RESUMO
We have identified macrocyclic inhibitors of the aspartic protease BACE, implicated in the etiology of Alzheimer's disease. An X-ray structure of screening hit 1 in the BACE active site revealed a hairpin conformation suggesting that constrained macrocyclic derivatives may also bind there. Several of the analogs we prepared were >100x more potent than 1, such as 7 (5 nM K(i)).
Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Compostos Macrocíclicos/química , Inibidores de Proteases/química , Quinazolinas/química , Secretases da Proteína Precursora do Amiloide/metabolismo , Ácido Aspártico Endopeptidases/metabolismo , Sítios de Ligação , Simulação por Computador , Humanos , Compostos Macrocíclicos/síntese química , Compostos Macrocíclicos/farmacologia , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacologia , Quinazolinas/síntese química , Quinazolinas/farmacologia , Relação Estrutura-AtividadeRESUMO
A series of (6,7-dimethoxy-2,4-dihydroindeno[1,2-c]pyrazol-3-yl)phenylamines has been optimized to preserve both potent kinase inhibition activity against the angiogenesis target, the receptor tyrosine kinase of Platelet-Derived Growth Factor-BB (PDGF-BB), and to improve the broad tumor cell antiproliferative activity of these compounds. This series culminates in the discovery of 17 (JNJ-10198409), a compound with anti-PDGFR-beta kinase activity (IC(50)=0.0042 microM) and potent antiproliferative activity in six of eight human tumor cell lines (IC(50) < 0.033 microM).
Assuntos
Antineoplásicos/farmacologia , Indanos/síntese química , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirazóis/síntese química , Receptores do Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Antineoplásicos/síntese química , Becaplermina , Linhagem Celular , Linhagem Celular Tumoral , Endotélio Vascular/efeitos dos fármacos , Humanos , Indanos/farmacologia , Concentração Inibidora 50 , Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-sis , Pirazóis/farmacologiaRESUMO
The addition of small amounts of solid KCN to solution and solid-phase esters in THF/MeOH/50% aqueous NH2OH increases the efficiency of their transformation to the corresponding hydroxamic acids.
Assuntos
Ácidos Hidroxâmicos/síntese química , Catálise , Ésteres , Indicadores e Reagentes , Estrutura MolecularRESUMO
Anti-AIDS drug candidate and non-nucleoside reverse transcriptase inhibitor (NNRTI) TMC125-R165335 (etravirine) caused an initial drop in viral load similar to that observed with a five-drug combination in naïve patients and retains potency in patients infected with NNRTI-resistant HIV-1 variants. TMC125-R165335 and related anti-AIDS drug candidates can bind the enzyme RT in multiple conformations and thereby escape the effects of drug-resistance mutations. Structural studies showed that this inhibitor and other diarylpyrimidine (DAPY) analogues can adapt to changes in the NNRTI-binding pocket in several ways: (1). DAPY analogues can bind in at least two conformationally distinct modes; (2). within a given binding mode, torsional flexibility ("wiggling") of DAPY analogues permits access to numerous conformational variants; and (3). the compact design of the DAPY analogues permits significant repositioning and reorientation (translation and rotation) within the pocket ("jiggling"). Such adaptations appear to be critical for potency against wild-type and a wide range of drug-resistant mutant HIV-1 RTs. Exploitation of favorable components of inhibitor conformational flexibility (such as torsional flexibility about strategically located chemical bonds) can be a powerful drug design concept, especially for designing drugs that will be effective against rapidly mutating targets.
