- Structure-guided design and synthesis of P1′ position 1-phenylcycloalkylamine-derived pentapeptidic BACE1 inhibitors
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Previously, we reported potent pentapeptidic BACE1 inhibitors with the hydroxymethylcarbonyl isostere as a substrate transition-state mimic. To improve the in vitro potency, we further reported pentapeptidic inhibitors with carboxylic acid bioisosteres at the P4 and P1′ positions. In the current study, we screened new P1′ position 1-phenylcycloalkylamine analogs to find non-acidic inhibitors that possess double-digit nanomolar range IC50 values. An extensive structure-activity relationship study was performed with various amine derivatives at the P1′ position. The most potent inhibitor of this pentapeptide series, KMI-1830, possessing 1-phenylcyclopentylamine at the P 1′ position had an IC50 value of 11.6 nM against BACE1 in vitro enzymatic assay.
- Tagad, Harichandra D.,Hamada, Yoshio,Nguyen, Jeffrey-Tri,Hidaka, Koushi,Hamada, Takashi,Sohma, Youhei,Kimura, Tooru,Kiso, Yoshiaki
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p. 5238 - 5246
(2011/10/08)
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- Design, synthesis and evaluation of a novel cyclohexanamine class of neuropeptide Y Y1 receptor antagonists
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A novel series of cyclohexanamine derivatives was designed and synthesized as potent and selective human neuropeptide Y Y1 receptor antagonists. Modification of high-throughput screening hit compound 1 resulted in the identification of compound 3i, which displays potent Y1 activity and good selectivity towards hERG K+ channel and serotonin transporter.
- Cho, Kaimei,Ando, Makoto,Kobayashi, Kensuke,Miyazoe, Hiroshi,Tsujino, Toshiaki,Ito, Sayaka,Suzuki, Tomoki,Tanaka, Takeshi,Tokita, Shigeru,Sato, Nagaaki
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scheme or table
p. 4781 - 4785
(2010/07/06)
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- (3R)-3-Amino-4-(2,4,5-trifluorophenyl)-N-{4-[6-(2-methoxyethoxy)benzothiazol-2-yl]tetrahydropyran-4-yl}butanamide as a potent dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes
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Novel series of 3-amino-N-(4-aryl-1,1-dioxothian-4-yl)butanamides and 3-amino-N-(4-aryltetrahydropyran-4-yl)butanamides were synthesized and evaluated as dipeptidyl peptidase IV (DPP-IV) inhibitors. Derivatives incorporating the 6-substituted benzothiazole group showed highly potent DPP-IV inhibitory activity. Oral administration of (3R)-3-amino-4-(2,4,5-trifluorophenyl)-N-{4-[6-(2-methoxyethoxy)benzothiazol-2-yl]tetrahydropyran-4-yl}butanamide (12u) reduced blood glucose excursion in an oral glucose tolerance test.
- Nitta, Aiko,Fujii, Hideaki,Sakami, Satoshi,Nishimura, Yutaka,Ohyama, Tomofumi,Satoh, Mikiya,Nakaki, Junko,Satoh, Shiho,Inada, Chifumi,Kozono, Hideki,Kumagai, Hiroki,Shimamura, Masahiro,Fukazawa, Tominaga,Kawai, Hideki
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scheme or table
p. 5435 - 5438
(2009/05/30)
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- A practical synthesis of tert-alkylamines via the ritter reaction with chloroacetonitrile
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Ritter reaction of tertiary alcohols with chloroacetonitrile and subsequent cleavage of chloroacetyl group in the resulting chloroacetamide with thiourea is an efficient procedure for synthesis of tert-alkylamines.
- Jirgensons,Kauss,Kalvinsh,Gold
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p. 1709 - 1712
(2007/10/03)
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- A reliable and efficient synthesis of SR 142801
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A convenient synthesis of the potent human NK-3 receptor antagonist SR 142801, (S)-(+)-N-{{3-[1-benzoyl-3-(3,4-dichlorophenyl)piperidin-3-yl]prop-1 -yl}-4-phenylpiperidin-4-yl}-N-methylacetamide [(S)-(+)-(15)], is described. Improvements over the previously reported procedure are the preparation of the intermediate 5 via the novel imide 3 and subsequent reaction with the nucleophile 14, which reacts, regioselectively, at the endocyclic nitrogen.
- Giardina,Grugni, Mario,Rigolio, Roberto,Vassallo, Marco,Erhard, Karl,Farina, Carlo
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p. 2307 - 2310
(2007/10/03)
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