62349-05-7Relevant academic research and scientific papers
Tracing binding modes in hit-to-lead optimization: Chameleon-like poses of aspartic protease inhibitors
Kuhnert, Maren,K?ster, Helene,Bartholom?us, Ruben,Park, Ah Young,Shahim, Amir,Heine, Andreas,Steuber, Holger,Klebe, Gerhard,Diederich, Wibke E.
supporting information, p. 2849 - 2853 (2015/03/04)
Successful lead optimization in structure-based drug discovery depends on the correct deduction and interpretation of the underlying structure-activity relationships (SAR) to facilitate efficient decision-making on the next candidates to be synthesized. Consequently, the question arises, how frequently a binding mode (re)-validation is required, to ensure not to be misled by invalid assumptions on the binding geometry. We present an example in which minor chemical modifications within one inhibitor series lead to surprisingly different binding modes. X-ray structure determination of eight inhibitors derived from one core scaffold resulted in four different binding modes in the aspartic protease endothiapepsin, a well-established surrogate for e.g. renin and β-secretase. In addition, we suggest an empirical metrics that might serve as an indicator during lead optimization to qualify compounds as candidates for structural revalidation.
Synthesis and local anaesthetic activity of some 2-aminoacetylamino-3-carbetoxy/anilido-4,5,6,7-tetrahydro-benzothiophenes
Gadad, A K,Kumar, Hemant,Shishoo, C J,Khazi, I M,Mahajanshetti, C S
, p. 298 - 301 (2007/10/02)
Twenty new 2-substituted aminoacetylamino-3-carbetoxy/anilido-4,5,6,7-tetrahydrobenzothiophenes (4a-4t) have been synthesised with a view to studying the effect of structural modification of carticaine (B) on the local anaesthetic activity and evaluated by Sollman's method as well as Bulbring and Wajda method using lignocaine hydrochloride as a standard.All the tested compounds show moderate to good activity and 4a has been found to be the most active drug comparable to the standard.
