160301-20-2Relevant academic research and scientific papers
Alkylidene Dihydropyridines Are Surrogates for Pyridylic Anions in the Conjugate Addition to α,β-Unsaturated Ketones
Fishlock, Dan,Orellana, Arturo,Sayyad, Ashik,Shi, Jiaqi
supporting information, (2021/12/27)
We show that alkylidene dihydropyridines, readily prepared from 4-alkylpyridines, behave as soft nucleophiles toward a range of α,β-unsaturated ketones under the influence of silyl Lewis acids to give the products of conjugate addition. In contrast to existing methods, which use strongly basic pyridylic anions, this reaction tolerates a wide array of functional groups, providing access to useful heterocyclic scaffolds.
Identification of orally available naphthyridine protein kinase D inhibitors
Meredith, Erik L.,Ardayfio, Ophelia,Beattie, Kimberly,Dobler, Markus R.,Enyedy, Istvan,Gaul, Christoph,Hosagrahara, Vinayak,Jewell, Charles,Koch, Keith,Lee, Wendy,Lehmann, HansJoerg,Mckinsey, Timothy A.,Miranda, Karl,Pagratis, Nikos,Pancost, Margaret,Patnaik, Anup,Phan, Dillon,Plato, Craig,Qian, Ming,Rajaraman, Vasumathy,Rao, Chang,Rozhitskaya, Olga,Ruppen, Thomas,Shi, Jie,Siska, Sarah J.,Springer, Clayton,Van Eis, Maurice,Vega, Richard B.,Von Matt, Anette,Yang, Lihua,Yoon, Taeyoung,Zhang, Ji-Hu,Zhu, Na,Monovich, Lauren G.
experimental part, p. 5400 - 5421 (2010/11/18)
A novel 2,6-naphthyridine was identified by high throughput screen (HTS) as a dual protein kinase C/D (PKC/PKD) inhibitor. PKD inhibition in the heart was proposed as a potential antihypertrophic mechanism with application as a heart failure therapy. As PKC was previously identified as the immediate upstream activator of PKD, PKD vs PKC selectivity was essential to understand the effect of PKD inhibition in models of cardiac hypertrophy and heart failure. The present study describes the modification of the HTS hit to a series of prototype pan-PKD inhibitors with routine 1000-fold PKD vs PKC selectivity. Example compounds inhibited PKD activity in vitro, in cells, and in vivo following oral administration. Their effects on heart morphology and function are discussed herein.
Structure-based design and synthesis of substituted 2-butanols as nonpeptidic inhibitors of HIV protease: Secondary amide series
Reich, Siegfried H.,Melnick, Michael,Pino, Mark J.,Fuhry, Mary Ann M.,Trippe, Anthony J.,Appelt, Krzysztof,Davies II, Jay F.,Wu, Bor-Wen,Musick, Linda
, p. 2781 - 2794 (2007/10/03)
The design, synthesis, and crystallographic analysis of protein- inhibitor complexes is described for a novel series of nonpeptidic HIV protease (HIV Pr) inhibitors. Beginning with a cocrystal structure of a Phe- Pro peptidomimetic bound to the HIV Pr, design was initiated that resulted in the substituted 2-butanol compound 8 as the lead compound (K(i) = 24.5 μM, racemic mixture). Modifications on the initial compound were then made on the basis of its cocrystal structure with HIV Pr and inhibition data, resulting in compounds with enhanced potency against the enzyme (compound 18, K(i) = 0.48 μM). These inhibitors were found to bind to the enzyme essentially as predicted on the basis of the original design hypothesis. Stereospecific synthesis of individual enantiomers confirmed the prediction of a binding preference for the S alcohol stereochemistry. Modest antiviral activity was demonstrated for several of the more potent HIV Pr inhibitors in a HIV-1 infected CEM-SS cell line.
