Cyclic Ureides

Vida, Julius A.; Gerry, Elisabeth H.

doi:10.1016/b978-0-12-721840-3.50011-8

Cited by 20 publications

(28 citation statements)

References 120 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The potent antiepileptic properties of α-substituted cyclic imides have been known for over fifty years (Chen et al, 1951;Vida & Gerry, 1977). For instance, 1,3-dimethyl-3-phenylpyrrolidine-2,5-dione (methsuximide) is a broad-spectrum anticonvulsant, valuable in the treatment of medically intractable epilepsy (Sigler et al, 2001).…”

Section: S1 Commentmentioning

confidence: 98%

Crystal structure of (E)-1-(4-methoxyphenyl)ethanoneO-dehydroabietyloxime

Rao¹,

Cui²,

Zheng³

2014

Acta Cryst E

View full text Add to dashboard Cite

show abstract

Section: S1 Commentmentioning

confidence: 98%

Crystal structure of (E)-1-(4-methoxyphenyl)ethanoneO-dehydroabietyloxime

Rao¹,

Cui²,

Zheng³

2014

Acta Cryst E

View full text Add to dashboard Cite

show abstract

“…Adolf von Baeyer reported the discovery of barbituric acid or malonylurea in 1864 and Mulder subsequently confirmed its chemical structure in 1873 (Vida & Gerry, 1977). There are three hypotheses about the origin of the term “barbiturates” (Dundee & Mellroy, 1982; Lopez‐Munos et al., 2005):…”

Section: Phenobarbitalmentioning

confidence: 99%

“…Subsequently, the barbiturates were classified into potentially active and inactive classes. In the active class (as hypnotics) there were 5,5‐disubstituted barbituric acids and thiobarbituric acids as well as 1,5,5‐trisubstituted barbituric acids (Sandberg, 1951; Vida & Gerry, 1977). Substitution of various alkyl and/or aryl moieties for the N and C‐5 hydrogens of barbituric acid yielded molecules that varied considerably in their dominant pharmacologic effect on laboratory animals, including inactive, sedative, and proconvulsant compounds (Prichard, 1980).…”

Section: Phenobarbitalmentioning

confidence: 99%

“… The efficacy of active anticonvulsant compounds (e.g., PHT), hitherto assessed solely by clinical observation, was now testable in preclinical studies that led to anticonvulsant animal models; To be effective, an AED does not need to be a sedative (Porter, 1986). It is still unclear whether PHT’s lack of sedative properties (compared to phenobarbital) is due to the hydantoin ring or to the different alkyl/aryl side‐chain moieties (diphenyl compared to phenyl and ethyl in the case of phenobarbital). Vida and Gerry summarized the following structure activity relationship (SAR) requirements for anticonvulsant activity of hydration derivatives (Vida & Gerry, 1977; Kupferberg, 1995): …”

Section: Phenobarbital‐related Compoundsmentioning

confidence: 99%

See 1 more Smart Citation

How did phenobarbital’s chemical structure affect the development of subsequent antiepileptic drugs (AEDs)?

Bialer¹

2012

Epilepsia

View full text Add to dashboard Cite

Summary Phenobarbital has been in clinical use as an antiepileptic drug (AED) since 1912. The initial clinical success of phenobarbital and other barbiturates affected the design of subsequent AEDs (e.g., phenytoin, primidone, ethosuximide), developed between 1938 and 1962, the chemical structures of which resemble that of phenobarbital. However, the empirical discovery of carbamazepine (1962) and the serendipitous discovery of valproic acid (1967) led to subsequent AEDs having chemical structures that are diverse and completely different from that of phenobarbital. Sixteen AEDs were introduced between 1990 and 2012. Most of these AEDs were developed empirically, using mechanism‐unbiased anticonvulsant animal models. The empirical nature of the discovery of these AEDs, coupled with their multiple mechanisms of action, explains their diverse chemical structures. The antiepileptic market is therefore crowded. Future design of new AEDs must have a potential for treating nonepileptic central nervous system (CNS) disorders (e.g., bipolar disorder, neuropathic pain, migraine prophylaxis, or restless legs syndrome). The barbiturates were once used as sedative‐hypnotic drugs, but have been largely replaced in this role by the much safer benzodiazepines. In contrast, phenobarbital is still used worldwide in epilepsy. Nevertheless, the development of nonsedating phenobarbital derivatives will answer a clinical unmet need and might make this old AED more attractive.

