- KRAS G12D INHIBITORS
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The present invention relates to compounds that inhibit KRas G12D. In particular, the present invention relates to compounds that inhibit the activity of KRas G12D, pharmaceutical compositions comprising the compounds and methods of use therefor.
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Paragraph 01377
(2021/03/05)
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- SPIRO-LACTAM AND BIS-SPIRO-LACTAM NMDA RECEPTOR MODULATORS AND USES THEREOF
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Disclosed are compounds having potency in the modulation of NMDA receptor activity. Such compounds can be used in the treatment of conditions such as depression and related disorders as well as other disorders.
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Page/Page column 44; 48; 58; 53; 59
(2019/08/26)
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- SPIRO-LACTAM AND BIS-SPIRO-LACTAM NMDA RECEPTOR MODULATORS AND USES THEREOF
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Disclosed are compounds having potency in the modulation of NMDA receptor activity. Such compounds can be used in the treatment of conditions such as depression and related disorders. Orally delivered formulations and other pharmaceutically acceptable delivery forms of the compounds, including intravenous formulations, are also disclosed.
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Page/Page column 35-36; 38-39; 40
(2018/03/28)
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- A mechanochemical approach to access the proline-proline diketopiperazine framework
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Ball milling was exploited to prepare a substituted proline building block by mechanochemical nucleophilic substitution. Subsequently, the mechanocoupling of hindered proline amino acid derivatives was developed to provide proline-proline dipeptides under solvent-free conditions. A deprotection-cyclization sequence yielded the corresponding diketopiperazines that were obtained with a high stereoselectivity which could be explained by DFT calculations. Using this method, an enantiopure disubstituted Pro-Pro diketopiperazine was synthesized in 4 steps, making 5 new bonds using a ball mill.
- Pétry, Nicolas,Benakki, Hafid,Clot, Eric,Retailleau, Pascal,Guenoun, Farhate,Asserar, Fatima,Sekkat, Chakib,Métro, Thomas-Xavier,Martinez, Jean,Lamaty, Frédéric
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p. 2169 - 2178
(2017/11/16)
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- Switching and Conformational Fixation of Amides Through Proximate Positive Charges
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Tertiary amides, which usually occur as cis/trans mixtures, can be effectively shifted to the cis conformation by placing a positive charge in close proximity to the amide carbonyl. This effect was used to prepare cis-configured prolyl amides and to facilitate a strongly rotamer-dependent radical cyclization. Taking charge of conformation: Tertiary amides, which usually occur as cis/trans mixtures, can be effectively shifted to the cis conformation by placing a positive charge in close proximity to the amide carbonyl. This effect was used to prepare cis-configured prolyl amides and to facilitate a strongly rotamer-dependent radical cyclization.
- Bartuschat, Amelie L.,Wicht, Karina,Heinrich, Markus R.
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p. 10294 - 10298
(2015/09/01)
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- New β-phospholactam as a carbapenem transition state analog: Synthesis of a broad-spectrum inhibitor of metallo-β-lactamases
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In an effort to test whether a transition state analog is an inhibitor of the metallo-β-lactamases, a phospholactam analog of carbapenem has been synthesized and characterized. The phospholactam 1 proved to be a weak, time-dependent inhibitor of IMP-1 (70%), CcrA (70%), L1 (70%), NDM-1 (53%), and Bla2 (94%) at an inhibitor concentration of 100 μM. The phospholactam 1 activated ImiS and BcII at the same concentration. Docking studies were used to explain binding and to offer suggestions for modifications to the phospholactam scaffold to improve binding affinities.
- Yang, Ke-Wu,Feng, Lei,Yang, Shao-Kang,Aitha, Mahesh,Lacuran, Alecander E.,Oelschlaeger, Peter,Crowder, Michael W.
