University of Southern California

The United States of America, As Represented by the Secretary, Department of Health and Human Services

Massachusetts Eye and Ear Infirmary

Tsrl, Inc.

University of California

Institut National De La Sante Et De La Recherche Medicale

Université Grenoble Alpes

Cnrs

The United States of America As Represented by the Nih Division of Extramural Inventions and Technology Resources (deitr)

Commissariat &#xc0; L'&#xc9;nergie Atomique Et Aux &#xc9;nergies Alternatives

Inserm

Boris A Kashemirov

Kai Chen

Charles E McKenna

John Hilfinger

Albert Edge

Michael J McKenna

William Sewell

Judith Kempfle

Woo Seok Kang

David Jung

Ivan S Krylov

Kim Nguyen

Valeria M Zakharova

Thomas D Wolfe

Michaela Serpi

Shuting Sun

Ichiro Nishimura

Eric T Richard

Akishige Hokugo

Charles E Mckenna

Patricia I Bonaz-Krause

Ulrika Tehler

Isabelle Favier

Larryn Peterson

Kanokkarn Saejueng

Chi Pham

Joy Lynn F Bala

Larryn W Peterson

Jinglei Lyu

Jaijun Fan

Flore Mietton

Elena Ferri

Jerome Govin

Carlo Petosa

Kenzo Morinaga

Amirsoheil Negahbani

This invention relates to drug conjugates useful for localized treatment of diseases or disorders of the middle ear and/or inner ear. Methods of treating diseases or disorders of the middle ear and/or inner ear, pharmaceutical compositions comprising the conjugates, and methods of inhibiting a Tropomyosin receptor kinase are also provided.

Phosphonate-drug conjugates

In certain embodiments osteoadsorptive fluorogenic substrates of cathepsin K (or other proteases) are provided. Utilizing a bisphosphonate targeting moiety, the fluorogenic substrates provide effective bone-targeted protease sensor(s). In certain embodiments the 'probes' comprise cleavable fluorophore-quencher pair linked by a cathepsin K (or other protease) peptide substrate and tethered to a bisphosphonate. Unlike existing probes that are cleared within a few days in vivo, the probes described herein (e.g., OFS-1) allow for monitoring resorption over the course of longer time periods with a single dose.

Osteoadsorptive fluorogenic substrate of cathepsin k for imaging osteoclast activity and migration

Antiviral compounds comprising prodrugs with differing side chains derived from a tyrosine substance in the form of a tyrosine amide in which the amide substituent side chain is an alkyl ether, thioether, or alkene. Embodiments of the compounds have a range of effective lipophilicity values allowing variation in aqueous solubility, oral bioavailability, cell permeability and in vivo activation properties. The embodiments have promoieties derived from a single amino acid, which are expected to have low toxicity. The features described above also make possible a novel 'precision medicine' approach to treatment of viral infections, whereby the prodrug variations can be exploited to match optimal activation of the prodrug to a given patient or strain of virus.

Broad spectrum antiviral compounds

The invention provides antifungal compounds, antifungal compositions, and intermediates for the preparation of antifungal compounds and antifungal compositions. The invention also provides methods of inhibiting fungi and methods of treating fungal infections, for example, with a compound or composition described herein. The antifungal compositions can include antifungal adjuvants such as essential oils or essential oil extracts, which adjuvants further improve the antifungal activity of the compositions.

Selective bromodomain inhibition of fungal Bdf1

An amino acid conjugate of a cyclic or acyclic nucleoside phosphonate is provided. In some cases, the amino acid conjugate is a tyrosine alkyl amide phosphonate ester conjugate of a cyclic or acyclic nucleoside phosphonate, and is useful as an antiviral compound. In certain cases, the tyrosine conjugate includes a long chain alkyl group on the carboxamide group of the tyrosine residue. In a method of preparing an acyclic tyrosine conjugate, a tert-butyloxycarbonyl (Boc) protected tyrosine residue containing a long chain alkyl group is reacted with an acyclic nucleoside phosphonate mono-ethyl ester in the presence of benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate to produce a Boc-protected nucleoside phosphonate di-ester, and the di-ester is deethylated and deprotected to produce the tyrosine conjugate. Methods of inhibiting viral replication and methods of treating a viral infection using the amino acid conjugate are also provided.

Method to improve antiviral activity of nucleotide analogue drugs

A tyrosine-based (phosphonylmethoxyalkyl)purine or -pyrimidine conjugate is provided. In some embodiments, the conjugate includes tyrosine based amino acid or dipeptide moieties of (S)-9-(3-hydroxy-2-phosphonyl-methoxypropyl)adenine or its cytosine analog. A method of synthesizing such conjugates based on Boc-protected amino acid or dipeptides is also provided. In addition, a method of isomerizing an (S,S)-diastereoisomer to an (S,R)-diastereoisomer of an amino acid-based or dipeptide-based conjugate by a process including transesterification is provided. A method of inhibiting viral infection and a method of treating viral infection based on (phosphonylmethoxyalkyl)purine or -pyrimidine conjugates is also provided.

Tyrosine-based prodrugs of antiviral agents

The present invention relates to drug derivatives and linkers. The invention specifically relates to compounds and methods of phosphonates and linkers, that are useful as carriers for imaging agents and useful in the treatment of various bone diseases.

Synthesis of drug conjugates via reaction with epoxide-containing linkers

Cidofovir or foscarnet based compounds having an amino acid or dipeptide esters are provided as prodrugs.

Phosphonyl ester conjugates as prodrugs

The present invention provides for Troika acids attached to a macroporous resin and Methods of preparing the same, including direct attachment of a Troika acid, and attachment of a Troika acid precursor followed by generation of the Troika acid in situ. Methods of functionalizing a resin to facilitate attachment are also described. Multiple Troika acids, comprising a pair of Troika acids joined together are described. Synthetic routes to both microporous and macroporous resins modified by introduction of a suitable Troika-type acid have been designed and validated. In a preferred embodiment, a macroporous Troika resin removes Cuand Nifrom aqueous solution with high affinity, and is selective against Mgor Ca. The materials of the present invention have advantages for metal removal from power plant waste water.

Chelating agents for heavy metal removal

Cidofovir-based compounds having an amino acid, dipeptide or tripeptide attached to a cidofovir or cyclic cidofovir framework. The compounds show enhanced oral bioavailability and increased binding to the PepT1 transporter. The present invention also provides compositions and methods for treating virus infections, and a method of preparing cidofovir.

Cidofovir peptide conjugates as prodrugs

Novel phosphonate compounds are provided including a phosphonoglyoxylamide ester, an &#x3b1;-keto phosphonophosphinate ester, a carbonylbisphosphonate analog of a nucleotide, and a diazomethylenebisphosphonate analog of a nucleotide, as well as methods of making synthetically and medically useful &#x3b1;-keto phosphonate compounds.

Preparation and use of &#x3b1;-keto phosphonates

.alpha.-(hydroxyimino)phosphonoacetic acids (also referred to as '.alpha.,.alpha.-disubstituted trifunctional oximes' and 'Troika Acids') and their derivatives, and methods to prepare them are disclosed. Also disclosed are the structures and fragmentation pathways of the .alpha.-(hydroxyimino)phosphonoacetic acids. The .alpha.-(hydroxyimino)phosphonoacetic acids and derivatives are useful as pH sensitive chelating agents, enzyme activated drugs, drug delivery agents, phosphorylating reagents and photo-activated reagents.

Preparation and use of .alpha.-(hydroxyimino) phosphonoacetic acids

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Los Angeles, CA, United States of America

Boris A Kashemirov