- DNA-Model-Based Design and Execution of Some Fused Benzodiazepine Hybrid Payloads for Antibody-Drug Conjugate Modality
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A new series with the tetrahydroisoquinoline-fused benzodiazepine (TBD) ring system combined with the surrogates of (1-methyl-1H-pyrrol-3-yl)benzene ( MPB ) payloads were designed and executed for conjugation with a monoclonal antibody for anticancer therapeutics. DNA models helped in rationally identifying modifications of the MPB binding component and guided structure-activity relationship generation. This hybrid series of payloads exhibited excellent in vitro activity when tested against a panel of various cancer cell lines. One of the payloads was appended with a lysosome-cleavable peptide linker and conjugated with an anti-mesothelin antibody via a site-specific conjugation method mediated by the enzyme bacterial transglutaminase (BTGase). Antibody-drug conjugate (ADC) 50 demonstrated good plasma stability and lysosomal cleavage. A single intravenous dose of ADC 50 (5 or 10 nmol/kg) showed robust efficacy in an N87 gastric cancer xenograft model.
- Sivaprakasam, Prasanna,McDonald, Ivar,Iwuagwu, Christiana,Chowdari, Naidu S.,Peese, Kevin M.,Langley, David R.,Cheng, Heng,Luzung, Michael R.,Schmidt, Michael A.,Zheng, Bin,Tan, Yichen,Cho, Patricia,Rakshit, Souvik,Lakshminarasimhan, Thirumalai,Guturi, Sivakrishna,Kanagavel, Kishorekumar,Kanusu, Umamaheswararao,Niyogi, Ankita G.,Sidhar, Somprabha,Vaidyanathan, Rajappa,Eastgate, Martin D.,Kotapati, Srikanth,Deshpande, Madhura,Pan, Chin,Cardarelli, Pina M.,Xie, Chunshan,Rao, Chetana,Holder, Patrick,Sarma, Ganapathy,Vite, Gregory,Gangwar, Sanjeev
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Read Online
- Process Development and Scale-up of a Multicomponent Synthesis of a 3-Methyl-1-aryl-1,2,4-triazole Building Block
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The classical preparation of 3-methyl-1-aryl-1,2,4-triazoles through an SNAr reaction pathway results in a mixture of N-regioisomers. Removal of the unwanted isomer reduces the yield and affects processability of the final product. In the prese
- Deerberg, Joerg,Fan, Yu,La Cruz, Thomas E.,Leung, Simon,Pathirana, Charles,Peddicord, Michael,Smith, Kristine M.,Tam, Annie,Treitler, Daniel S.,Vanyo, Dale
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Read Online
- Identification and Preclinical Evaluation of the Bicyclic Pyrimidine γ-Secretase Modulator BMS-932481
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A triazine hit identified from a screen of the BMS compound collection was optimized for potency, in vivo activity, and off-target profile to produce the bicyclic pyrimidine γ-secretase modulator BMS-932481. The compound showed robust reductions of Aβsub
- Boy, Kenneth M.,Guernon, Jason M.,Zuev, Dmitry S.,Xu, Li,Zhang, Yunhui,Shi, Jianliang,Marcin, Lawrence R.,Higgins, Mendi A.,Wu, Yong-Jin,Krishnananthan, Subramaniam,Li, Jianqing,Trehan, Ashok,Smith, Daniel,Toyn, Jeremy H.,Meredith, Jere E.,Burton, Catherine R.,Kimura, S. Roy,Zvyaga, Tatyana,Zhuo, Xiaoliang,Lentz, Kimberley A.,Grace, James E.,Denton, Rex,Morrison, John S.,Mathur, Arvind,Albright, Charles F.,Ahlijanian, Michael K.,Olson, Richard E.,Thompson, Lorin A.,Macor, John E.
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supporting information
p. 312 - 317
(2019/03/08)
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- ANTIPROLIFERATIVE COMPOUNDS AND CONJUGATES MADE THEREFROM
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A compound capable of inhibiting cell proliferation, having a structure according to formula (I) wherein the variables in formula (I) are as defined in the specification. Such compounds are useful as anti-cancer agents, especially in antibody-drug conjugates.
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Paragraph 0275
(2018/05/03)
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- FUSED MORPHOLINOPYRIMIDINES AND METHODS OF USE THEREOF
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The present disclosure relates to Fused Morpholinopyrimidines, pharmaceutical compositions comprising an effective amount of a Fused Morpholinopyrimidine and methods for using a Fused Morpholinopyrimidine in the treatment of a neurodegenerative disease, comprising administering to a subject in need thereof an effective amount of a Fused Morpholinopyrimidine.
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Paragraph 1023
(2017/05/14)
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- FUSED MORPHOLINOPYRIMIDINES AND METHODS OF USE THEREOF
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The present disclosure relates to Fused Morpholinopyrimidines, pharmaceutical compositions comprising an effective amount of a Fused Morpholinopyrimidine and methods for using a Fused Morpholinopyrimidine in the treatment of a neurodegenerative disease, comprising administering to a subject in need thereof an effective amount of a Fused Morpholinopyrimidine.
