The Scripps Research Institute

The University of Texas System

Other

Bristol-Myers Squibb Compnay

Abide Therapeutics, Inc.

The Scripps Institute

Dale L Boger

Richard A Lerner

David A Cheresh

Bruce A Beutler

Steven J Henriksen

Chi-Huey Wong

Benjamin F Cravatt

Todd Kevin Jones

Cheryl A Grice

Sanjeev Gangwar

Qian Zhang

Lawrence B Snyder

Kim D Janda

Soan Cheng

Fukang Yang

Justin S Cisar

Norton B Gilula

Gary E Siuzdak

Peter L Myers

Jon A Ashley

Ben Cravatt

Katerina Otrubova

Bruce Beutler

A diprovocim compound that corresponds in structure to structural Formula V is disclosed, wherein A, W, Z, R, R, Rand R(when present) are defined within. A diprovocim compound has immune-adjuvant properties on human and mouse cells in culture and on in vivo immunization of mice. A composition containing a diprovocim and a method of using a compound are also disclosed. The immunostimulatory activity of a diprovocim compound is similar to that of LPS, to which there is no apparent structural similarity. A contemplated compound bears no structural similarity to either the TLR1/TLR2 lipoprotein agonists nor to any other synthetic TLR agonist, and is remarkably easy to prepare and synthetically modify. 

Diprovocims: a new and potent class of TLR agonists

Synthetically-derived and previously inaccessible modifications of 20'-hydroxy-vinca derivative compounds such as vinblastine, vincristine or vindesine are disclosed that are a stunning 100-fold more active than the natural product (IC's 50-75 pM vs 7 nM, HCT116), and are now accessible as a result of advances in the total synthesis of the natural product. Illustrative new ultra-potent vinblastines bind tubulin with much higher affinity and likely further disrupt the tubulin head-to-tail &#x3b1;/&#x3b2; dimer-dimer interaction by virtue of the strategic placement of an added conformationally well-defined, rigid and extended C20&#x2032;-urea along the adjacent protein-protein interface. Added molecular complexity was used to markedly enhance target binding and functional biological activity, and represents a general approach to improving the properties of other natural products targeting a protein-protein interaction. A pharmaceutical composition containing an ultra-potent 20&#x2032;-hydroxy-vinca derivative compound and a method of treating cancerous cells with such a compound are also disclosed.

Ultra-potent vinca alkaloids: added molecular complexity further disrupts the tublin dimer-dimer interface

A C-terminus modification to a binding pocket-modified vancomycin introduces a quaternary ammonium salt that provides a binding pocket-modified vancomycin analog with a second mechanism of action that is independent of D-Ala-D-Ala/D-Ala-D-Lac binding. The modification disrupts cell wall integrity and induces cell wall permeability complementary to the glycopeptide inhibition of cell wall synthesis, and provides synergistic improvements in antimicrobial potency (200-fold) against vancomycin-resistant bacteria. Combining the C-terminus and binding pocket modifications with an orthogonal (4-chlorobiphenyl) methyl addition to the vancomycin disaccharide provides even more potent antimicrobial agents whose activity can be attributed to three independent and synergistic mechanisms of action, only one of which requires D-Ala-D-Ala/D-Ala-D-Lac binding. The resulting modified vancomycins display little propensity for acquired resistance through serial exposure of vancomycin-resistant Enterococci and their durability against such challenges as well as their antimicrobial potency follow predicable trends. Methods of treatment with and compositions containing the modified vancomycins are disclosed.

Peripheral modifications on pocket-redesigned vancomycin analogs synergistically improve antimicrobial potency and durability

A vinca alkaloid compound substituted at the 20'-position with a carboxamido group is disclosed. The carbonyl of the carboxamido group is bonded to a 20&#x2032;-amino group and to a ring system that contains up to three 5-, 6- or 7-membered rings that are fused or otherwise bonded together. Each ring can be carbocyclic or heterocyclic, with a heterocyclic ring containing up to three hetero ring atoms that are the same or different and are selected from nitrogen, oxygen and sulfur. The ring system can include up to four substituent groups other than hydrogen that are discussed within. Methods of preparing the compounds are disclosed as are compositions for their use and methods of treatment using d compound. A particularly preferred compound has an activity in specified cancer cell growth inhibition assays that is the same or better than its parental, unsubstituted vinca compound and is not subject to Pgp-mediated efflux.

Vinblastine 20&#x2033; amides: synthetic analogs that maintain or improve potency and simultaneously overcome Pgp-derived efflux and resistance

The total synthesis and evaluation of key analogs of vancomycin containing single atom changes in the binding pocket are disclosed as well as their peripherally modified, N-(hydrophobe-substituted) derivatives exemplified by a N-4-(4'-chlorobiphenyl)-methyl derivative and their pharmaceutically acceptable salts are disclosed. Their evaluation indicates the combined pocket and peripherally modified analogs exhibit a remarkable spectrum of antimicrobial activity and truly impressive potencies against both vancomycin-sensitive and -resistant bacteria, and likely benefit from two independent and synergistic mechanisms of action. A pharmaceutical composition containing a contemplated compound or its pharmaceutically acceptable salt is disclosed, as is a method of treating a bacterial infection in a mammal by administering an antibacterial amount of a contemplated compound or its salt as above to an infected mammal in need of treatment.

