A chiral β-amino acid containing three contiguous chiral centers was synthesized efficiently in 11 steps, employing enantio-enriched β-ketoester as a key intermediate, via stereoselective catalytic hydrogenation of the corresponding enamide. Stereoselective 1,4-addition of a methyl group and protonation were key to the preparation of the desired acid 12. Mild and efficient reaction conditions were applied to the enamine formation and protection to avoid epimerization at C-4 of compounds 13 and 14. The final compound was found to display potent affinity for the α2δ-protein that is a recognized drug target for the treatment of a variety of diseases.

A novel class of reversible inhibitors of Interleukin-1β-converting enzyme (ICE, caspase-1) were discovered by iterative structure-based design. Guided by the X-ray crystal structure of analogues 1, 7 and 10 bound to ICE, we have designed a nonpeptide series of small molecule inhibitors. These compounds incorporate an arylsulfonamide moiety which replaces Val-His unit (P3-P2 residues) amino acids of the native substrate. The synthesis of the core structure, structure–activity relationships (SARs), and proposed binding orientation based on molecular modeling studies for this series of ICE inhibitors are described.

A series of compounds was designed and prepared as inhibitors of interleukin-1beta converting enzyme (ICE), also known as caspase-1. These inhibitors, which employ a diphenyl ether sulfonamide, were designed to improve potency by forming favorable interactions between the diphenyl ether rings and the prime side hydrophobic region. An X-ray crystal structure of a representative member of the diphenyl ether sulfonamide series bound to the active site of caspase-1 was obtained.

Incorporation of 4-phosphonodifluoromethyl-phenylalanine (F2Pmp) and 4-phosphono-phenylalanine into SH2 targeted peptides and peptidomimetic ligands was found to effect binding affinity and selectivity of these ligands toward the Src and Abl SH2 domains. Furthermore, dipeptide analogs containing these phosphonate amino acids were used to produce prodrugs with excellent cellular delivery and reconversion rates.

The design of potent and selective non-peptide antagonists of endothelin-1 (ET-1) and its related isopeptides are important tools defining the role of ET in human diseases. In this report we will describe the detailed structure-activity relationship (SAR) studies that led to the discovery of a potent series of butenolide ETA selective antagonists. Starting from a micromolar screening hit, PD012527, use of Topliss decision tree analysis led to the discovery of the nanomolar ET(A) selective antagonist PD155080. Further structural modifications around the butenolide ring led directly to the subnanomolar ETA selective antagonist PD156707, IC50's = 0.3 (ET(A)) and 780 nM (ET(B)). This series of compounds exhibited functional activity exemplified by PD156707. This derivative inhibited the ETA receptor mediated release of arachidonic acid from rabbit renal artery vascular smooth muscle cells with an IC50 = 1.1 nM and also inhibited the ET-1 induced contraction of rabbit femoral artery rings (ETA mediated) with a pA2 = 7.6. PD156707 also displayed in vivo functional activity inhibiting the hemodynamic responses due to exogenous administration of ET-1 in rats in a dose dependent fashion. Evidence for the pH dependence of the open and closed tautomerization forms of PD156707 was demonstrated by an NMR study. X-ray crystallographic analysis of the closed butenolide form of PD156707 shows the benzylic group located on the same side of the butenolide ring as the gamma-hydroxyl and the remaining two phenyl groups on the butenolide ring essentially orthogonal to the butenolide ring. Pharmacokinetic parameters for PD156707 in dogs are also presented.

The specific association of an SH2 domain with a phosphotyrosine (pTyr)-containing sequence of another protein precipitates a cascade of intracellular molecular interactions (signals) which effect a wide range of intracellular processes. The nonreceptor tyrosine kinase Src, which has been associated with breast cancer and osteoporosis, contains an SH2 domain. Inhibition of Src SH2-phosphoprotein interactions by small. molecules will aid biological proof-of-concept studies which may lead to the development of novel therapeutic agents. Structure-based design efforts have focused on reducing the size and charge of Src SH2 ligands while increasing their ability to penetrate cells and reach the intracellular Src SH2 domain target. In this report we describe the synthesis, binding affinity, and Src SH2 cocrystal structure of a small, novel, nonpeptide, urea-containing SH2 domain ligand.

Based on the X-ray structures of the pp60Src (Src) SH2 domain complexed with two high affinity phosphopeptide ligands (Glu-Pro-Gln-pTyr-Glu-Glu-Ile-Pro-Ile-Tyr-Leu, and Ac-pTyr-Glu-D-Hcy-NH2; Hcy = homocyclohexylalanine), we report herein the design and structure-activity relationships of a series of novel dipeptide ligands targeting the Src SH2 domain.

Potent ligands of the Src SH2 domain, discovered through structure-based drug design efforts, with the general structure Ac-pTyr-Glu-NRR′ are disclosed.

