24, prepared by incorporating the dipeptide mimetics 1 to 4 is discussed. Of these hybrids, 23 and 24, analogs that incorporated the imidazole and oxazole mimetics as well as optimized variants at positions 3 to 5, were found to have 70 to 80 nM binding affinity comparable to the parent peptide in DRB 1*0401 binding and were also active in DRB1*0101 binding, while being resistant to proteolysis by cathepsin B. Both of these compounds showed inhibitory activity in an antigen-stimulated T-cell proliferation assay, indicating their potential to suppress autoimmune responses and as leads for therapeutic agents to treat RA.

One hundred sixty-eight multiply substituted 1,4-benzodiazepines have been prepared by a five-step solid-phase combinatorial approach using syn-phase crowns as a solid support and a hydroxymethyl-phenoxy-acetamido linkage (Wang linker). The substituents of the 1,4-benzodiazepine scaffold have been varied in the -3, -5, -7, and 8-positions and the combinatorial library was evaluated in a chole cys to kinin (CCK) radioligand binding assay. 3-Alkylated 1,4-benzodiazepines with selectivity towards the CCK-B (CCK2) receptor have been optimized on the lipophilic side chain, the ketone moiety, and the stereochemistry at the 3-position. Various novel 3-alkylated compounds were synthesized and [S]3-propyl-5-phenyl-1,4-benzodiazepin-2-one, [S]NV-A, has shown a CCK-B selective binding at about 180 nM. Fifty-eight compounds of this combinatorial library were purified by preparative TLC and 25 compounds were isolated and fully characterized by TLC, IR, APCI-MS, and 1H/13C-NMR spectroscopy.