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1.
ACS Med Chem Lett ; 9(8): 815-820, 2018 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-30128073

RESUMO

Herein we describe the development of a series of pyrazolopyrimidinone phosphodiesterase 2A (PDE2) inhibitors using structure-guided lead identification and design. The series was derived from informed chemotype replacement based on previously identified internal leads. The initially designed compound 3, while potent on PDE2, displayed unsatisfactory selectivity against the other PDE2 isoforms. Compound 3 was subsequently optimized for improved PDE2 activity and isoform selectivity. Insights into the origins of PDE2 selectivity are described and verified using cocrystallography. An optimized lead, 4, demonstrated improved performance in both a rodent and a nonhuman primate cognition model.

2.
Bioorg Med Chem Lett ; 28(8): 1392-1396, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29548573
3.
Org Lett ; 11(2): 345-7, 2009 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-19093828

RESUMO

The palladium-catalyzed Suzuki-Miyaura reaction has been utilized as one of the most powerful methods for C-C bond formation. However, Suzuki reactions of electron-deficient 2-heterocyclic boronates generally give low conversions and remain challenging. The successful copper(I) facilitated Suzuki coupling of 2-heterocyclic boronates that is broad in scope is reported. Use of this methodology affords greatly enhanced yields of these notoriously difficult couplings. Furthermore, mechanistic investigations suggest a possible role of copper in the catalytic cycle.


Assuntos
Ácidos Borônicos/química , Cobre/química , Compostos Heterocíclicos/química , Catálise
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