Src homology-2 (SH2) domains, containing approximately 100 amino acid residues, are noncatalytic motifs involved with intracellular signal transduction. These domains can be found on nonreceptor kinases, phosphatases, and in regulatory adapter proteins among others. SH2 domains bind proteins containing phosphotyrosine (pTyr) residues in a sequence specific manner. Our efforts have focused on designing peptide mimetic ligands for the SH2 domain of the nonreceptor tyrosine kinase pp60src. We employed the cocrystal structure of the 11mer Glu-Pro-Gln-pTyr-Glu-Glu-Ile-Pro-IIe-Tyr-Leu IC50 = 800 nM as a starting point for our design efforts. These efforts have resulted in the discovery of tripeptide ligands containing D-amino acids that are only 2-fold less potent than the 11mer.

We have designed and synthesized a series of phosphorylated penta- and tri-peptides of general structures R-x-Glu-Glu-Ile-Glu and R-x-Glu-D-Trp-NH2, where R-x represents a phosphotyrosine mimetic. These peptides show binding affinity to pp60(src) SH2 domain in the micromolar range. Data are presented that provide an account of their structure-activity relationships and specificity properties. Copyright (C) 1996 Elsevier Science Ltd

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTDiscovery of a Novel Series of Orally Active Non-Peptide Endothelin-A (ETA) Receptor-Selective AntagonistsAnnette M. Doherty, William C. Patt, Jeremy J. Edmunds, Kent A. Berryman, Billy R. Reisdorph, Mark S. Plummer, Aurash Shahripour, Chet Lee, Xue-Min Cheng, and Cite this: J. Med. Chem. 1995, 38, 8, 1259–1263Publication Date (Print):April 1, 1995Publication History Published online1 May 2002Published inissue 1 April 1995https://pubs.acs.org/doi/10.1021/jm00008a002https://doi.org/10.1021/jm00008a002research-articleACS PublicationsRequest reuse permissionsArticle Views379Altmetric-Citations98LEARN 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 InRedditEmail Other access optionsGet e-AlertscloseSupporting Info (3)»Supporting Information Supporting Information Get e-Alerts

A series of renin inhibitors were designed to examine the topography of the contiguous binding pocket of renin that is normally occupied by the P1 and P3 side chains. Molecular modeling suggested that extending the P1 hydrophobic side chain into the adjacent hydrophobic S3 enzyme pocket was feasible. Novel transition state isosteres with modified P1 --> P3 side chains were synthesized and provided enhanced binding affinity when incorporated into renin inhibitors in which the P3 Phe was substituted by Gly. In a complementary approach, the binding affinities of a variety of P3-P4-modified peptidomimetic renin inhibitors that lacked substantial hydrophobic side chains at these sites were measured.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

A total synthesis of dl-beta-amyrin (1) is reported, utilizing as the key step a cyclization of a polyolefin having a fluorine atom as the cation-stabilizing (C-S) auxiliary. Thus polyene substrate 7, upon acid-catalyzed cyclization, gave fluoropentacycle 8, a compound having five fused rings and bearing six of the eight chiral centers found in the natural product beta-amyrin (1). The preparation of polyene 7 required the development of stereoselective methods for introducing the three alkene bonds of the cyclopentenol side chain. The trisubstituted 11-cis alkene was formed by stereoselective inversion of the corresponding trans alkene, utilizing an epoxidation/elimination sequence (84% yield, cis:trans 99:1). A new method of producing the tetrasubstituted 7-trans fluoroalkene bond was developed utilizing the Trost palladium-catalyzed alkylation of keto ester 18 with allylic acetate 17 (83% yield, trans:cis 88:12). The trisubstituted 3-trans alkene was constructed by the Brady-Julia rearrangement of cyclopropylcarbinol 22, giving bromide 23 (82% yield, trans:cis 97:3). Optimum conditions for cyclization of cyclopentenol 7 afforded 8 in 65-70% yield. The fluorine atom acting as a C-S auxiliary at pro-C-13 in 7 exerted regiocontrol over the cyclization process, creating a 6-membered ring C and enhancing the yield of pentacyclic product. Conversion of 8 to dl-beta-amyrin (1) entailed oxidative removal of the C-22 allene group, regioselective elimination of the C-13 fluorine atom to produce the C-12 alkene, enlargement and functionalization of ring A, and establishment of the trans A/B ring fusion. The identity of synthetic dl-beta-amyrin was unequivorally established by comparison of its chromatographic and spectral properties with those of the natural product. This study, together with the earlier papers in this series, enlarges the scope of practical biomimetic synthesis of polycyclic natural (and unnatural) triterpenes to include pentacyclic compounds.

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTBiomimetic polyene cyclizations. Cationic cyclization of a substrate having an internal acetylenic bond. Synthesis of euphol and tirucallolWilliam R. Bartlett, William S. Johnson, Mark S. Plummer, and Vernon R. Small Jr.Cite this: J. Org. Chem. 1990, 55, 7, 2215–2224Publication Date (Print):March 1, 1990Publication History Published online1 May 2002Published inissue 1 March 1990https://pubs.acs.org/doi/10.1021/jo00294a043https://doi.org/10.1021/jo00294a043research-articleACS PublicationsRequest reuse permissionsArticle Views888Altmetric-Citations23LEARN 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 InRedditEmail Other access optionsGet e-Alertsclose Get e-Alerts

AbstractStarting from the furan (I) the tricyclic intermediate (V) is synthesized.