| Autor: |
Comer E; Center for the Science of Therapeutics, Broad Institute , 7 Cambridge Center, Cambridge, Massachusetts 02142, United States., Beaudoin JA, Kato N, Fitzgerald ME, Heidebrecht RW, Lee Md 4th, Masi D, Mercier M, Mulrooney C, Muncipinto G, Rowley A, Crespo-Llado K, Serrano AE, Lukens AK, Wiegand RC, Wirth DF, Palmer MA, Foley MA, Munoz B, Scherer CA, Duvall JR, Schreiber SL |
| Jazyk: |
angličtina |
| Zdroj: |
Journal of medicinal chemistry [J Med Chem] 2014 Oct 23; Vol. 57 (20), pp. 8496-502. Date of Electronic Publication: 2014 Oct 13. |
| DOI: |
10.1021/jm500994n |
| Abstrakt: |
Here, we describe medicinal chemistry that was accelerated by a diversity-oriented synthesis (DOS) pathway, and in vivo studies of our previously reported macrocyclic antimalarial agent that derived from the synthetic pathway. Structure-activity relationships that focused on both appendage and skeletal features yielded a nanomolar inhibitor of P. falciparum asexual blood-stage growth with improved solubility and microsomal stability and reduced hERG binding. The build/couple/pair (B/C/P) synthetic strategy, used in the preparation of the original screening library, facilitated medicinal chemistry optimization of the antimalarial lead. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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