- 2-AMINOPYRIMIDINE DERIVATIVE, PREPARATION METHOD AND USE THEREOF
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The disclosure provides an aminopyrimidine derivative for preventing and treating diseases related to IDH mutation, a preparation method and use thereof. Specifically, the disclosure provides a compound of Formula I, a stereoisomer, racemate thereof, or pharmaceutically acceptable salt thereof. The compound of the general Formula I has isocitrate dehydrogenase 1 (IDH1) inhibitory activity and can treat cancer induced by IDH1 mutation.
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Paragraph 0095-0096
(2021/03/04)
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- HETEROCYCLIC COMPOUNDS AS MUTANT IDH INHIBITORS
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The present disclosure relates generally to compounds useful in treatment of conditions associated with mutant isocitrate dehydrogenase (mt-IDH), particularly mutant IDH1 enzymes. Specifically, the present invention discloses compound of formula (IA), which exhibits inhibitory activity against mutant IDH1 enzymes. Method of treating conditions associated with excessive activity of mutant IDH1 enzymes with such compound is disclosed. Uses thereof, pharmaceutical composition, and kits are also disclosed.
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Paragraph 0400-0401
(2020/07/16)
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- Discovery of new small molecule inhibitors targeting isocitrate dehydrogenase 1 (IDH1) with blood-brain barrier penetration
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Isocitrate dehydrogenase 1 (IDH1), which catalyzes the conversion of isocitrate to α-ketoglutarate, is one of key enzymes in the tricarboxylic acid cycle (TCA). Hotspot mutation at Arg132 in IDH1 that alters the function of IDH1 by further converting the α-ketoglutarate(α-KG) to 2-hydroxyglutarate (2-HG) have been identified in a variety of cancers. Because the IDH1 mutations occur in a significant portion of gliomas and glioblastomas, it is important that IDH1 inhibitors have to be brain penetrant to treat IDH1-mutant brain tumors. Here we report the efforts to design and synthesize a novel serial of mutant IDH1 inhibitors with improved activity and the blood-brain barrier (BBB) penetration. We show that compound 5 exhibits good brain exposure and potent 2-HG inhibition in a HT1080-derived mouse xenograft model, which makes it a potential preclinical candidate to treat IDH1-mutant brain tumors.
- Cao, Hengyi,Zhu, Guangya,Sun, Lin,Chen, Ge,Ma, Xinxin,Luo, Xiao,Zhu, Jidong
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- Optimization of 3-Pyrimidin-4-yl-oxazolidin-2-ones as Orally Bioavailable and Brain Penetrant Mutant IDH1 Inhibitors
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Mutant isocitrate dehydrogenase 1 (IDH1) is an attractive therapeutic target for the treatment of various cancers such as AML, glioma, and glioblastoma. We have evaluated 3-pyrimidin-4-yl-oxazolidin-2-ones as mutant IDH1 inhibitors that bind to an allosteric, induced pocket of IDH1R132H. This Letter describes SAR exploration focused on improving both the in vitro and in vivo metabolic stability of the compounds, leading to the identification of 19 as a potent and selective mutant IDH1 inhibitor that has demonstrated brain penetration and excellent oral bioavailability in rodents. In a preclinical patient-derived IDH1 mutant xenograft tumor model study, 19 efficiently inhibited the production of the biomarker 2-HG.
- Zhao, Qian,Manning, James R.,Sutton, James,Costales, Abran,Sendzik, Martin,Shafer, Cynthia M.,Levell, Julian R.,Liu, Gang,Caferro, Thomas,Cho, Young Shin,Palermo, Mark,Chenail, Gregg,Dooley, Julia,Villalba, Brian,Farsidjani, Ali,Chen, Jinyun,Dodd, Stephanie,Gould, Ty,Liang, Guiqing,Slocum, Kelly,Pu, Minying,Firestone, Brant,Growney, Joseph,Heimbach, Tycho,Pagliarini, Raymond
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supporting information
p. 746 - 751
(2018/06/25)
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- Discovery and Evaluation of Clinical Candidate IDH305, a Brain Penetrant Mutant IDH1 Inhibitor
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Inhibition of mutant IDH1 is being evaluated clinically as a promising treatment option for various cancers with hotspot mutation at Arg132. Having identified an allosteric, induced pocket of IDH1R132H, we have explored 3-pyrimidin-4-yl-oxazolidin-2-ones as mutant IDH1 inhibitors for in vivo modulation of 2-HG production and potential brain penetration. We report here optimization efforts toward the identification of clinical candidate IDH305 (13), a potent and selective mutant IDH1 inhibitor that has demonstrated brain exposure in rodents. Preclinical characterization of this compound exhibited in vivo correlation of 2-HG reduction and efficacy in a patient-derived IDH1 mutant xenograft tumor model. IDH305 (13) has progressed into human clinical trials for the treatment of cancers with IDH1 mutation.
