- 4-Substituted 2-amino-3,4-dihydroquinazolines with a 3-hairpin turn side chain as novel inhibitors of BACE-1
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Herein, we report the identification, design, and synthesis of a series of 4-substituted 2-amino-3,4-dihydroquinazolines with hairpin turn side chains as novel inhibitors of BACE-1. The dihydroquinazoline derivatives were rationally designed by modifying the amide group and relocating the α -hydrophobic substituent on the hairpin turn side chain of lead compound 2 to the C4-position on the 3,4-dihydroquinazoline scaffold to facilitate interactions with the S1, S2 and S1′ subsites of BACE-1. Among these derivatives, two compounds exhibited potent BACE-1 inhibitory activity: 4-methyl-substituted (22a, BACE-1 CFA IC50 = 0.38 μM; BACE-1 WCA IC50 = 0.14 μM) and 4-cyclohexylmethyl-substituted (22b, BACE-1 CFA IC50 = 0.49 μM; BACE-1 WCA IC50 = 0.14 μM) 2-amino-3,4-dihydroquinazoline, each bearing a side chain of N-cyclohexyl-N-((1-methyl-1H-pyrazol-4-yl)methyl amide. The results suggest that the structural modifications maintain the hairpin turn topology similar to that of compound 2 and provide an additional interaction with the S2 subsite.
- Chen, Grace Shiahuy,Chern, Ji-Wang,Hsieh, Chen-En,Hung, Pei-Yun,Jagtap, Ajit Dhananjay,Kondekar, Nagendra B.,Yang, Chia-Ron
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- A Mechanism for Reductive Amination Catalyzed by Fungal Reductive Aminases
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Reductive aminases (RedAms) catalyze the asymmetric reductive amination of ketones with primary amines to give secondary amine products. RedAms have great potential for the synthesis of bioactive chiral amines; however, insights into their mechanism are currently limited. Comparative studies on reductive amination of cyclohexanone with allylamine in the presence of RedAms, imine reductases (IREDs), or NaBH3CN support the distinctive activity of RedAms in catalyzing both imine formation and reduction in the reaction. Structures of AtRedAm from Aspergillus terreus, in complex with NADPH and ketone and amine substrates, along with kinetic analysis of active-site mutants, reveal modes of substrate binding, the basis for the specificity of RedAms for reduction of imines over ketones, and the importance of domain flexibility in bringing the reactive participants together for the reaction. This information is used to propose a mechanism for their action and also to expand the substrate specificity of RedAms using protein engineering.
- Sharma, Mahima,Mangas-Sanchez, Juan,France, Scott P.,Aleku, Godwin A.,Montgomery, Sarah L.,Ramsden, Jeremy I.,Turner, Nicholas J.,Grogan, Gideon
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p. 11534 - 11541
(2018/11/23)
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- A biocatalytic cascade for the amination of unfunctionalised cycloalkanes
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Here we describe a one-pot, three-enzyme, cascade involving a cytochrome P450 monooxygenase, an alcohol dehydrogenase and a reductive aminase for the synthesis of secondary amines from cycloalkanes. Amine product concentrations of up to 19.6 mM were achieved. The preparative scale amination of cyclohexane was also demonstrated with a space-time yield of 2 g L-1 d-1.
- Tavanti, Michele,Mangas-Sanchez, Juan,Montgomery, Sarah L.,Thompson, Matthew P.,Turner, Nicholas J.
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supporting information
p. 9790 - 9793
(2017/12/08)
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- SUBSTITUTED AMINO-BENZIMIDAZOLES, MEDICAMENTS COMPRISING SAID COMPOUND, THEIR USE AND THEIR METHOD OF MANUFACTURE
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The present invention relates to substituted amino-benzimidazoles of general formula (1) wherein the groups R1 to R14 and A, are defined as in the specification and claims and the use thereof for the treatment of Alzheimer's disease (AD) and similar diseases.
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Page/Page column 95
(2009/09/05)
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- Discovery of novel, potent benzamide inhibitors of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) exhibiting oral activity in an enzyme inhibition ex vivo model
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We report the discovery of potent benzamide inhibitors of 11β-hydroxysteroid dehydrogenase (11β-HSD1). The optimization and correlation of in vitro and in vivo metabolic stability will be described. Through modifications to our initial lead 2, we discovered pyridyl compound 13. This compound has a favorable pharmacokinetic profile across three species and showed a dose-dependent decrease in adipose 11β-HSD1 activity in a monkey ex vivo pharmacodynamic model.
- Julian, Lisa D.,Wang, Zhulun,Bostick, Tracy,Caille, Seb,Choi, Rebekah,DeGraffenreid, Michael,Di, Yongmei,He, Xiao,Hungate, Randall W.,Jaen, Juan C.,Liu, Jinsong,Monshouwer, Mario,McMinn, Dustin,Rew, Yosup,Sudom, Athena,Sun, Daqing,Tu, Hua,Ursu, Stefania,Walker, Nigel,Yan, Xuelei,Ye, Qiuping,Powers, Jay P.
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experimental part
p. 3953 - 3960
(2009/04/10)
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- Benzamide derivatives and uses related thereto
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Benzamide derivatives of formulae I and II, and pharmaceutically acceptable salts, solvates, stereoisomers, and prodrugs thereof, and pharmaceutical compositions comprising the same, are described and have therapeutic utility, particularly in the treatment of diabetes, obesity, and related conditions and disorders: wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, and R12 are defined as provided herein.
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Page/Page column 50
(2008/06/13)
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- Amido compounds and their use as pharmaceuticals
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The present invention relates to inhibitors of 11-β hydroxyl steroid dehydrogenase type 1, antagonists of the mineralocorticoid receptor MR, and pharmaceutical compositions thereof. The compounds of the invention can be useful in the treatment of various diseases associated with expression or activity of 11-β hydroxyl steroid dehydrogenase type 1 and/or diseases associated with aldosterone excess.
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Page/Page column 24
(2010/02/15)
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- 2(1H)-Quinolinone derivatives as novel anti-arteriostenotic agents showing anti-thrombotic and anti-hyperplastic activities
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In order to search for anti-arteriostenotic agents, a series of 2(1H)- quinolinone derivatives was synthesized and evaluated for anti-thrombotic activity and for anti-hyperplastic activity. From this series, (-)-6-[3-[3- cyclopropyl-3-[(1R,2R)-2-hydroxycycyclohexyl]ureido]propoxy]-2(1H)- quinolinone (1p, OPC-33509) was selected as the best candidate by balancing the efficacy on anti-thrombosis and anti-hyperplasia.
- Koga, Yasuo,Kihara, Yoshito,Okada, Minoru,Inoue, Yoshihiro,Tochizawa, Shirou,Toga, Kazuyuki,Tachibana, Kazue,Kimura, Yukio,Nishi, Takao,Hidaka, Hiroyoshi
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p. 1471 - 1476
(2007/10/03)
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