A series of C-Terminal amino alcohol dipeptide Aβ inhibitors

Garofalo, Albert W.; Wone, David W.G.; Phuc, Angela; Audia, James E.; Bales, Cheryl A.; Dovey, Harry F.; Dressen, Darren; Folmer, B.; Goldbach, Erich; Guinn, Ashley C.; Latimer, Lee H.; Mabry, Thomas E.; Nissen, Jeffrey S.; Pleiss, Michael A.; Sohn, Stephen; Thorsett, Eugene D.; Tung, Jay S.; Wu, Jing

doi:10.1016/s0960-894x(02)00684-4

Cited by 22 publications

(15 citation statements)

References 6 publications

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“…Moreover, the very potent γ-secretase inhibitor N-[N- NH 4 Cl, H 2 O/EtOH, reflux; [12] (d) 3,5-difluoromandelic acid, EDC, HOBt, DIEA, NMM, THF, rt; [13] 49% (12, for 3 steps (a), (b), and (c)); 4% (13a + 13b, for 3 steps (c), (a), and (d)). (14); (c) 3,5-difluorophenylacetic acid, BOP, DIEA, CH 2 Cl 2 , rt; 88% (15); (d ) 3,5-difluoromandelic acid, Cl 3 COCOCl, activated charcoal, THF, rt [15] then DIEA, CH 2 Cl 2 , rt; 21% (16a + 16b); (e) TFA, CH 2 Cl 2 , rt; quantitative; (f ) Boc 2 O, DIEA, CH 2 Cl 2 , rt; 80% (17); (g) 6-aminocaproyl 2,3-di-O-benzyl-l-ascorbic acid trifluoroacetic acid salt, [14] BOP, DIEA, CH 2 Cl 2 , rt; 60%; (h) TFA, CH 2 Cl 2 , rt; quantitative (18); (i) 3,5-difluorophenylacetic acid, BOP, DIEA, CH 2 Cl 2 , rt; 73%; ( j) 3,5-difluoromandelic acid, Cl 3 COCOCl, activated charcoal, THF, rt [15] then DIEA, CH 2 Cl 2 , rt; 26%; (k) LiOH, CaCl 2 , Pr i OH/H 2 O, rt; [14,16] 58% (19), [14] 22% (20).…”

Section: Resultsmentioning

confidence: 99%

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Design of β-Secretase Inhibitors by Introduction of a Mandelyl Moiety in DAPT Analogues

Pietrancosta¹,

Quéléver²,

Laras³

et al. 2005

Aust. J. Chem.

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We report the synthesis of two series of compounds with 3,5-difluoromandelyl-alanyl or 3,5-difluorophenylacetyl-alanyl backbones coupled to various heterocyclic or peptidic moieties. These two series of compounds were evaluated for their inhibitory properties on β-secretase (BACE-1) enzymatic assay, a target enzyme for Alzheimer’s disease (AD) pathology. We found that both diastereomers obtained from the racemic mixture 7 of the coumarin derivative bearing a mandelyl moiety were the most potent BACE-1 inhibitors studied in this work (IC50 = 1 × 10−6 M). Analysis of the obtained results led to the hypothesis that introduction of a difluoromandelyl residue in place of a difluorophenylacetyl moiety may induce β-secretase inhibitory activity.

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Section: Resultsmentioning

confidence: 99%

“…[6,7] Nevertheless, various studies suggest caution in testing γ-secretase inhibitors on humans. The major concern surrounding the use of potent γ-secretase inhibitors forAD clinical treatments lies in their side effects at the level of neural stem cell differentiation as well as in the control of gliogenesis.…”

Section: Introductionmentioning

confidence: 99%

Design of β-Secretase Inhibitors by Introduction of a Mandelyl Moiety in DAPT Analogues

Pietrancosta¹,

Quéléver²,

Laras³

et al. 2005

Aust. J. Chem.

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“…Researchers in a collaboration between Elan and Lilly have prepared LY-374973 or DAPT (24), an alanine-phenylglycine derivative, with a 20 nM IC 50 [236][237][238]. A number of related structures have been prepared and patented [239][240][241][242][243][244][245][246][247][248][249][250][251][252][253][254], and a recent manuscript describes the SAR of related aminoalcohol dipeptides [255]. In addition, two peptidic analogs incorporating a heterocyclic moiety 25 [256][257][258] and LY-411575 (ELN-44989) (26) [252,259,260] have IC 50 s of 0.3 and 0.1 nM, respectively.…”

Section: Processing Of Amyloid Precursor Protein To β-Amyloid Peptidementioning

confidence: 99%

Emerging β-Amyloid Therapies for the Treatment of Alzheimer's Disease

Conway¹,

Baxter²,

Felsenstein³

et al. 2004

Frontiers in Medicinal Chemistry - Online

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Alzheimer's Disease (AD) is a progressive neurodegenerative disorder marked by loss of memory, cognition, and behavioral stability. AD is defined pathologically by extracellular neuritic plaques comprised of fibrillar deposits of β-amyloid peptide (Aβ) and neurofibrillary tangles comprised of paired helical filaments of hyperphosphorylated tau. Current therapies for AD, such as cholinesterase inhibitors, treat the symptoms but do not modify the progression of the disease. The etiology of AD is unclear. However, data from familial AD mutations (FAD) strongly support the "amyloid cascade hypothesis" of AD, i.e. that neurodegeneration in AD is initiated by the formation of neurotoxic β-amyloid (Aβ) aggregates; all FAD mutations increase levels of Aβ peptide or density of Aβ deposits. The likely link between Aβ aggregation and AD pathology emphasizes the need for a better understanding of the mechanisms of Aβ production. This review summarizes current therapeutic strategies directed at lowering Aβ levels and decreasing levels of toxic Aβ aggregates through (1) inhibition of the processing of amyloid precursor protein (APP) to Aβ peptide, (2) inhibition, reversal or clearance of Aβ aggregation, (3) cholesterol reduction and (4) Aβ immunization.

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“…Chirally pure l-propargylglycine attracts particular interest owing to the special characteristics of its triple bond. Even without utilizing the acetylenic side chain for structural modifications, chirally pure propargylglycine and its analogues have been widely used as starting materials or intermediates in the synthesis of drugs for treatment of Alzheimer's disease (Garofalo et al, 2002), muscle contraction associated disease (Isaac et al, 2001), cancer, rheumatoid arthritis and osteoarthritis (Natchus et al, 2001). However, the readily available commercial form of propargylglycine is the racemic dl mixture, making it attractive to consider enzymatic kinetic resolution using PheDH mutants (Paradisi et al, 2007) as a route to the chirally pure l-and denantiomers.…”

Section: Introductionmentioning

confidence: 99%