- Cho, Young Shin,Levell, Julian R.,Liu, Gang,Caferro, Thomas,Sutton, James,Shafer, Cynthia M.,Costales, Abran,Manning, James R.,Zhao, Qian,Sendzik, Martin,Shultz, Michael,Chenail, Gregg,Dooley, Julia,Villalba, Brian,Farsidjani, Ali,Chen, Jinyun,Kulathila, Raviraj,Xie, Xiaoling,Dodd, Stephanie,Gould, Ty,Liang, Guiqing,Heimbach, Tycho,Slocum, Kelly,Firestone, Brant,Pu, Minying,Pagliarini, Raymond,Growney, Joseph D.
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supporting information
p. 1116 - 1121
(2017/10/18)
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- Synthesis method of Fmoc-O-tert-butyl-L-threoninol
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The present invention relates to a synthesis method of Fmoc-O-tert-butyl-L-threoninol, and mainly solves the technical problems that in a process of Fmoc-thr(tbu)-oh reduction by sodium borohydride, the reaction temperature is strictly required and a FMoc protecting group is decomposed, resulting in low yield and high cost. The synthesis method of the invention comprises the following steps: a. L-threonine reacts with thionyl chloride to form L-threonine methyl ester hydrochloride; b. the L-threonine methyl ester hydrochloride under the action of sodium hydroxide is reacted with benzyl chloroformate to produce z-thr-ome; c. the Z-thr-ome reacts with introduced isobutene in the presence of methylene chloride and concentrated sulfuric acid, and alkali adjustment treatment is carried out to obtain z-thr (tbu)-ome; d. in the presence of acetone and water, the Z-thr(tbu)-ome is saponified with added alkali to obtain z-thr(tbu)-oh; e. the Z-thr(tbu)-oh is reduced to z-thr(tbu)-ol by sodium borohydride in tetrahydrofuran; f. the z-thr(tbu)-ol is hydrogenated in methanol to obtain H-thr(tbu)-ol; and g. N-(9-fluorenylmethoxycarbonyloxy)succinimide is added to the H-thr(tbu)-ol to obtain the Fmoc-O-tert-butyl -L-threoninol.
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- MUTANT IDH1 INHIBITORS
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The present application provides compounds of Formula I: Formula (I) that are useful as inhibitors of mutant IDH1, pharmaceutical compositions, and uses for the treatment of cancer.
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Page/Page column 27; 28
(2018/01/19)
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- 3-PYRIMIDIN-4-YL-OXAZOLIDIN-2-ONES AS INHIBITORS OF MUTANT IDH
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The invention is directed to a formula (I), or a pharmamceutically acceptable salt thereof, wherein R1, R2a, R2b and R3-R7 are herein. The invention is also directed to compositions containing a compound of formula (I) and to the use of such compounds in the inhibition of mutant IDH proteins having a neomorphic activity. The invention is further directed to the use of a compound of formula (I) in the treatment of diseases or disorders associated with such mutant IDH proteins including, but not limited to, cell-proliferation disorders, such as cancer.
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Page/Page column 388
(2014/09/29)
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- Efficient access to enantiopure γ4-amino acids with proteinogenic side-chains and structural investigation of γ4- asn and γ4-ser in hybrid peptide helices
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Hybrid peptides composed of α- and β-amino acids have recently emerged as new class of peptide foldamers. Comparatively, γ- and hybrid γ-peptides composed of γ4-amino acids are less studied than their β-counterparts. However, recent investigations reveal that γ4-amino acids have a higher propensity to fold into ordered helical structures. As amino acid side-chain functional groups play a crucial role in the biological context, the objective of this study was to investigate efficient synthesis of γ4-residues with functional proteinogenic side-chains and their structural analysis in hybrid-peptide sequences. Here, the efficient and enantiopure synthesis of various N- and C-terminal free-γ4-residues, starting from the benzyl esters (COOBzl) of N-Cbz-protected (E)-α,β-unsaturated γ-amino acids through multiple hydrogenolysis and double-bond reduction in a single-pot catalytic hydrogenation is reported. The crystal conformations of eight unprotected γ4-amino acids (γ4-Val, γ4-Leu, γ4-Ile, γ4-Thr(OtBu), γ4-Tyr, γ4-Asp(OtBu), γ4- Glu(OtBu), and γ-Aib) reveals that these amino acids adopted a helix favoring gauche conformations along the central Cγi£ Cβ bond. To study the behavior of γ4- residues with functional side chains in peptide sequences, two short hybrid γ-peptides P1 (Ac-Aib-γ4-Asn-Aib-γ4-Leu- Aib-γ4-Leu-CONH2) and P2 (Ac-Aib- γ4-Ser-Aib-γ4-Val-Aib-γ4-Val- CONH2) were designed, synthesized on solid phase, and their 12-helical conformation in single crystals were studied. Remarkably, the γ4-Asn residue in P1 facilitates the tetrameric helical aggregations through interhelical H bonding between the side-chain amide groups. Furthermore, the hydroxyl side-chain of γ4-Ser in P2 is involved in the interhelical H bonding with the backbone amide group. In addition, the analysis of 87 γ4-residues in peptide single-crystals reveal that the γ4-residues in 12-helices are more ordered as compared with the 10/12- and 12/14-helices. Copyright
- Jadhav, Sandip V.,Misra, Rajkumar,Singh, Sumeet K.,Gopi, Hosahudya N.
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supporting information
p. 16256 - 16262
(2013/12/04)
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