- Prescreening of Nicotine Hapten Linkers in Vitro To Select Hapten-Conjugate Vaccine Candidates for Pharmacokinetic Evaluation in Vivo
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Since the demonstration of nicotine vaccines as a possible therapeutic intervention for the effects of tobacco smoke, extensive effort has been made to enhance nicotine specific immunity. Linker modifications of nicotine haptens have been a focal point for improving the immunogenicity of nicotine, in which the evaluation of these modifications usually relies on in vivo animal models, such as mice, rats or nonhuman primates. Here, we present two in vitro screening strategies to estimate and predict the immunogenic potential of our newly designed nicotine haptens. One utilizes a competition enzyme-linked immunoabsorbent assay (ELISA) to profile the interactions of nicotine haptens or hapten-protein conjugates with nicotine specific antibodies, both polyclonal and monoclonal. Another relies on computational modeling of the interactions between haptens and amino acid residues near the conjugation site of the carrier protein to infer linker-carrier protein conjugation effect on antinicotine antibody response. Using these two in vitro methods, we ranked the haptens with different linkers for their potential as viable vaccine candidates. The ELISA-based hapten ranking was in an agreement with the results obtained by in vivo nicotine pharmacokinetic analysis. A correlation was found between the average binding affinity (IC50) of the haptens to an anti-Nic monoclonal antibody and the average brain nicotine concentration in the immunized mice. The computational modeling of hapten and carrier protein interactions helps exclude conjugates with strong linker-carrier conjugation effects and low in vivo efficacy. The simplicity of these in vitro screening strategies should facilitate the selection and development of more effective nicotine conjugate vaccines. In addition, these data highlight a previously under-appreciated contribution of linkers and hapten-protein conjugations to conjugate vaccine immunogenicity by virtue of their inclusion in the epitope that binds and activates B cells.
- Arutla, Viswanath,Leal, Joseph,Liu, Xiaowei,Sokalingam, Sriram,Raleigh, Michael,Adaralegbe, Adejimi,Liu, Li,Pentel, Paul R.,Hecht, Sidney M.,Chang, Yung
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- HETEROARYLDIHYDROPYRIMIDINE DERIVATIVES AND METHODS OF TREATING HEPATITIS B INFECTIONS
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Provided herein are compounds useful for the treatment of HBV infection in a subject in need thereof, pharmaceutical compositions thereof, and methods of inhibiting, suppressing, or preventing HBV infection in the subject.
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Page/Page column 131; 132
(2020/07/14)
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- METHODS OF RATIONAL NICOTINE HAPTEN DESIGN AND USES THEREOF
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Provided herein are methods for rational design of nicotine haptens. More particularly, provided herein are methods for designing, selecting, and synthesizing nicotine haptens and nicotine hapten conjugates. Also provided herein are novel nicotine haptens and methods for using nicotine haptens to treat nicotine addiction.
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Paragraph 0094
(2017/01/19)
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- INDAZOLYL THIADIAZOLAMINES AND RELATED COMPOUNDS FOR INHIBITION OF RHO-ASSOCIATED PROTEIN KINASE AND THE TREATMENT OF DISEASE
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The invention provides indazolyl thiadiazolamines and related compounds, pharmaceutical compositions, methods of inhibiting Rho-associated protein kinase, and methods of treating inflammatory disorders, immune disorders, fibrotic disorders, and other medical disorders using such compounds. An exemplary indazolyl thiadiazolamine compound is an N-(5-[5-[(1H4ndazol-5-yl)amino]-1,3,4-thiadiazol-2-yl]pyridin-3-yl)acetamide compound.
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Paragraph 00421
(2016/09/22)
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- Tetrahydroquinazolinone Derivatives as PARP Inhibitors
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Disclosed are compounds of formula (I), their tautomeric forms, stereoisomers, and pharmaceutically acceptable salts thereof, wherein R1-R6, R7a-d, R8a-d, A, M, n, and p are as defined in the specification, pharmaceutical compositions including a compound, tautomer, stereoisomer, or salt thereof, and methods of treating or preventing diseases or disorders, for example, cancer, that are amenable to treatment or prevention by inhibiting the PARP enzyme of a subject.
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Paragraph 0700 - 0703
(2015/06/10)
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- TETRAHYDROQUINAZOLINONE DERIVATIVES AS PARP INHIBITORS
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Disclosed are compounds of formula (I), their tautomeric forms, stereoisomers, and pharmaceutically acceptable salts thereof, wherein R1-R6, R7a-d, R8a-d, A, M, n, and p are as defined in the specification, pharmaceutical compositions including a compound, tautomer, stereoisomer, or salt thereof, and methods of treating or preventing diseases or disorders, for example, cancer, that are amenable to treatment or prevention by inhibiting the PARP enzyme of a subject.
