An extension of our previously reported series of macrocyclic ortho-aminobenzamide Hsp90 inhibitors is reported. Addition of a second methyl group to the tether provided analogs that show increased potency in binding as well as cell-proliferation assays and, more importantly, are stable toward microsomes. We wish to disclose the discovery of a macrocycle which showed impressive biomarker activity 24-h post dosing and which demonstrated prolonged exposure in tumors. When studied in a lung cancer xenograft model, the compound demonstrated significant tumor size reduction.

Development of a large-scale enantioselective synthesis of a lead compound containing a 3-aryl-3-trifluoromethyl-2-aminopropanol core is described. A single isomer of 3,3-disubstituted acrylic acid derivative was prepared via Perkin condensation or Horner-Wadsworth-Emmons olefination, followed by hydrolysis. The acid was converted to a chiral acryloxazolidinone derivative. Hydrogenation of the latter on Pd/C in the presence of MgBr(2) proceeded via a chelation-controlled conformation to yield the desired isomer with high selectivity. Subsequent Evans azidation, hydrogenation, reductive cleavage of the chiral auxiliary, and sulfonylation afforded the target compound as a single isomer in high overall yield.

Development of a scalable synthesis of WAY-315193 is described. Use of LiHMDS as a base and Ti(O-i-Pr)(4) as a Lewis acid was optimal for efficient and reproducible addition of indolinone anion to epoxyalcohol. Conversion of indolinone diol to indolinone aminoalcohol was achieved via monotosylation-methylamination. The possibility of selective formation of the amidine side product, as well as its utilization for alternative selective preparation of the target aminoalcohol, was demonstrated.

An alternative synthesis of WAY-253752, 1, a novel, dual-acting SSRI/5HT(1A) antagonist, was developed and used for the first scale-up. Initially, the target compound was synthesized as part of a diasteromeric mixture separated by chiral preparative HPLC. The new route was designed around intermediates suitable for chiral resolution, and its conditions were successfully determined.

An alternative synthesis of WAY-262398, 1, a novel, dual-acting SSRI/5-HT1A antagonist, has been developed. The target compound was initially synthesized as a part of diastereomeric mixture which was separated by chiral preparative HPLC. The new route was designed around intermediates suitable for chiral resolution and/or chiral reduction of a suitable intermediate. Both processes had to be employed to achieve the target optical purity.

As a result of an economically challenging environment within the pharmaceutical industry, pharmaceutical companies and their departments must increase productivity and cut costs to stay in line with the market. Discovery-led departments such as the medicinal chemistry and lead optimization groups focus on synthesizing large varieties of compounds in minimal amounts, while the chemical development groups must then deliver a few chosen leads employing an optimized synthesis method and using multi-kilogram quantities of material. A research group at the discovery-development interface has the task of medium-scale synthesis which is important in the lead selection stage. The primary objective of this group is the initial scale-up of promising leads for extensive physicochemical and biological testing. The challenge of the interface group involves overcoming synthetic issues within the rigid, accelerated timelines.

The isomeric mixture of ethyl 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2- and −3-carboxylates (14 and 15), derived from a proline meso-ionic synthon, demonstrated remarkably different stabilities towards alkaline hydrolysis. On that basis, a nonchromatographic, highly efficient method for their large-scale separation was developed. The desired isomer 14 was converted into 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carbaldehyde, a key intermediate in the synthesis of bicyclic heteroaryl-substituted 6-alkylidene penems.

The synthesis of pyrimidine containing dendrimer-like dianionic inhibitors of the respiratory syncytial virus is described; their biological activity is compared with that of triazine compounds with the similar structure.

Through high throughput screening of various libraries, substituted styryl naphthalene 6 was identified as an HCMV protease inhibitor. Optimization of various regions of the lead molecule using parallel synthesis resulted in 1,6-substituted naphthalenes 19d-i. These compounds displayed good potency and were selective over elastase, trypsin, and chymotrypsin. The optimization approach on lead compound 6 in three different regions of the molecule using parallel solution-phase synthesis and the corresponding SAR are discussed in detail.

Background: RFI-641, a small dendrimer-like compound, is a potent and selective inhibitor of respiratory syncytial virus (RSV), which is currently a clinical candidate for the treatment of upper and lower respiratory tract infections caused by RSV. RFI-641 inhibits RSV growth with an IC50 value of 50 nM and prevents syncytia formation in tissue culture. RSV contains of three surface glycoproteins, a small hydrophobic (SH) protein of unknown function, and attachment (G) and fusion (F) proteins that enable binding and fusion of virus, respectively, with target cells. Because of their role in attachment and fusion, the G and F surface proteins are prominent targets for therapeutic intervention. RFI-641 was previously shown to bind purified preparations of RSV fusion protein. Based on this observation, in conjunction with the biological results, it was speculated that the fusion event might be the target of these inhibitors.Results: A fusion assay based upon the relief of self-quenching of octadecyl rhodamine R18 was used to determine effects of the inhibitors on binding and fusion of RSV. The results show that RFI-641 inhibits both RSV–cell binding and fusion events. The inhibition of RSV is mediated via binding to the fusion protein on the viral surface. A closely related analog, WAY-158830, which is much less active in the virus-infectivity assay does not inhibit binding and fusion of RSV with Vero cells.Conclusions: RFI-641, an in vivo active RSV inhibitor, is shown to inhibit both binding and fusion of RSV with cells, events that are early committed steps in RSV entry and pathogenicity. The results described here demonstrate that a non-peptidic, small molecule can inhibit binding and fusion of enveloped virus specifically via interaction with the viral fusion protein.

ADVERTISEMENT RETURN TO ISSUEPREVLetterNEXTNovel and Specific Respiratory Syncytial Virus Inhibitors That Target Virus FusionWei-dong Ding, Boris Mitsner, Girija Krishnamurthy, Ann Aulabaugh, Cynthia D. Hess, Joe Zaccardi, Mark Cutler, Boris Feld, Anna Gazumyan, Yuri Raifeld, Antonia Nikitenko, Stanley A. Lang, Yakov Gluzman, Bryan O'Hara, and George A. EllestadView Author Information Departments of Bioorganic/Enzymology, Wyeth-Lederle Vaccines and Pediatrics, Medicinal Chemistry, and Infectious Diseases, Wyeth-Ayerst Research, Pearl River, New York 10965 Cite this: J. Med. Chem. 1998, 41, 15, 2671–2675Publication Date (Web):June 23, 1998Publication History Received20 April 1998Published online23 June 1998Published inissue 1 July 1998https://pubs.acs.org/doi/10.1021/jm980239ehttps://doi.org/10.1021/jm980239erapid-communicationACS PublicationsCopyright © 1998 American Chemical SocietyRequest reuse permissionsArticle Views467Altmetric-Citations40LEARN 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 SUBJECTS:Fluorescence,Infectious diseases,Inhibitors,Noncovalent interactions,Peptides and proteins Get e-Alerts