Patents by Inventor Dale Boger
Dale Boger has filed for patents to protect the following inventions. This listing includes patent applications that are pending as well as patents that have already been granted by the United States Patent and Trademark Office (USPTO).
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Patent number: 10975101Abstract: 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 (IC50'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 ?/? dimer-dimer interaction by virtue of the strategic placement of an added conformationally well-defined, rigid and extended C20?-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.Type: GrantFiled: May 30, 2017Date of Patent: April 13, 2021Assignee: THE SCRIPPS RESEARCH INSTITUTEInventor: Dale Boger
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Patent number: 10934326Abstract: 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.Type: GrantFiled: October 31, 2017Date of Patent: March 2, 2021Assignee: THE SCRIPPS RESEARCH INSTITUTEInventor: Dale Boger
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Publication number: 20200317696Abstract: 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 (IC50'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 ?/? dimer-dimer interaction by virtue of the strategic placement of an added conformationally well-defined, rigid and extended C20?-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.Type: ApplicationFiled: May 30, 2017Publication date: October 8, 2020Inventor: Dale Boger
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Patent number: 10689381Abstract: 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?-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.Type: GrantFiled: August 1, 2018Date of Patent: June 23, 2020Assignee: The Scripps Research InstituteInventor: Dale Boger
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Publication number: 20190119277Abstract: 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?-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.Type: ApplicationFiled: August 1, 2018Publication date: April 25, 2019Inventor: Dale Boger
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Patent number: 9918959Abstract: 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, R1, R2, R3, R4 and W are defined within. Also disclosed are a method of its preparation and use, as well as a pharmaceutical composition containing the same.Type: GrantFiled: August 5, 2015Date of Patent: March 20, 2018Assignees: The Board of Regents of the University of Texas System, The Scripps Research InstituteInventors: Dale Boger, Bruce Beutler
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Patent number: 9611271Abstract: 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?-position carbon atom is secondary, whereas the distal nitrogen atom can be unsubstituted only when the compound contains an optionally present 10?-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.Type: GrantFiled: August 23, 2013Date of Patent: April 4, 2017Assignee: SCRIPPS RESEARCH INSTITUTEInventor: Dale Boger
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Patent number: 9586974Abstract: 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-indole2), 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.Type: GrantFiled: March 20, 2014Date of Patent: March 7, 2017Assignee: The Scripps Research InstituteInventor: Dale Boger
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Publication number: 20150291610Abstract: 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?-position carbon atom is secondary, whereas the distal nitrogen atom can be unsubstituted only when the compound contains an optionally present 10?-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.Type: ApplicationFiled: August 23, 2013Publication date: October 15, 2015Inventor: Dale Boger
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Patent number: 8377981Abstract: A unique class of N-acyl O-amino phenol prodrugs of CBI-TMI and CBI-indole2 were synthesized and shown to be prodrugs, subject to reductive activation by nucleophilic cleavage of a weak N—O bond, effectively releasing the free drug in functional cellular assays for cytotoxic activity approaching or matching the activity of the free drug, yet remain essentially stable to ex vivo DNA alkylation conditions. Most impressively, assessment of the in vivo antitumor activity of a representative O-(acylamino) prodrug, 8, indicate that they approach the potency and exceed the efficacy of the free drug itself (CBI-indole2), indicating that the inactive prodrugs not only effectively release the free drug in vivo, but that they offer additional advantages related to a controlled or targeted release in vivo.Type: GrantFiled: November 13, 2008Date of Patent: February 19, 2013Assignee: The Scripps Research InstituteInventor: Dale Boger
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Publication number: 20110112163Abstract: A unique class of N-acyl O-amino phenol prodrugs of CBI-TMI and CBI-indole2 were synthesized and shown to be prodrugs, subject to reductive activation by nucleophilic cleavage of a weak N—O bond, effectively releasing the free drug in functional cellular assays for cytotoxic activity approaching or matching the activity of the free drug, yet remain essentially stable to ex vivo DNA alkylation conditions. Most impressively, assessment of the in vivo antitumor activity of a representative O-(acylamino) prodrug, 8, indicate that they approach the potency and exceed the efficacy of the free drug itself (CBI-indole2), indicating that the inactive prodrugs not only effectively release the free drug in vivo, but that they offer additional advantages related to a controlled or targeted release in vivo.Type: ApplicationFiled: November 13, 2008Publication date: May 12, 2011Inventor: Dale Boger
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Publication number: 20080096931Abstract: Certain oxadiazole ketone compounds are useful as FAAH inhibitors. Such compounds may be used in pharmaceutical compositions and methods for the treatment of disease states, disorders, and conditions mediated by fatty acid amide hydrolase (FAAH) activity. Thus, the compounds may be administered to treat anxiety, pain, inflammation, sleep disorders, eating disorders, or movement disorders (such as MS).Type: ApplicationFiled: October 19, 2007Publication date: April 24, 2008Applicant: The Scripps Research InstituteInventor: Dale Boger