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Page/Page column 108
(2014/02/15)
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- NOVEL OXADIAZOLE COMPOUNDS
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Novel oxadiazole compounds, pharmaceutical compositions containing such compounds and the use of those compounds or compositions as agonists or antagonists of the S1P family of G protein-coupled receptors for treating diseases associated with modulation o
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Page/Page column 208-209
(2011/06/26)
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- Pyrrolopyrazinyl Urea Kinase Inhibitors
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The present invention relates to the use of novel pyrrolopyrazinyl urea derivatives of Formula I, wherein the variables R1, R2, R3, R4, and R5 are defined as described herein, which inhibit JAK and are useful for the treatment of auto-immune and inflammatory diseases.
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Page/Page column 47
(2010/06/19)
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- ARYL-PHENYL-SULFONAMIDO-CYCLOALKYL COMPOUNDS AND THEIR USE
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The present invention pertains generally to the field of therapeutic compounds, and more specifically to certain aryl-phenyl-sulfonamido-cycloalkyl compounds of the following formula (collectively referred to herein as "APSAC compounds"). The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, in treatment, for example, of inflammation and/or joint destruction and/or bone loss; of disorders mediated by excessive and/or inappropriate and/or prolonged activation of the immune system; of inflammatory and autoimmune disorders, for example, rheumatoid arthritis, psoriasis, psoriatic arthritis, chronic obstructive pulmonary disease (COPD), atherosclerosis, inflammatory bowel disease, ankylosing spondylitis, and the like; of disorders associated with bone loss, such as bone loss associated with excessive osteoclast activity in rheumatoid arthritis, osteoporosis, cancer-associated bone disease, Paget's disease and the like, etc.; and of cancer, such as a haematological malignancy, a solid tumour, etc. Formula (I).
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Page/Page column 91
(2010/04/25)
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- DERIVATIVES OF 6,7-DIHYDRO-5H-IMIDAZO[1,2-α]IMIDAZOLE-3- CARBOXYLIC ACID AMIDES
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Derivatives of 6,7-dihydro-5H-imidazo[1,2-α]imidazole-3-carboxylic acid amide exhibit good inhibitory effect upon the interaction of CAMs and Leukointegrins and are thus useful in the treatment of inflammatory disease.
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Page/Page column 96
(2009/07/03)
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- Amine Compounds
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There is provided a compound exhibiting an activity of suppressing immune response with reduced adverse drug reactions, which compound is useful in the chemotherapy for preventing or treating, for example, a wide range of various autoimmune diseases including systemic erythematodes, chronic rheumatoid arthritis, Type I diabetes, inflammatory bowel disease, biliary cirrhosis, uveitis, multiple sclerosis or other disorders, or chronic inflammatory diseases, or cancers, lymphoma or leukemia, or resistance to organ or tissue transplantation or rejection against transplantation. Novel amine compounds having an S1P1/Edg1 receptor agonist effect, possible stereoisomers or racemic bodies of the compounds, or pharmacologically acceptable salts, hydrates or solvates of the compound, the stereoisomers or the racemic bodies, or prodrugs of the compounds, the stereoisomers, the racemic bodies, the salts, the hydrates or the solvates, are provided.
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Page/Page column 173
(2008/12/08)
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- NOVEL COMPOUNDS
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There is provided a compound of formula (I): processes for the manufacture thereof, pharmaceutical compositions thereof and uses in therapy.
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Page/Page column 108
(2008/06/13)
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- ALKYLAMINO, ARYLAMINO, AND SULFONAMIDO CYCLOPENTYL AMIDE MODULATORS OF CHEMOKINE RECEPTOR ACTIVITY
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Compounds of the formula (I) which are modulators of chemokine receptor activity useful in the prevention or treatment of certain inflammatory and immunoregulatory disorders and diseases, allergic diseases, atopic conditions including allergic rhinitis, dermatitis, conjunctivitis, and asthma, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis, and pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which chemokine receptors are involved.
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Page/Page column 15
(2010/11/27)
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- 2-CARBOCYCLOAMINO-4-IMIDAZ0LYLPYRIMIDINES AS AGENTS FOR THE INHBITION OF CELL PROLIFERATION
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Compounds of formula (I): which possess cell cycle inhibitory activity are described.
