- Discovery of phenylpyrrolidine derivatives as a novel class of retinol binding protein 4 (RBP4) reducers
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Retinol-binding protein 4 (RBP4) is a potential drug target for metabolic and ophthalmologic diseases. A high-throughput screening of our compound library has identified a small-molecule RBP4 reducer 7a, as a hit compound. Aiming to provide a suitable too
- Nakamura, Shinji,Kamaura, Masahiro,Akao, Yuichiro,Nakamura, Natsuko,Mizukami, Atsushi,Goto, Akihiko,Furuyama, Naoki,Cho, Nobuo,Kasai, Shizuo
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supporting information
(2021/12/30)
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- Targeting Alzheimer's disease by investigating previously unexplored chemical space surrounding the cholinesterase inhibitor donepezil
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A series of twenty seven acetylcholinesterase inhibitors, as potential agents for the treatment of Alzheimer's disease, were designed and synthesised based upon previously unexplored chemical space surrounding the molecular skeleton of the drug donepezil, which is currently used for the management of mild to severe Alzheimer's disease. Two series of analogues were prepared, the first looking at the replacement of the piperidine ring in donepezil with different sized saturated N-containing ring systems and the second looking at the introduction of different linkers between the indanone and piperidine rings in donepezil. The most active analogue 5,6-dimethoxy-1-oxo-2,3-dihydro-1H-inden-2-yl 1-benzylpiperidine-4-carboxylate (67) afforded an in vitro IC50value of 0.03 ± 0.07 μM against acetylcholinesterase with no cytotoxicity observed (IC50of >100 μM, SH-SY5Y cell line). In comparison donepezil had an IC50of 0.05 ± 0.06 μM and an observed cytotoxicity IC50of 15.54 ± 1.12 μM. Molecular modelling showed a strong correlation between activity and in silico binding in the active site of acetylcholinesterase.
- van Greunen, Divan G.,Cordier, Werner,Nell, Margo,van der Westhuyzen, Chris,Steenkamp, Vanessa,Panayides, Jenny-Lee,Riley, Darren L.
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p. 671 - 690
(2017/02/10)
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- Design, synthesis, and characterization of novel, nonquaternary reactivators of GF-inhibited human acetylcholinesterase
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The goal of this research was to identify structurally novel, non-quaternarypyridinium reactivators of GF (cyclosarin)-inhibited hAChE that possess the capacity to mediate in vitro reactivation of GF-inhibited human acetylcholinesterase (hAChE). New compounds were designed, synthesized and assessed in GF-inhibited hAChE assays. Structure activity relationships for AChE binding and reactivation of GF-inhibited hAChE were developed. Lead compounds from two different chemical series, represented by compounds 17 and 38, displayed proficient in vitro reactivation of GF-inhibited hAChE, while also possessing low inhibition of native enzyme.
- McHardy, Stanton F.,Bohmann, Jonathan A.,Corbett, Michael R.,Campos, Bismarck,Tidwell, Michael W.,Thompson, Paul Marty,Bemben, Chris J.,Menchaca, Tony A.,Reeves, Tony E.,Cantrell Jr., William R.,Bauta, William E.,Lopez, Ambrosio,Maxwell, Donald M.,Brecht, Karen M.,Sweeney, Richard E.,McDonough, John
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p. 1711 - 1714
(2014/04/17)
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- Concise synthesis of bicyclic aminals by way of catalytic intramolecular C-H amination and evaluation of their reactivity as iminium precursors
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The concise synthesis of fused bicyclic aminals by way of intramolecular rhodium-catalyzed C-H amination is reported as well as the evaluation of their reactivity as iminium precursors. In contrast to the well-studied N,O-acetal systems, the aminals synthesized were found to be particularly stable under reaction conditions used for nucleophilic addition.