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Publication number: 20070203156Abstract: Certain oxazole ketone compounds are useful as FAAH inhibitors. Such compounds may be used in pharmaceutical compositions and methods for the treatment of disease states, disorders, and conditions mediated by fatty acid amide hydrolase (FAAH) activity. Thus, the compounds may be administered to treat anxiety, pain, inflammation, sleep disorders, eating disorders, or movement disorders (such as MS).Type: ApplicationFiled: February 20, 2007Publication date: August 30, 2007Applicant: The Scripps Research InstituteInventor: Dale Boger
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Publication number: 20070173438Abstract: [?[CH2NH]PG4] glycopeptide antibiotic analogs are reengineered forms of glycopeptides that exhibit antimicrobial activity against both wild type and glycopeptide antibiotic resistant strains of microorganisms. For example, [?[CH2NH]Tpg4] vancomycin aglycon is a reengineered form of vancomycin that exhibits antimicrobial activity (MIC=31 ?g/mL) against both wild type and VanA resistant organism (E. faecalis BM4166). The VanA resistant organism achieves its resistance, upon glycopeptide antibiotic challenge, by remodeling its D-Ala-D-Ala peptidoglycan cell wall precursor to D-Ala-D-Lac. [?[CH2NH]PG4] glycopeptide antibiotic analogs have an altered glycopeptide backbone wherein the carbonyl of the fourth amino acid residue of the glycopeptide backbone has been replaced with a methylene. This alteration of the glycopeptide backbone imparts dual binding affinities for both D-Ala-D-Ala and D-Ala-D-Lac and dual antimicrobial activities for both wild type and resistant strains.Type: ApplicationFiled: January 16, 2007Publication date: July 26, 2007Applicant: The Scripps Research InstituteInventor: Dale Boger
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Publication number: 20070167377Abstract: Potent human inhibitors of human glycinamide ribonucleotide transformylase and of aminoimidazole carboxamide ribonucleotide transformylase are designed, synthesized, and characterized.Type: ApplicationFiled: April 7, 2003Publication date: July 19, 2007Inventors: Dale Boger, Ian Wilson
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Publication number: 20060211769Abstract: Angiogenesis, tumor growth, and metalloproteinase 2 (MMP2) interaction with integrin-?v?3 are inhibited by an inhibitor compound of formula: wherein G1 and G2 are each independently —NH—C(O)—O—(CH2)v—(C6H4)—X3; Y1 and Y2 are each independently —OH or C1-C4 alkoxy; X1 and X2 are each independently halo or C1-C4 alkoxy; X3 is fluoro, nitro, C1-C4 alkyl, C1-C4 alkoxy, or C1-C4 perfluoroalkyl; Z is —C?C—, —C6H4—, cis —CH?CH—, trans —CH?CH—, cis —CH2—CH?CH—CH2—, trans —CH2—CH?CH—CH2—, 1,4-naphthyl, cis-1,3-cyclohexyl, trans-1,3-cyclohexyl, cis-1,4-cyclohexyl, or trans-1,4-cyclohexyl; A is H or a covalent bond; m and n are each 1; t is an integer having a value of 0 or 1; p and r are each 2, and v is 1; with the proviso that when A is H, t is 0, and when A is a covalent bond, t is 1.Type: ApplicationFiled: May 24, 2006Publication date: September 21, 2006Inventors: Dale Boger, David Cheresh
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Publication number: 20060167271Abstract: A purified compound and its pharmaceutically acceptable salt that inhibits the binding between the integrin intracellular or cytoplasmic tail polypeptide and Paxillin, a pharmaceutical composition containing that compound or salt and a method of treating a biological function in an animal using that compound or salt are disclosed. The purified compound corresponds in structure to Formula I, wherein W1 and W2, X1, X2 and X3 and Y are defined within.Type: ApplicationFiled: October 30, 2003Publication date: July 27, 2006Inventors: Mark Ginsberg, Dale Boger
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Publication number: 20060111359Abstract: Improved competitive inhibitors of FAAH employ an ?-keto heterocyclic pharmacophore and a binding subunit having a ?-unsaturation. The ?-keto heterocyclic pharmacophore and a binding subunit are attached to one another, preferably by a hydrocarbon chain. The improvement lies in the use of a heterocyclic pharmacophore selected from oxazoles, oxadiazoles, thiazoles, and thiadiazoles that have alkyl or aryl substituents at their 4 and/or 5 positions. The improved competitive inhibitors of FAAH display enhanced activity over conventional competitive inhibitors of FAAH.Type: ApplicationFiled: October 8, 2003Publication date: May 25, 2006Applicant: The Scripps Research InstituteInventor: Dale Boger
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Publication number: 20060100212Abstract: Certain oxadiazole ketone compounds are useful as FAAH inhibitors. Such compounds may be used in pharmaceutical compositions and methods for the treatment of disease states, disorders, and conditions mediated by fatty acid amide hydrolase (FAAH) activity. Thus, the compounds may be administered to treat anxiety, pain, inflammation, sleep disorders, eating disorders, or movement disorders (such as MS).Type: ApplicationFiled: October 14, 2005Publication date: May 11, 2006Applicant: The Scripps Research InstituteInventor: Dale Boger
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Publication number: 20050239785Abstract: Potent inhibitors of fatty acid amide hydrolase (FAAH) are constructed having Ki's below 200 pM and activities 102-103 times more potent than the corresponding trifluoromethyl ketones. The potent inhibitors combine several features, viz.: 1.) an ?-keto heterocylic head group; 2.) a hydrocarbon linkage unit employing an optimal C12-C8 chain length; and 3.) a phenyl or other ?-unsaturation corresponding to the arachidonyl ?8,9/?11,12 and/or oleyl ?9,10 positions. A preferred ?-keto heterocylic head group is ?-keto N4 oxazolopyridine, with incorporation of a second weakly basic nitrogen. Fatty acid amide hydrolase is an enzyme responsible for the degradation of oleamide (an endogenous sleep-inducing lipid) and anandamide (an endogenous ligand for cannabinoid receptors).Type: ApplicationFiled: March 28, 2005Publication date: October 27, 2005Applicant: The Scripps Research InstituteInventor: Dale Boger