Elevated levels of human lipoprotein-associated phospholipase A2 (Lp-PLA2) are associated with cardiovascular disease and dementia. A fragment screen was conducted against Lp-PLA2 in order to identify novel inhibitors. Multiple fragment hits were observed in different regions of the active site, including some hits that bound in a pocket created by movement of a protein side chain (approximately 13 Å from the catalytic residue Ser273). Using structure guided design, we optimized a fragment that bound in this pocket to generate a novel low nanomolar chemotype, which did not interact with the catalytic residues.

A novel 4-hydroxyl(diphenyl)methyl substituted quinuclidine series was discovered as a very promising class of muscarinic antagonists. The structure-activity relationships of the connectivity of the diphenyl moiety to the quinuclidine core and around the ring nitrogen side chain are described. Computational docking studies using an homology model of the M-3 receptor readily explained the observed structure-activity relationship of the various compounds. Compound 14o was identified as a very potent, slowly reversible M-3 antagonist with a very long in vivo duration of bronchoprotection.

A new strategy for the facile synthesis of azabicyclo[m.n.1]alkenes (m = 3-5; n = 3, 2) has been developed that involves the ring-closing metathesis (RCM) reaction of cis-2,6-dialkenyl-N-acyl piperidine derivatives. The requisite 2,6-dialkenylpiperidines may be readily prepared in six steps starting from glutarimide (11) or three steps from 4-methoxypyridine (25). In one example that establishes the practical utility of the procedure, the functionalized 8-azabicyclo[3.2.1]octane 32, which is a potential intermediate for the syntheses of various tropane alkaloids, was prepared. Additionally, a new route for the construction of the bridged tetrahydro-beta-carboline ring system 5 has been developed that features the ring-closing metathesis of the enyne 45 to construct the bridging ring in 46. This concise route to 46 also features a potentially general and useful procedure for the one-step preparation of a terminal alkyne from an ester function. Selective oxidation of the vinyl group in 46 afforded the unsaturated aldehyde 47, which may serve as a useful intermediate in syntheses of several Sarpagine alkaloids.

A facile and general entry to functionalized bridged bicyclic nitrogen heterocycles has been developed that involves the ring-closing metathesis (RCM) of cis-2,6-dialkenyl-N-acyl piperidines that were readily prepared from glutarimide or 4-methoxypyridine.

Lithiation of the N-2,4,6-triisopropylbenzenesulfonyl-2-pyrroline (16) and treatment of the resulting cyclic vinyllithium reagent with R2CuCNLi2 produced an acyclic vinyl organometallic species that, when treated with an electrophile (H2O or RX), gave the homoallylic sulfonamides 18a-k in 37-93% yields and in > 95% diastereoselectivity. The deprotection of a representative homoallylic sulfonamide 18d was achieved in 83% yield by sonication in the presence of lithium wire and catalytic 4,4'-di-tert-butylbiphenyl (DBB). The efficacy of this general procedure for the production of homoallylic amine derivatives is demonstrated by the preparation of the diene amine 25, a key intermediate in the synthesis of a squalene synthetase inhibitor.

ADVERTISEMENT RETURN TO ISSUEPREVCommunicationNEXTIndole Resin: A Versatile New Support for the Solid-Phase Synthesis of Organic MoleculesKimberly G. Estep, Christopher E. Neipp, Linda M. Stephens Stramiello, Mavis D. Adam, Martin P. Allen, Shaughnessy Robinson, and Eric J. RoskampView Author Information Pfizer Central Research, Eastern Point Road, Groton, Connecticut 06340 Cite this: J. Org. Chem. 1998, 63, 16, 5300–5301Publication Date (Web):July 11, 1998Publication History Received3 April 1998Published online11 July 1998Published inissue 1 August 1998https://doi.org/10.1021/jo9806052Copyright © 1998 American Chemical SocietyRequest reuse permissionsArticle Views1034Altmetric-Citations73LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit Read OnlinePDF (46 KB) Get e-AlertscloseSupporting Info (1)»Supporting Information Supporting Information SUBJECTS:Amides,Amines,Indoles,Organic polymers,Urea Get e-Alerts