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Your search keyword '"Pamela S. Keim"' showing total 2 results
Start Over Author "Pamela S. Keim" Publisher american chemical society (acs)
2 results on '"Pamela S. Keim"'

1. Discovery of (R)-4-Cyclopropyl-7,8-difluoro-5-(4-(trifluoromethyl)phenylsulfonyl)-4,5-dihydro-1H-pyrazolo[4,3-c]quinoline (ELND006) and (R)-4-Cyclopropyl-8-fluoro-5-(6-(trifluoromethyl)pyridin-3-ylsulfonyl)-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline (ELND007): Metabolically Stable γ-Secretase Inhibitors that Selectively Inhibit the Production of Amyloid-β over Notch

Author

Anna Liao, Gary Probst, Pamela S. Keim, Kang Hu, Roy K. Hom, David A. Quincy, Michael S. Dappen, Grace T. Kwong, Jenifer Smith, Martin L. Neitzel, Ying-zi Xu, Elizabeth F. Brigham, Kevin P. Quinn, Frédérique Bard, Minghua Sun, Jing Wu, John-Michael Sauer, Dora Kholodenko, Hongbin Zhang, William Wallace, Matthew N. Mattson, Patricia Sacayon, Jacek Jagodzinski, Hing L. Sham, Brian T. Peterson, Simeon Bowers, Jennifer Marugg, Guriqbal S. Basi, Lee H. Latimer, Susanna S. Hemphill, Darren B. Dressen, Karina Wong, Kevin Tanaka, Michael P. Bova, Pamela Santiago, Daniel K. Ness, Anh P. Truong, Wes Zmolek, Lany Ruslim, Christopher Willits, Michael K. Lee, Andrei W. Konradi, Xiaocong M. Ye, Lam Nguyen, Chris M. Semko, Ted A. Yednock, Ruth N. Motter, Albert W. Garofalo, Erich Goldbach, Pearl Tanaka, and Danielle L. Aubele

Subjects
Trifluoromethyl, biology, Stereochemistry, Quinoline, In vitro, chemistry.chemical_compound, chemistry, In vivo, Drug Discovery, biology.protein, medicine, Molecular Medicine, Structure–activity relationship, Chirality (chemistry), Amyloid precursor protein secretase, Semagacestat, medicine.drug
Abstract

Herein, we describe our strategy to design metabolically stable γ-secretase inhibitors which are selective for inhibition of Aβ generation over Notch. We highlight our synthetic strategy to incorporate diversity and chirality. Compounds 30 (ELND006) and 34 (ELND007) both entered human clinical trials. The in vitro and in vivo characteristics for these two compounds are described. A comparison of inhibition of Aβ generation in vivo between 30, 34, Semagacestat 41, Begacestat 42, and Avagacestat 43 in mice is made. 30 lowered Aβ in the CSF of healthy human volunteers.

Published
2013

2. Covalent structure of apolipoprotein A-II from Macaca mulatta serum high-density lipoproteins

Author

Robert E. Fellows, Celina Edelstein, Robert L. Heinrikson, Pamela S. Keim, Claudia M. Noyes, and Angelo M. Scanu

Subjects
chemistry.chemical_classification, Apolipoprotein B, biology, Stereochemistry, Apolipoprotein A-II, Haplorhini, Macaca mulatta, Biochemistry, Peptide Fragments, Amino acid, Serine, Blood serum, chemistry, biology.protein, Animals, Macaca, Trypsin, Amino Acid Sequence, Amino Acids, Apoproteins, Peptide sequence, Cysteine, Lipoprotein
Abstract

The covalent structure of apolipoprotein A-II, isolated from the serum high-density lipoprotein of a single male Rhesus monkey (Macaca mulatta), was determined. The amino acid sequence of this 77-residue polypeptide is: < Glu-Ala-Glu-Glu-Pro/sup 5/-Ser-Val-Glu-Ser-Leu/sup 10/-Val-Ser-Gln-Tyr-Phe/sup 15/-Gln-Thr-Val-Thr-Asp/sup 20/-Tyr-Gly-Lys-Asp-Leu/sup 25/-Met-G lu-Lys-Val-Lys/sup 30/-Ser-Pro-Glu-Leu-Gln/sup 35/-Ala-Gln-Ala-Lys-Ala/sup 40/-Tyr-Phe-Glu-Lys-Ser/sup 45/-Lys-Glu-Gln-Leu-Thr/sup 50/-Pro-Leu-Val-Lys-Lys/sup 55/-Ala-Gly-Thr-Asp-Leu/sup 60/-Val-Asn-Phe-Leu-Ser/sup 65/-Tyr-Phe-Val-Glu-Leu/sup 70/-Arg-Thr-Gln-Pro-Ala/sup 75/-Thr-Gln-COOH. A comparison of this structure to that of the monomeric form of human apolipoprotein A-II reveals a high degree of homology except for six conservative amino acid replacements (positions 3, 6, 40, 53, 59, and 71). Of particular structural significance is the replacement of cysteine by serine in position 6. This explains why Rhesus A-II exists in monomeric form, contrary to the established dimeric nature of the human protein.

Published
1976

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