- Rodriguez-Lucena, David,Morin, Marie S.T.,Compain, Philippe
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scheme or table
p. 155 - 162
(2012/04/04)
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- Disubstituted pyrimidines as Lck inhibitors
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We have developed a family of 4-benzimidazolyl-N-piperazinethyl-pyrimidin-2-amines that are subnanomolar inhibitors of Lck. A subset of these Lck inhibitors, with heterocyclic substituents at the benzimidazole C5, are also low-nanomolar inhibitors of cell
- Hunt, Julianne A.,Beresis, Richard T.,Goulet, Joung L.,Holmes, Mark A.,Hong, Xinfang J.,Kovacs, Ernest,Mills, Sander G.,Ruzek, Rowena D.,Wong, Frederick,Hermes, Jeffrey D.,Park, Young-Whan,Salowe, Scott P.,Sonatore, Lisa M.,Wu, Lin,Woods, Andrea,Zaller, Dennis M.,Sinclair, Peter J.
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supporting information; experimental part
p. 5440 - 5443
(2010/04/26)
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- Rifamycin derivatives
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Novel rifamycin derivatives of formula I (both hydroquinone and corresponding quinone (C1-C4) forms): or their salts, hydrates or prodrugs thereof, wherein: a preferred R comprises hydrogen, acetyl; L is a linker, a preferred linker group elements selected from any combination of 1 to 5 groups shown FIG. 1, provided L is not wherein R1 is H, methyl or alkyl. The inventive compounds exhibit valuable antibiotic properties. Formulations having these compounds can be used in the control or prevention of infectious diseases in mammals, both humans and non-humans. In particular, the compounds exhibit a pronounced antibacterial activity, even against multiresistant strains of microbes.
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Page/Page column 17
(2008/06/13)
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- PYRROLIDINE DERIVATIVES AS MUSCARINIC RECEPTOR ANTAGONISTS
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This invention relates to pyrrolidine derivatives, which are useful, among other uses, for the treatment of various diseases of the respiratory, urinary and gastrointestinal systems mediated through muscarinic receptors. Processes for the preparation of described compounds, pharmaceutical compositions containing the described compounds and the methods for treating the diseases mediated through muscarinic receptors are also provided.
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Page/Page column 21-22
(2010/10/20)
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- PYRROLIDINE DERIVATIVE OR SALT THEREOF
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[PROBLEMS] To provide a compound which can be used for the treatment of a disease associated with a calcium-sensing receptor (CaSR), particularly hyperparathyroidism. [MEANS FOR SOLVING PROBLEMS] It is found that a novel pyrrolidine derivative having an aminomethyl group substituted by an arylaklyl group or the like or a salt thereof has an excellent CaSR agonistic modulation effect and also has an excellent selectivity in the inhibition of CYP2D6 which may cause a drug-drug interaction. Thus, the novel pyrrolidine derivative is useful as a therapeutic agent for a disease associated with CaSR (e.g., hyperparathyroidism, renal osteodystrophy and hypercalcemia).
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Page/Page column 63
(2008/06/13)
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- Pyrazolyl derivatives, preparation process and intermediates of this process as medicinal products and pharmaceutical compositions containing them
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The present invention relates to the novel derivatives of formula (I) in which A is, if it is present, a (C1-C6) alkyl, a (C3-C6) alkenyl, a (C3-C6) alkynyl, a (C3-C7) cycloalkyl or a (C5-C7) cycloalkenyl, R1 is an NR6R7, (C4-C7) azacycloalkyl, (C5-C7) azacycloalkenyl, (C5-C9) azabicycloalkyl or (C5-C9) azabicycloalkenyl group; A-R1 is such that the nitrogen of R1 and the nitrogen in the 1-position of the pyrazole are necessarily separated by at least two carbon atoms, R3 is an H, halogen, OH, SH, NH2, ORc, SRc, SORa, SO2Ra, NHCHO, NRaRb, NHC(O)Ra, NHC(S)Ra or NHSO2Ra, R4 is an aryl or heteroaryl; and R5 is an H, halogen, CF3, CHF2, CH2F, linear or branched (C1-C6) alkyl or (C3-C7) cycloalkyl to their racemates, enantiomers and diastereoisomers and to their mixtures, their tautomers and to their pharmaceutically acceptable salts.
