Design, synthesis, and SAR of substituted acrylamides as factor Xa inhibitors

Song, Yonghong; Clizbe, Lane A.; Bhakta, C.; Teng, Willy; Li, Wenhao; Wu, Yanhong; Jia, Zhaozhong J.; Zhang, Penglie; Wang, Lingyan; Doughan, Brandon; Su, Ting; Kanter, James; Woolfrey, John; Wong, Paul; Huang, Brian; Tran, Katherine; Sinha, Uma; Park, Gary; Reed, Andrea; Malinowski, J; Hollenbach, Stan; Scarborough, Robert M.; Zhu, Bing‐Yan

doi:10.1016/s0960-894x(02)00199-3

Cited by 15 publications

(7 citation statements)

References 14 publications

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“…Notably, a phenolic nucleophile did not work with 3,3-difluoropropenes (i.e., Scheme , eq 2), where an elimination side reaction was predominant. Sulfur-based nucleophiles, such as an alkyl- and an arylthiolate, as well as a thiocarboxylate, all behaved nicely (Table , entries 2–4), and the desired products 2c – e could be obtained in very good to excellent yields . The use of cyanide (Table , entry 5) as the nucleophile provided the β-cyanomonofluoroalkene 2f in 96% yield.…”

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Exploiting a Difference in Leaving Group Ability: An Approach to β-Substituted Monofluoroalkenes Using gem-Chlorofluoropropenes

2016

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The superior nucleofuge character of chlorine over fluorine was taken advantage of in the selective SN2' substitution reaction of gem-chlorofluoropropenes, allowing for the clean formation of β-substituted monofluoroalkenes under metal-free conditions. Numerous N-, S-, O-, and C-nucleophiles behaved nicely in this system. Further synthetic transformations of selected monofluoroalkenes were also accomplished.

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confidence: 99%

“…Finally, to further extend the utility of this new approach, we investigated potential transformations of the monofluoroalkenes generated (Scheme ). For instance, reduction of the thioester moiety of 2c with LiAlH 4 provided an excellent yield of β-mercaptomonofluoroalkene 14 . Hydrolysis of nitrile 2f under basic conditions gave acid 15 in 74% yield.…”

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confidence: 99%

Exploiting a Difference in Leaving Group Ability: An Approach to β-Substituted Monofluoroalkenes Using gem-Chlorofluoropropenes

2016

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“…More recently, Aggarwal et al have reported the use of methanolic quinuclidine to promote the efficient reaction between acrylamide and activated aromatic aldehydes, including a lone example of reaction with benzaldehyde itself giving the allylic alcohol product in 55% yield. It was therefore our view that considerable room for scope expansion of Baylis−Hillman reactions involving acrylamide existed, particularly in view of the recent interest in α-substituted acrylamide derivatives as novel radical polymerization monomers and targets for both antithrombotic and antidepression drug design …”

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confidence: 99%

Acrylamide in the Baylis−Hillman Reaction: Expanded Reaction Scope and the Unexpected Superiority of DABCO over More Basic Tertiary Amine Catalysts

2004

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DMAP, DBU, and quinuclidine efficiently promote novel hydroalkoxylation reactions of acrylamide in primary alcohol solvents. DABCO is a comparatively poor hydroalkoxylation promoter and can effect clean, selective Baylis-Hillman reactions between acrylamide and aldehydes in alcoholic/aqueous media in which more basic nucleophilic catalysts promote hydroalkoxylation preferentially. Optimization of the reaction conditions has allowed acrylamide to be reacted with a range of aromatic aldehydes in moderate to excellent yields, including the first examples involving deactivated, electron-rich substrates such as p-tolualdehyde and o-anisaldehyde.

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“…Significant improvement in oral bioavailability was achieved by applying an amidoxime prodrug strategy to highly potent, amidine containing, fluoroacrylamide factor Xa inhibitors [156,157]. The amidine containing factor Xa inhibitor 121 (Fig.…”

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confidence: 99%

Arginine Mimetic Structures in Biologically Active Antagonists and Inhibitors

Mašič

2006

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Peptidomimetics have found wide application as bioavailable, biostable, and potent mimetics of naturally occurring biologically active peptides. L-Arginine is a guanidino group-containing basic amino acid, which is positively charged at neutral pH and is involved in many important physiological and pathophysiological processes. Many enzymes display a preference for the arginine residue that is found in many natural substrates and in synthetic inhibitors of many trypsin-like serine proteases, e.g. thrombin, factor Xa, factor VIIa, trypsin, and in integrin receptor antagonists, used to treat many blood-coagulation disorders. Nitric oxide (NO), which is produced by oxidation of L-arginine in an NADPH- and O(2)-dependent process catalyzed by isoforms of nitric oxide synthase (NOS), exhibits diverse roles in both normal and pathological physiologies and has been postulated to be a contributor to the etiology of various diseases. Development of NOS inhibitors as well as analogs and mimetics of the natural substrate L-arginine, is desirable for potential therapeutic use and for a better understanding of their conformation when bound in the arginine binding site. The guanidino residue of arginine in many substrates, inhibitors, and antagonists forms strong ionic interactions with the carboxylate of an aspartic acid moiety, which provides specificity for the basic amino acid residue in the active side. However, a highly basic guanidino moiety incorporated in enzyme inhibitors or receptor antagonists is often associated with low selectivity and poor bioavailability after peroral application. Thus, significant effort is focused on the design and preparation of arginine mimetics that can confer selective inhibition for specific trypsin-like serine proteases and NOS inhibitors as well as integrin receptor antagonists and possess reduced basicity for enhanced oral bioavailability. This review will describe the survey of arginine mimetics designed to mimic the function of the arginine moiety in numerous peptidomimetic compounds (thrombin inhibitors, factor Xa inhibitors, factor VIIa inhibitors, integrin receptor antagonists, nitric oxide synthase inhibitors), with the aim of obtaining better activity, selectivity and oral bioavailability.

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Design, synthesis, and SAR of substituted acrylamides as factor Xa inhibitors

Cited by 15 publications

References 14 publications

Exploiting a Difference in Leaving Group Ability: An Approach to β-Substituted Monofluoroalkenes Using gem-Chlorofluoropropenes

Exploiting a Difference in Leaving Group Ability: An Approach to β-Substituted Monofluoroalkenes Using gem-Chlorofluoropropenes

Acrylamide in the Baylis−Hillman Reaction: Expanded Reaction Scope and the Unexpected Superiority of DABCO over More Basic Tertiary Amine Catalysts

Arginine Mimetic Structures in Biologically Active Antagonists and Inhibitors

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