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Page/Page column 56
(2008/06/13)
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- TETRAHYDROPYRANYL CYCLOPENTYL TETRAHY-DROPYRIDOPYRIDINE MODULATORS OF CHEMOKINE RECEPTOR ACTIVITY
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Compounds of Formula I (wherein n, R1, R3, R4, R5, R6, R7, R8, R9, R10, R15, R16, Y and Z are as defined herein) which are modulators of chemokine receptor activity and are useful in the prevention or treatment of certain inflammatory and immunoregulatory
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- PHENYL ACETAMIDES
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The invention relates to the phenyl acetamides of formula (I), to a method for producing them and to their use for producing drugs for use in the treatment and/or prophylaxis of human or animal diseases, especially cardiovascular diseases.
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Page/Page column 30-31
(2010/02/14)
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- 3,3-DISUBSTITUTED TETRAHYDROPYRANYL CYCLOPENTYL AMIDE MODULATORS OF CHEMOKINE RECEPTOR ACTIVITY
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Compounds of Formula I (wherein n, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R15, R16, R17, R18, Y and Z are as defined herein) which are modulators of chemokine receptor activity and are useful in the prevention or treatment of certain inflammatory and im
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Page/Page column 29
(2008/06/13)
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- Synthesis and DNA binding properties of saturated distamycin analogues
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A series of saturated heterocyclic analogues of distamycin were prepared and examined. A fluorescent intercalator displacement (FID) assay conducted on p[dA]-p[dT] DNA to obtain C50 values and a hairpin deoxyoligonucleotide containing an A/T-rich binding site was used to evaluate DNA binding affinity. It is observed that saturated heterocycles greatly reduce the DNA binding relative to distamycin.
- Woods, Craig R.,Faucher, Nicolas,Eschgfaller, Bernd,Bair, Kenneth W.,Boger, Dale L.
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p. 2647 - 2650
(2007/10/03)
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- Asymmetric synthesis and structure-activity relationship of the four stereoisomers of the antibiotic amidinomycin part 1: The synthesis
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The natural amidinomycin ((1R, 3S)-14) and its three stereoisomers are synthesized from homochiral 3-oxocyclopentanecarboxylic acids (1a) by asymmetric methods, which are based on an asymmetric reductive amination to produce methyl cis-N-(1-phenylethyl)-3-aminocyclo-pentanecarboxylates (3b) via optically active methyl N-(1-phenylethyl)-3-iminocyclopentane- carboxylates (2b) for the cis-isomers of 14. Optically pure trans-3- aminocyclopentane-carboxylic acids (4a) are obtained from the homochiral keto acids 1a via asymmetric reductive amination of 3- hydroxyiminocyclopentanecarboxylic acids (5a) and lead to the trans-isomers of 14.
- Sung, Sun-Young,Frahm, August Wilhelm
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p. 291 - 300
(2007/10/03)
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- Chirospecific Synthesis of (1S,3R)-1-Amino-3-(hydroxymethyl)cyclopentane, Precursor for Carbocyclic Nucleoside Synthesis. Dieckmann Cyclization with an α-Amino Acid
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Carbocyclic nucleosides are important isosters of nucleosides possessing a variety of antiviral and antineoplastic activities.We report here a new method for the chirospecific synthesis of (1S,3R)-1-amino-3-(hydroxymethyl)cyclopentane.This compound is a key precursor for the synthesis of some carbocyclic nucleosides.The method involves (1) an improved synthesis of (S)-2-aminoadipic acid; (2) Dieckmann cyclization of this α-amino acid to an aminocyclopentanone; and (3) elaboration of the latter to the target (1S,3R)-1-amino-3-(hydroxymethyl)cyclopentane.The starting (S)-2-aminoadipic acid δ-methyl ester was prepared enantiomerically pure from (S)-aspartic acid in 51percent overall yield.Dieckmann condensation converted this amino acid to a (methoxycarbonyl)-cyclopentanone, and reduction of the ketone followed by elimination yielded (S)-3--1-(methoxycarbonyl)cyclopentene.Reduction of the double bond gave a mixture of the cis and trans diastereomers.This mixture was converted to a single diastereomer by epimerization and trapping of the cis isomer as (1S,4R)-2-(9-phenylfluoren-9-yl)-2-azabicycloheptan-3-one.Hydrolytic cleavage of the lactam followed by reduction gave (1S,3R)-1-amino-3-(hydroxymethyl)cyclopentane.
- Bergmeier, Stephen C.,Cobas, Agustin A.,Rapoport, Henry
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p. 2369 - 2376
(2007/10/02)
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