- Discovery, Structure-Activity Relationships, and in Vivo Evaluation of Novel Aryl Amides as Brain Penetrant Adaptor Protein 2-Associated Kinase 1 (AAK1) Inhibitors for the Treatment of Neuropathic Pain
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Effective treatment of chronic pain, in particular neuropathic pain, without the side effects that often accompany currently available treatment options is an area of significant unmet medical need. A phenotypic screen of mouse gene knockouts led to the d
- Hartz, Richard A,Ahuja, Vijay T.,Nara, Susheel J.,Kumar, C.M. Vijaya,Brown, Jeffrey M.,Bristow, Linda J.,Rajamani, Ramkumar,Muckelbauer, Jodi K.,Camac, Daniel,Kiefer, Susan E.,Hunihan, Lisa,Gulianello, Michael,Lewis, Martin,Easton, Amy,Lippy, Jonathan S.,Surti, Neha,Pattipati, Sreenivasulu N.,Dokania, Manoj,Elavazhagan, Saravanan,Dandapani, Kumaran,Hamman, Brian D.,Allen, Jason,Kostich, Walter,Bronson, Joanne J.,Macor, John E.,Dzierba, Carolyn D.
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p. 11090 - 11128
(2021/08/03)
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- 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.
- Cardarelli, Pina M.,Cheng, Heng,Cho, Patricia,Chowdari, Naidu S.,Deshpande, Madhura,Eastgate, Martin D.,Gangwar, Sanjeev,Guturi, Sivakrishna,Holder, Patrick,Iwuagwu, Christiana,Kanagavel, Kishorekumar,Kanusu, Umamaheswararao,Kotapati, Srikanth,Lakshminarasimhan, Thirumalai,Langley, David R.,Luzung, Michael R.,McDonald, Ivar,Niyogi, Ankita G.,Pan, Chin,Peese, Kevin M.,Rakshit, Souvik,Rao, Chetana,Sarma, Ganapathy,Schmidt, Michael A.,Sidhar, Somprabha,Sivaprakasam, Prasanna,Tan, Yichen,Vaidyanathan, Rajappa,Vite, Gregory,Xie, Chunshan,Zheng, Bin
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supporting information
p. 404 - 412
(2021/03/03)
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- CATHEPSIN K INHIBITOR AND APPLICATION THEREOF
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The invention relates to capthepsin K inhibitors and uses thereof, specifically relates to a class of compounds having the formula (I) which are used for treating or preventing cathepsin dependent diseases or conditions, specifically, wherein the cathepsin is capthepsin K. The compounds and compositions thereof can be used as bone resorption inhibitors for the treatment of associated diseases.
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Paragraph 0363
(2018/07/29)
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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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- Inhibitors of inosine monophosphate dehydrogenase: SARs about the N-[3-methoxy-4-(5-oxazolyl)phenyl moiety
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The first reported structure-activity relationships (SARs) about the N-[3-methoxy-4-(5-oxazolyl)phenyl moiety for a series of recently disclosed inosine monophosphate dehydrogenase (IMPDH) inhibitors are described. The syntheses and in vitro inhibitory values for IMPDH II, and T-cell proliferation (for select analogues) are given.
- Iwanowicz, Edwin J.,Watterson, Scott H.,Guo, Junqing,Pitts, William J.,Murali Dhar,Shen, Zhongqi,Chen, Ping,Gu, Henry H.,Fleener, Catherine A.,Rouleau, Katherine A.,Cheney, Daniel L.,Townsend, Robert M.,Hollenbaugh, Diane L.
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p. 2059 - 2063
(2007/10/03)
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- Compounds derived from an amine nucleus that are inhibitors of IMPDH enzyme
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The present invention discloses the identification of the novel inhibitors of IMPDH (inosine-5′-monophosphate dehydrogenase). The compounds and pharmaceutical compositions disclosed herein are useful in treating or preventing IMPDH mediated diseases, such as transplant rejection and autoimmune diseases.
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