N-(hydrophobe-substituted) vancosaminyl [&#x3a8;-[C(=NH) NH] Tpg] vancomycin and [&#x3a8;-[CHNH]Tpg] vancomycin

seco-Cyclopropapyrroloindole compounds of formula (I) where Hal, R, R, and Rare as defined in the application, are potent anti-cancer agents that can be used in antibody-drug conjugates.

Seco-cyclopropapyrroloindole compounds, antibody-drug conjugates thereof, and methods of making and use

Provided herein are pyrazole compounds and pharmaceutical compositions comprising said compounds. The subject compounds and compositions are useful as modulators of one or more of MAGL, ABHD6, and FAAH. Furthermore, the subject compounds and compositions are useful for the treatment of, for example, pain, solid tumors and/or obesity.

Pyrazole compounds and methods of making and using same

A TLR-independent adjuvant compound that corresponds in structure to Formula I, below, or its pharmaceutically acceptable salt is disclosed in which X, Y, Z, n, R, R, R, Rand W are defined within. Also disclosed are a method of its preparation and use, as well as a pharmaceutical composition containing the same.

TLR-independent small molecule adjuvants

The invention is directed to glycopeptide antibiotics and their aglycones that are engineered to overcome bacterial resistance by replacement of a single, specific peptide carboxamide group in the core peptide of the glycopeptide antibiotic with an amidine group. The amidine pseudopeptide analog of the glycopeptide is effective in killing vancomycin-resistant bacteria at therapeutically achievable concentrations in a patient. For example, a [&#x3a8;[C(&#x2550;NH)NH]Tpg]-vancomycin aglycon designed to exhibit the dual binding to D-Ala-D-Ala and D-Ala-D-Lac needed to reinstate activity against vancomycin-resistant bacteria has been shown to overcome a common mode of bacterial resistance to the 'last resort' antibiotics of the glycopeptide class. The pseudopeptide amidine analogs can be prepared from corresponding pseudopeptide thioamide analogs, which can be prepared synthetically, semi-synthetically, or biosynthetically.

Glycopeptide antibiotic analogs effective against vancomycin-resistant bacterial strains

A MD-2:TLR4 complex agonist compound is disclosed whose structure corresponds to Formula (I), as defined within. Also disclosed are a method of its preparation and use, as well as a pharmaceutical composition containing the same. 

Neoseptins: small molecule adjuvants

A vinca alkaloid compound that is substituted at the 20'-position with a urea or thiourea group is disclosed. The urea's proximal nitrogen atom bonded to the 20&#x2032;-position carbon atom is secondary, whereas the distal nitrogen atom can be unsubstituted only when the compound contains an optionally present 10&#x2032;-fluoro substituent, and is otherwise preferably mono- or di-substituted. Methods of preparing the compounds are disclosed as are compositions for their use and methods of treatment using a compound.

C20' urea derivatives of vinca alkaloids

A group of cyclic N-acyl O-amino phenol CBI derivatives were synthesized and shown to be pro-drugs, subject to reductive activation by cleavage of a N-0 bond, effectively releasing the free drug in functional in vitro cellular assays for cytotoxic activity approaching the activity of the free drug, yet remain essentially stable to ex vivo DNA alkylation conditions. Assessment of the in vivo antitumor activity of a representative pro-drug indicates that a contemplated pro-drug approaches the potency and exceeds the efficacy of the free drug itself (CBI-indole), indicating that the inactive pro-drugs not only effectively release the free drug in vivo, but that they offer additional advantages related to a controlled or targeted release in vivo.

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Compounds are disclosed that are effective in inhibition of fatty acid amide hydrolase, an enzyme responsible for catabolism of endogenous cannabinoids such as anandamide. The compounds are useful as analgesic compounds and as sleep-inducing compounds, that can be orally administered, and that can have a relatively long duration of effect. Methods of preparation of the compounds are also provided. The compounds are conformationally constrained analogs of heterocyclylketones such as oxazolylketones.

Alpha-ketoheterocycles and methods of making and using

The invention provides prodrugs of DNA-reactive analogs of duocarmycin and CC-1065 anticancer agents, wherein a cyclic prodrug form, such as carbamate, thionocarbamate, or carbamimidate, can be hydrolyzed by the patient in vivo to yield a respective bioactive agent comprising a DNA-alkylating moiety and a binding/targeting moiety. The DNA-reactive moiety is a &#x3b3;-spirocyclohexenone fused to a heterocyclyl group which can be produced by endogenous hydrolysis of a cyclic carbamate prodrug of the invention. The cyclic carbamate prodrug produces no residual byproduct during activation in vivo. Methods of synthesis and biological methods and data are also provided.

Cyclic prodrugs of duocarmycin analogs

The invention provides a series of -&#x3b1;ketoheterocyclic compounds, for example, compounds of formula (I). The compounds can inhibit fatty acid amide hydrolase and can be useful for treatment of malconditions modulated by fatty acid amide hydrolase. The invention further provides methods of making compounds of formula (I), useful intermediates for the preparation of compounds of formula (I), and methods of using compounds of formula (I) and compositions thereof.

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La Jolla, CA, United States of America

Dale L Boger