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supporting information
p. 5855 - 5859
(2013/10/22)
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- N-Heterocyclic dicarboxylic acids: Broad-spectrum inhibitors of metallo-β-lactamases with co-antibacterial effect against antibiotic-resistant bacteria
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In an effort to identify novel, broad-spectrum inhibitors against the metallo-β-lactamases (MβLs), several N-heterocyclic derivatives were tested as inhibitors of MβLs CcrA, ImiS, and L1, which are representative enzymes from the distinct MβL subclasses. Three N-heterocyclic dicarboxylic acid derivatives were competitive inhibitors of CcrA and L1, exhibiting K i values ≤2 μM, while only 2,4-thiazolidinedicarboxylic acid (1b) was a competitive inhibitor of ImiS. Two 2-mercapto-1,3,4-thiadiazole derivatives were noncompetitive inhibitors of CcrA and ImiS, exhibiting K i values 7 μM; however, these same compounds did not inhibit L1. Two 2-mercapto-1,3,4-triazole derivatives were shown not to inhibit any of the tested MβLs. The N-heterocyclic derivatives were tested for antibacterial activity by examining the MIC values for existing antibiotics in the presence/absence of these derivatives. Consistent with the steady-state inhibition data, the inclusion of three N-heterocyclic dicarboxylic acid derivatives resulted in lower MIC values when using Escherichia coli BL21(DE3) cells containing the CcrA or L1 plasmids or Klebsiella pneumoniae (ATCC 700603), while 1b was the only dicarboxylic acid derivative to lower the MIC value of E. coli cells containing the ImiS plasmid. Inclusion of the 2-mercapto-1,3,4- thiadiazole derivatives resulted in lower MIC values for E. coli cells containing ImiS or L1 plasmids; however, these derivatives did not alter the MIC values for K. pneumoniae or E. coli cells containing the L1 plasmid. None of the N-heterocyclic derivatives affected the MIC of two methicillin resistant Staphylococcus aureus (MRSA) strains. Taken together, these studies demonstrate that N-heterocyclic dicarboxylic acids 1a-c and pyridylmercaptothiadiazoles 2a,b are good scaffolds for future broad-spectrum inhibitors of the MβLs.
- Feng, Lei,Yang, Ke-Wu,Zhou, Li-Sheng,Xiao, Jian-Min,Yang, Xia,Zhai, Le,Zhang, Yi-Lin,Crowder, Michael W.
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scheme or table
p. 5185 - 5189
(2012/09/07)
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- Visible-light-triggered release of nitric oxide from N-pyramidal nitrosamines
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Although many organic/inorganic compounds that release nitric oxide (NO) upon photoirradiation (phototriggered caged-NOs) have been reported, their photoabsorption wavelengths mostly lie in the UV region, because X - NO bonds (X=heteroatom and metal) generally have rather strong π-bond character. Thus, it is intrinsically difficult to generate organic compounds that release NO under visible light irradiation. Herein, the structures and properties of N-pyramidal nitrosamine derivatives of 7-azabicyclo[2.2.1]heptanes that release NO under visible light irradiation are described. Bathochromic shifts of the absorptions of these nitrosamines, attributed to HOMO (n)-LUMO (π*) transitions associated with the nonplanar structure of the N - NO moiety, enable the molecules to absorb visible light, which results in N - NO bond cleavage. Thus, these compounds are innate organic caged-NOs that are uncaged by visible light. A visible difference: Nitrosamine derivatives of 7-azabicyclo[2.2.1]heptanes undergo N - NO bond cleavage upon exposure to visible light at wavelengths longer than 420a nm, thereby releasing NO. Bathochromic shifts of the absorptions of these nitrosamines are attributed to HOMO (n)-LUMO (π*) transitions associated with the nonplanar structure of the N - NO moiety (see figure). Copyright
- Karaki, Fumika,Kabasawa, Yoji,Yanagimoto, Takahiro,Umeda, Nobuhiro,Firman,Urano, Yasuteru,Nagano, Tetsuo,Otani, Yuko,Ohwada, Tomohiko
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experimental part
p. 1127 - 1141
(2012/03/26)
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- Synthesis of both enantiomers of C2 symmetric trans-2,5- bis(hydroxymethyl)pyrrolidine. Lipase mediated sequential kinetic resolutions
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Lipase mediated sequential kinetic resolution has been employed to give both enantiomers of trans-2,5-bis(hydroxymethyl)pyrrolidine in optically pure form. The effect of different parameters on the ee and yields in these resolutions are also reported.
- Sibi,Lu
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p. 4915 - 4918
(2007/10/02)
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- Amino Acids, 14. - Diastereoselective Addition of Benzenesulfenyl Chloride to 1-Acryloylproline Esters
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(S)-Proline esters (S)-1 react with acryloyl chloride (2) to give 1-acryloylproline esters (S)-3 in good yields.Addition of benzenesulfenyl chloride (6) to (S)-3 at -95 deg C in dichloromethane results in 1-proline esters
- Effenberger, Franz,Isak, Heinz
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p. 545 - 552
(2007/10/02)
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- Base-Catalysed Epimerization Behavior and Unusual Reactivity of N-Substituted Derivatives of 2,5-Dicarbalkoxypyrrolidine. Preparation of a Novel Mixed Carbamic Carbonic Anhydride by a 4-(Dimethylamino)pyridine-Catalyzed Acylation
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The equilibration of cis-trans isomers of 1-substituted 2,5-dicarbalkoxypyrrolidine derivatives (1 = CH2Ph, H, CN, CO2R) results in nearly 1:1 mixtures, contrary to a literature report for 1-benzyl-2,5-dicarbalkoxypyrrolidine.Apparent conversion to the tr
- Kemp, D.S.,Curran, Timothy P.
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p. 5729 - 5731
(2007/10/02)
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