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Page/Page column 59-60
(2008/06/13)
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- Design and synthesis of potent, orally active, inhibitors of carboxypeptidase U (TAFIa)
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A series of 3-mercapto-propionic acid derivatives that function as reversible inhibitors of carboxypeptidase U have been prepared. We present a successful design strategy using cyclic, low basicity guanidine mimetics resulting in potent, selective and bioavailable inhibitors of carboxypeptidase U (TAFIa).
- Polla, Magnus O.,Tottie, Louise,Norden, Carita,Linschoten, Marcel,Muesil, Djordje,Trumpp-Kallmeyer, Susanne,Aukrust, Inger R.,Ringom, Rune,Holm, Kjetil H.,Neset, Siren M.,Sandberg, Marcel,Thurmond, John,Yu, Peng,Hategan, Georgeta,Anderson, Herb
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p. 1151 - 1175
(2007/10/03)
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- Beta lactam compounds and their use as inhibitors of tryptase
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Beta lactam compounds are provided which have the structure wherein B, A, D, R1, R2, R3 and X1 are as defined herein, and which are useful as inhibitors of tryptase, thrombin, trypsin, Factor Xa, Factor VIIa, and urokinase-type plasminogen activator and may be employed in preventing and/or treating asthma and allergic rhinitis.
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Page/Page column 36-37
(2010/02/07)
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- AROMATIC AMIDES
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This application relates to a compound of formula I (or a pharmaceutically acceptable salt thereof) as defined herein, pharmaceutical compositions thereof, and its use as an inhibitor of factor Xa, as well as a process for its preparation and intermediates therefor.
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- Sodium channel modulators
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The invention provides sodium channel modulating compounds of formula I: wherein X, Y, Q, R1, w, and R2 have any of the values defined in the specification, and salts thereof, which are useful for treating diseases or conditions associated with sodium channel activity, such as neuropathic pain. The invention also provides pharmaceutical compositions comprising a compound of formula (I) or a salt thereof, as well as therapeutic methods comprising administering such a compound or salt to a mammal (e.g. a human).
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- Pyridine derivatives
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Pyridine compounds of general formula: wherein —R1represents in which R11is hydrogen, C1-6alkyl, halogen, hydroxy, C1-12alkoxy, nitro, amino, C1-6alkylsulfonylamino, C1-6alkoxycarbonyl, C1-6alkylamino, di(C1-6alkyl)amino, C1-6alkanoylamino, phenyl C1-6alkylamino, phenylsulfonylamino, or —O—(CH2)n—R111; R2represents hydrogen or halogen; R3represents hydrogen, —CR31R32R33, or —NR34R35; R4is hydrogen, carbamoyl, CN, carboxyl, etc.; R5is amino, C1-6alkylamino, di C1-6alkylamino, etc. or salt thereof. The compound has an excellent anti-inflammatory activity, and other biological activity.
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- Src kinase inhibitor compounds
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Pyrimidine compounds (Formula I), or their pharmaceutically acceptable salts, hydrates, solvates, crystal forms and individual diastereomers, and pharmaceutical compositions including the same, which are inhibitors of tyrosine kinase enzymes, and as such are useful in the prophylaxis and treatment of protein tyrosine kinase-associated disorders, such as immune diseases, hyperproliferative disorders and other diseases in which inappropriate protein kinase action is believed to play a role, such as cancer, angiogensis, atheroscelerosis, graft rejection, rheumatoid arthritis and psoriasis.
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- LTA4 Hydrolase inhibitors
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The present invention provides compounds of the formula Ar1-Q-Ar2-Y-R-Z and pharmaceutically acceptable salts thereof wherein Ar1 and Ar2 are optionally substituted aryl moieties, Z is an optionally substituted nitrogen-containing moiety which may be an acyclic, cyclic or bicyclic amine or an optionally substituted monocyclic or bicyclic nitrogen-containing heteroaromatic moiety; Q is a linking group capable of linking two aryl groups; R is an alkylene moiety; Y is a linking moiety capable of linking an aryl group to an alkylene moiety and wherein Z is bonded to R through a nitrogen atom. The compounds and pharmaceutical compositions of the present invention are useful in the treatment of inflammatory diseases which are mediated by LTB4 production, such as proriasis, ulcerative colitis, IBD and asthma.
