- Discovery of 3,4,6-Trisubstituted Piperidine Derivatives as Orally Active, Low hERG Blocking Akt Inhibitors via Conformational Restriction and Structure-Based Design
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A series of 3,4-disubstituted piperidine derivatives were obtained based on a conformational restriction strategy and a lead compound, A12, that exhibited potent in vitro and in vivo antitumor efficacies; however, obvious safety issues limited its further development. Thus, systematic exploration of the structure-activity relationship of compound A12, involving the phenyl group, hinge-linkage, and piperidine moiety, led to the discovery of the superior 3,4,6-trisubstituted piperidine derivative E22. E22 showed increased potency in Akt1 and cancer cell inhibition, remarkably reduced human ether-a-go-go-related gene blockage, and significantly improved safety profiles. Compound E22 also exhibited good kinase selectivity, had a good pharmacokinetic profile, and displayed very potent in vivo antitumor efficacy, with over 90% tumor growth inhibition in the SKOV3 xenograft model. Further mechanistic studies were conducted to demonstrate that compound E22 could significantly inhibit the phosphorylation of proteins downstream of Akt kinase in cells and tumor tissue from the xenograft model.
- Dong, Xiaowu,Zhan, Wenhu,Zhao, Mengting,Che, Jinxin,Dai, Xiaoyang,Wu, Yizhe,Xu, Lei,Zhou, Yubo,Zhao, Yanmei,Tian, Tian,Cheng, Gang,Jin, Zegao,Li, Jia,Shao, Yanfei,He, Qiaojun,Yang, Bo,Weng, Qinjie,Hu, Yongzhou
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- Telescoped Continuous Flow Synthesis of Optically Active γ-Nitrobutyric Acids as Key Intermediates of Baclofen, Phenibut, and Fluorophenibut
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The two-step flow asymmetric synthesis of chiral γ-nitrobutyric acids as key intermediates of the GABA analogues baclofen, phenibut, and fluorophenibut is reported on a multigram scale. The telescoped process comprises an enantioselective Michael-type add
- ?tv?s, Sándor B.,Kappe, C. Oliver,Llanes, Patricia,Pericàs, Miquel A.
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supporting information
p. 8122 - 8126
(2020/11/03)
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- TRICYCLIC DERIVATIVE
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Disclosed are compounds useful as inhibitors of phosphodiesterase 1 (PDE1), compositions thereof, and methods of using the same.
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Paragraph 0265; 0267
(2016/04/20)
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- Chemical assembly systems: Layered control for divergent, continuous, multistep syntheses of active pharmaceutical ingredients
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While continuous chemical processes have attracted both academic and industrial interest, virtually all active pharmaceutical ingredients (APIs) are still produced by using multiple distinct batch processes. To date, methods for the divergent multistep continuous production of customizable small molecules are not available. A chemical assembly system was developed, in which flow-reaction modules are linked together in an interchangeable fashion to give access to a wide breadth of chemical space. Control at three different levels - choice of starting material, reagent, or order of reaction modules - enables the synthesis of five APIs that represent three different structural classes (γ-amino acids, γ-lactams, β-amino acids), including the blockbuster drugs Lyrica and Gabapentin, in good overall yields (49-75%).
- Ghislieri, Diego,Gilmore, Kerry,Seeberger, Peter H.
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p. 678 - 682
(2015/03/04)
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- Water-compatible iminium activation: Organocatalytic Michael reactions of carbon-centered nucleophiles with enals
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(Chemical Equation Presented) A pool of water-compatible catalysts, namely the chiral prolinol-based catalysts 1, has been developed for highly enantioselective C-C bond-forming Michael reactions in water (see scheme). The synthesis of (S)-Rolipram, a type IV phosphodiesterase inhibitor, was also demonstrated.
- Palomo, Claudio,Landa, Aitor,Mielgo, Antonia,Oiarbide, Mikel,Puente, Angel,Vera, Silvia
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p. 8431 - 8435
(2008/09/19)
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- A short and convenient chemoenzymatic synthesis of both enantiomers of 3-phenylGABA and 3-(4-chlorophenyl)GABA(Baclofen)
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Both enantiomers of the pharmacologically active GABA analogues 4-amino-3-phenyl and 4-amino-3-(4-chlorophenyl)butyric acid (Baclofen) with high enantiomeric excesses were synthesized by a chemoenzymatic method involving α-chymotrypsin mediated kinetic resolutions of the corresponding 3-phenyl- and 3-(4-chlorophenyl)-4-nitrobutyric acid methyl ester precursors.
- Felluga, Fulvia,Gombac, Valentina,Pitacco, Giuliana,Valentin, Ennio
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p. 1341 - 1345
(2007/10/03)
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- Synthesis of both enantiomers of baclofen using (R)- and (S)-N-phenylpantolactam as chiral auxiliaries
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Esterification of racemic 4-nitro-3-(4-chlorophenyl)butanoic acid with (R)- or (S)-N-phenylpantolactam as the chiral auxiliary allowed us to obtain the (3R,3′R)- or (3S,3′S)-nitro esters with >98:2 dr after column chromatography. Hydrolysis of the resulti
- Camps, Pelayo,Munoz-Torrero, Diego,Sanchez, Laura
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p. 2039 - 2044
(2007/10/03)
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- Potential GABAB Receptor Antagonists. VII. The Synthesis of 2-(4-Chlorophenyl)-3-nitropropan-1-amine and Related Analogues of Baclofen
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3-Nitro-2-phenylpropan-1-amine and 2-(4-chlorophenyl)-3-nitropropan-1-amine have been synthesized by the addition of nitrous acid to the corresponding trifluoroacetylaminomethylstyrenes followed by reduction of the double bond with sodium borohydride.A more general and efficient route involves the Michael addition of nitroalkane anions to methyl cinnamates followed by Curtius degradation of the corresponding acids. 2-(4-Chlorophenyl)-3-nitropropan-1-amine is a specific agonist of GABA and the GABAB receptor, with about half the activity of racemic baclofen at the isolated guinea pig ileum.Methylation or dimethylation at C3 decreases activity markedly.
- Abbenante, Giovanni,Hughes, Robert,Prager, Rolf H.
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p. 1441 - 1452
(2007/10/02)
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- (Substituted-phenyl)-5-oxo-2-pyrrolidinepropanoic acids and esters thereof, and use for reversing electroconvulsive shock-induced amnesia
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Certain 5-oxo-3-(unsubstituted-phenyl)- or 5-oxo-3-(substituted phenyl)-2-pyrrolidinepropanoic acids and 5-oxo-β-(unsubstituted-phenyl)- or 5-oxo-β-(substituted-phenyl)-2-pyrrolidinepropanoic acids, their pharmaceutically acceptable esters and metal and amine cation salts, pharmaceutical compositions employing these compounds, and a method of treating senility or of reversing amnesia are disclosed.
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- 1-(Substituted-aryl)-dihydro-1H-pyrrolizine-3,5-[2H,6H-]diones and use for reversing amnesia
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1-(Substituted-aryl)-dihydro-1H-pyrrolizine-3,5-[2H,6H]-diones are effective cognition activating agents for the treatment of senility and for reversing amnesia. Pharmaceutical compositions containing these compounds and a method of treating senility or of reversing amnesia are also disclosed.
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