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Paragraph 0740
(2015/08/03)
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- NOVEL SUBSTITUTED TRIAZOLE DERIVATIVES AS GAMMA SECRETASE MODULATORS
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The present invention is concerned with novel substituted triazole derivatives of Formula (I) wherein Het1, R1, R2, A1, A2, A3, A4, L1, and L2 have the mean
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Page/Page column 28
(2012/12/13)
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- COMPOUNDS FOR THE REDUCTION OF β-AMYLOID PRODUCTION
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The present disclosure provides a series of compounds of the formula (I) which modulate β-amyloid peptide (β-AP) production and are useful in the treatment of Alzheimer's Disease and other conditions affected by β-amyloid peptide (β-AP) production.
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Page/Page column 42-43
(2011/02/24)
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- NOVEL SUBSTITUTED BICYCLIC TRIAZOLE DERIVATIVES AS GAMMA SECRETASE MODULATORS
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The present invention is concerned with novel substituted bicyclic triazole derivatives of Formula (I) wherein Het1, R1, R2, A1, A2, A3, A4, L1, and L2 have the meaning defined in the claims. The compounds according to the present invention are useful as gamma secretase modulators. The invention further relates to processes for preparing such novel compounds, pharmaceutical compositions comprising said compounds as an active ingredient as well as the use of said compounds as a medicament.
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Page/Page column 71
(2011/08/04)
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- NOVEL SUBSTITUTED TRIAZOLE DERIVATIVES AS GAMMA SECRETASE MODULATORS
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The present invention is concerned with novel substituted triazole derivatives of Formula (I) wherein Het1, R1, R2, A1, A2, A3, A4, L1, and L2 have the meaning defined in the claims. The compounds according to the present invention are useful as gamma sec
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Page/Page column 60
(2011/08/04)
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- NEW COMPOUNDS MODULATING GAMMA-SECRETASE AND THEIR USE IN THE TREATMENT OF ALPHA BETA RELATED PATHOLOGIES, SUCH AS ALZHEIMER'S DISEASE
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The present invention relates to novel compounds of formulae (I) and (II) and therapeutically acceptable salts thereof, their pharmaceutical compositions processes for making them and their use in therapeutic methods for treatment and/or prevention of var
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Page/Page column 120
(2010/12/17)
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- BICYCLIC COMPOUNDS FOR THE REDUCTION OF BETA-AMYLOID PRODUCTION
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The present disclosure provides a series of compounds of the formula (I) which reduce β-amyloid peptide (β-AP) production and are useful in the treatment of Alzheimer's Disease and other conditions affected by β-amyloid peptide (β-AP) production, wherein
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Page/Page column 39-40
(2010/08/08)
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- SUBSTITUTED BICYCLIC IMIDAZOLE DERIVATIVES AS GAMMA SECRETASE MODULATORS
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The present invention is concerned with novel substituted bicyclic imidazole derivatives of Formula (I) wherein R0, R1, R3, R4, X, A1, A2, A3, A4, Y1, Y2 and Y3 have the meaning defined in the claims. The compounds according to the present invention are useful as gamma secretase modulators. The invention further relates to processes for preparing such novel compounds, pharmaceutical compositions comprising said novel compound as an active ingredient as well as the use of said compounds as a medicament.
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Page/Page column 48
(2010/08/05)
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- NOVEL SUBSTITUTED BENZOXAZOLE, BENZIMIDAZOLE, OXAZOLOPYRIDINE AND IMIDAZOPYRIDINE DERIVATIVES AS GAMMA SECRETASE MODULATORS
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The present invention is concerned with novel substituted benzoxazole, benzimidazole, oxazolopyridine and imidazopyridine derivatives of Formula (I) wherein R1, R2, R3, R4, X, A1, A2, A3, A4, Y1, Y2, Y3 and Z have the meaning defined in the claims. The compounds according to the present invention are useful as gamma secretase modulators. The invention further relates to processes for preparing such novel compounds, pharmaceutical compositions comprising said compounds as an active ingredient as well as the use of said compounds as a medicament.
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Page/Page column 62
(2010/09/17)
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- NOVEL SUBSTITUTED INDAZOLE AND AZA-INDAZOLE DERIVATIVES AS GAMMA SECRETASE MODULATORS
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The present invention is concerned with novel substituted indazole and aza-indazole derivatives of Formula (I), wherein R1, R2, R3, R4, Y, A1, A2, A3, A4, X1, X2, X3 and Het1 have the meaning defined in the claims. The compounds according to the present invention are useful as gamma secretase modulators. The invention further relates to processes for preparing such novel compounds, pharmaceutical compositions comprising said compounds as an active ingredient as well as the use of said compounds as a medicament.
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Page/Page column 46
(2010/12/31)
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- MODULATORS FOR AMYLOID BETA
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The invention relates to compounds of formula wherein the substituents are as described in claim 1. Compounds of formula I are modulators for amyloid beta and thus, they may be useful for the treatment or prevention of a disease associated with the deposi
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Page/Page column 76
(2009/09/07)
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