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Page 43, 197
(2010/01/31)
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- SRC kinase inhibitor compounds
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Pyrimidine compounds (Formula I), or their pharmaceutically acceptable salts, hydrates, solvates, crystal forms and individual diastereomers, and pharmaceutical compositions including the same, which are inhibitors of tyrosine kinase enzymes, and as such are useful in the prophylaxis and treatment of proteins tyrosine kinase-associated disorders, such as immune diseases, hyperproliferative disorders and other diseases in which inappropriate protein kinase action is believed to play a role, such as cancer, angiogensis, atheroscelerosis, graft rejection, rheumatoid arthritis and psoriasis.
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- Aminoborohydrides. 11. Facile reduction of N-alkyl lactams to the corresponding amines using lithium aminoborohydrides
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Formula presented Various five- and six-membered N-alkyl lactams were reduced to the corresponding cyclic amines using lithium N,N-dialkylaminoborohydrides (LAB). Most of the reductions were essentially complete after refluxing in THF for 2 h. The cyclic amine products were easily isolated after an aqueous workup in very good to excellent yields. It is possible to selectively reduce most functional groups, such as esters, in the presence of a lactam using LAB reagents.
- Flaniken, John M.,Collins, Christopher J.,Lanz, Marc,Singaram, Bakthan
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p. 799 - 801
(2008/02/12)
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- Oxadiazoles useful in the treatment of senile dementia
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A class of novel oxadiazoles, substituted on one of the ring carbon atoms with a non-aromatic azacyclic or azabicyclic ring, and substituted on the other ring carbon atom with a substituent of low lipophilicity; are potent muscarinic agonists, and have good CNS penetrability. The compounds are therefore useful in the treatment of neurological and mental illnesses.
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- Angiotensin II antagonists
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This invention provides novel heterocyclic derivatives, their pharmaceutical formulations, and their use for antagonizing angiotensin II receptors in mammals.
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- Angiotensin II antagonist intermediates
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This invention provides novel heterocyclic derivatives, their pharmaceutical formulations, and their use for antagonizing angiotensin II receptors in mammals.
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- Cyclic amine derivatives, pharmaceutical compositions containing these compounds and methods for preparing them
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Disclosed are new cyclic amine derivatives of the formula I STR1 wherein the substituents are defined in the specification. These compounds are useful as for treating sinus tachycardia.
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- The Use of the β-Amino-Alcohol-N-Oxide Derivatives in the Synthesis of 2,3 or 4-Alkyl Substituted NH Pyrrolidines
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Nonstabilized azomethine ylides generated from the various β-amino alcohols N-oxides 13, 17, 23 and 24 undergo cycloaddition reactions with unactivated alkenes to afford the corresponding pyrrolidines 14a-g, 18a-g, 25 und 27 in moderate to good yields.These compounds are precursors of NH pyrrolidines substituted in position 2, 3 or 4.
- Roussi, Georges,Zhang, Jidong
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p. 5161 - 5172
(2007/10/02)
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- 3-Alkenyl-1-azabicyclo(3.2.0)hept-2-ene-2-carboxylic acid compounds
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The invention relates to an antimicrobial compound of the formula: STR1 in which R1 is carboxy or protected carboxy, R2 is hydroxy(lower)alkyl or protected hydroxy(lower)alkyl, R3 and R4 are each hydrogen or low
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- A 3+2 CYCLOADDITION ROUTE TO N-H PYRROLIDINES DEVOID OF ELECTRON-WITHDRAWING GROUPS
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N-H pyrrolidines are obtained from intermolecular 3+2 cycloaddition reactions between nonactivated olefins and ylide generated from amine N-oxide 1 structurally designed in such a way as to allow easy dealkylation of the cycloadduct.
- Roussi, Georges,Zhang, Jidong
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p. 3481 - 3482
(2007/10/02)
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