Practical Synthesis of Chiral Emopamil Left Hand as a Bioactive Motif

Kimura, Teiji; Yamamoto, Noboru; Suzuki, Yuichi; Kawano, Kimiko; Norimine, Yoshihiko; Ito, Koichi; Nagato, Satoshi; Iimura, Youichi; Yonaga, Masahiro

doi:10.1021/jo020166d

Cited by 34 publications

(18 citation statements)

References 11 publications

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“…Then, the reaction mixture was filtered through a pad of celite, and the filtrate was concentrated under reduced pressure. Purification by silica gel column chromatography (EtOAc/hexanes, 30:70) afforded 200 mg (89%) of compound 12 as a colorless oil (Kimura et al, 2002) 142.70, 129.98, 117.70, 117.29, 114.75, 111.62, 70.18, 70.06, 60.41, 36.66, 35.07, 33.53, 27.91, 20.01, 14.24, 14.22].…”

Section: Rational Design Of Visual Cycle Modulatorsmentioning

confidence: 99%

Rational Tuning of Visual Cycle Modulator Pharmacodynamics

Kiser

Zhang

Badiee

et al. 2017

J Pharmacol Exp Ther

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Modulators of the visual cycle have been developed for treatment of various retinal disorders. These agents were designed to inhibit retinoid isomerase [retinal pigment epithelium-specific 65 kDa protein (RPE65)], the rate-limiting enzyme of the visual cycle, based on the idea that attenuation of visual pigment regeneration could reduce formation of toxic retinal conjugates. Of these agents, certain ones that contain primary amine groups can also reversibly form retinaldehyde Schiff base adducts, which contributes to their retinal protective activity. Direct inhibition of RPE65 as a therapeutic strategy is complicated by adverse effects resulting from slowed chromophore regeneration, whereas effective retinal sequestration can require high drug doses with potential off-target effects. We hypothesized that the RPE65-emixustat crystal structure could help guide the design of retinaldehydesequestering agents with varying degrees of RPE65 inhibitory activity. We found that addition of an isopropyl group to the central phenyl ring of emixustat and related compounds resulted in agents effectively lacking in vitro retinoid isomerase inhibitory activity, whereas substitution of the terminal 6-membered ring with branched moieties capable of stronger RPE65 interaction potentiated inhibition. The isopropyl derivative series produced discernible visual cycle suppression in vivo, albeit much less potently than compounds with a high affinity for the RPE65 active site. These agents were distributed into the retina and formed Schiff base adducts with retinaldehyde. Except for one compound [3-amino-1-(3-isopropyl-5-((2,6,6-trimethylcyclohex-1-en-1-yl)methoxy)phenyl)propan-1-ol (MB-007)], these agents conferred protection against retinal phototoxicity, suggesting that both direct RPE65 inhibition and retinal sequestration are mechanisms of potential therapeutic relevance.

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Section: Rational Design Of Visual Cycle Modulatorsmentioning

confidence: 99%

Rational Tuning of Visual Cycle Modulator Pharmacodynamics

Kiser

Zhang

Badiee

et al. 2017

J Pharmacol Exp Ther

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“…(Scheme 4). [17] In conclusion, we described the development of novel chiral pyrimidine and pyrazine-oxazoline ligands and their effective application in the enantioselective palladium-catalyzed Heck reaction of acyclic trisubstituted olefins bearing linear or branched substituents.T he Heck products were . [19] Finally,( R)-verapamil 12 was obtained (0.98 g, 2.15 mmol) after three additional steps:i )Dess-Martin oxidation of the 11,i i) oxime formation, and iii)oxime decomposition after activation by 1,1'-carbonyldiimidazole (CDI).…”

Section: Methodsmentioning

confidence: 99%

Quaternary Stereogenic Centers through Enantioselective Heck Arylation of Acyclic Olefins with Aryldiazonium Salts: Application in a Concise Synthesis of (R)‐Verapamil

2015

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We describe herein ah ighly regio-and enantioselective Pd-catalyzed Heck arylation of unactivated trisubstituted acyclic olefins to provide all-carbon quaternary stereogenic centers.C hiral N,Nligands of the pyrimidine-and pyrazino-oxazoline class were developed for that purpose, providing the desired products in good to high yields with enantiomeric ratios up to > 99:1. Both linear and branched substituents on the olefins were well-tolerated. The potential of this new method is demonstrated by the straightforward synthesis of several O-methyl lactols and lactones containing quaternary stereocenters,together with aconcise enantioselective total synthesis of the calcium channel blocker verapamil.

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“…Similarly, Sammakia's group achieved the total synthesis of the oxopolyene macrolide RK-397 using this process as one of the key steps (Scheme 113). 141 As described, the aldehyde 184 possessing the desired C30 and C31 stereocenters in the target was obtained in 95% yield with 24:1 diastereoselectivity by the rearrangement of 183.…”

Section: Scheme 106mentioning

confidence: 98%