Download Annual Reports in Medicinal Chemistry, Vol. 35 by Annette M. Doherty, William K. Hagmann PDF

By Annette M. Doherty, William K. Hagmann

Annual experiences in Medicinal Chemistry presents well timed and demanding reports of significant themes in medicinal chemistry including an emphasis on rising issues within the organic sciences that are anticipated to supply the foundation for totally new destiny cures.

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North, Mol. , 53, 969 (1998). Chapter 4. Secretase Inhibitors as Therapeutics for Alzheimer's Disease Richard E. OIson and Lorin A. S. in 1998, claiming 22,824 individuals (1). The disease affects 7-10% of those over 65 years of age; the prevalence among those 80 years of age or older may be >40% (2-5). Beginning with mild cognitive impairment, the clinical course proceeds through significant, then profound dementia, loss of motor function, and death (6,7). S. each year (8). In view of the aging population, the societal burden of AD is likely to increase significantly.

O,J O . ,=oc-------"x. 5 3R=Glu Letters DenoteAmino Acids 4R = H y-$ECRETASE Characterization of ~,-Secretase - y-Secretase appears to be a member of a small group of proteases capable of intramembrane cleavage (64). A cleavage mechanism involving prior removal of the cleavage site from the membrane environment has also been proposed (72). Mutation studies demonstrate that ~,secretase has loose sequence specificity, tolerating many hydrophobic residues near the scissile bonds (65-67). In a study using a C99 construct as substrate, systematic substitution of TMD residues carboxy to A~42with phenylalanine changed A~40 vs A~42 cleavage specificity in a manner consistent with a helical substrate model.

J. W. B. C. Rice, F. Porreca, J. Pharmacol. Exp. , 273, 359-366, (1995). 39. L. M. Hawkins, Invest. Drugs, 2, 1313-1326, (1999). 40. H. Bridge, Neuropsychopharmacology, 13, 269 (1995). 41. D. Gordh, Pain, 51,249 (1992). 42. M. C. Hunter, A. Dray, Trends Pharmacol. Sci. 20, 337-342, (1999). 43. C. Parsons, New Developments in Glutamate Pharmacology, Orlando, FL, March 4-5, (1999). 44. A. Quartaroli, American Pain Society Annual Meeting (1997). 45. M. Linders Curr. Opin. CPNS Invest. , 167-170, (1999).

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