show abstract

“…Our examination of the literature (12) suggests that, although the contribution of lipophilicity cannot be ignored (13), the anticonvulsant activity of a hydantoin depends primarily upon its ability to bind to the phenytoin receptor. Any attempt to model this process requires information concerning the nature of this receptor and its chemical constitution.…”

Section: Of Ref 7)mentioning

confidence: 99%

Phenceptin: a biomimetic model of the phenytoin receptor

Wolfe¹,

Bowers²,

Shin³

et al. 1988

Can. J. Chem.

View full text Add to dashboard Cite

Can. J. Chem. 66, 2751(1988. 5,s-Diphenylhydanytoin (phenytoin) is the most widely used anticonvulsant drug, but has many side effects. Although its chemical mode of action is unknown, phenytoin is believed to function primarily by interference with the transport of sodium ions across the neuronal membrane. Structure-activity and lipophilicity-activity studies suggest that the drug interacts with its receptor through hydrogen bonding to the N3-C4 amide bond, and an aromatic-aromatic interaction with the C5 substituent. Since sodium channels are cysteine-rich peptides, whose function depends upon the cysteineecystine redox process, it has been hypothesized that the action of the phenytoin receptor may be mimicked by a properly designed cyclodepsipeptide containing a cystinyl moiety, a cavity lined with five oxygen atoms oriented in the trigonal-bipyramidal manner appropriate for selective transport of sodium ions, and a site for the binding of phenytoin. A computer programme and strategy were developed to permit the three-dimensional structures of potential target molecules to be viewed, prior to synthesis. Use of this programme led to the discovery of Boc-~-cystinyl-glycyI-~-prolyl-glycyl-~-prolyl-~-cystine-OCHPh. This compound, termed phenceptin, was synthesized from a linear precursor containing tert-butoxycarbonyl protection at the N-terminus, benzhydryl ester protection at the C-terminus, and trityl protection at sulfur. Detritylation and cyclization to phenceptin were accomplished with iodine in methanol-pyridine. Using an n-octanol membrane to study the kinetics of ion transport, phenceptin was found to transport sodium ions selectively, but only in its oxidized, cyclic form. This transport was inhibited significantly by one mol-equiv. of phenytoin, and not at all by biologically inactive analogs of the drug. The nature of the binding of phenytoin to phenceptin was examined by nuclear magnetic resonance, in n-CsD17-OH solvent, and found to involve hydrogen bonding of the drug to a glycine residue whose oxygen atom is involved in complexation to sodium ions. SAUL WOLFE, RAYMOND JOHN BOWERS, HEE-SOOK SHIN, CHANG-KOOK SOHN, DONALD FREDRIC WEAVER ET KIYULLYANG. Can. J. Chem. 66, 2751 (1988). La diphCnyl-5,s hydantoyne (phtnytoi'ne) est le mtdicament le plus utilist comme anticonvulsivant; toutefois, il provoque de nombreuses rkactions secondaires. MCme si son mode d'action chimique est inconnu, on croit que la phtnytoi'ne agit principalement par interftrence avec le transport des ions sodium a travers les membranes neuronales. Des etudes de structure/activitC et caractere liphophilique/activitt suggkrent que la drogue interagit avec son rtcepteur par le biais de liaisons hydrogknes avec la liaison amide N3-C4 et par une interaction aromatique/aromatique avec le substituant en C5. Puisque les canaux du sodium sont des peptides riches en cysttine dont la fonction dtpend du processus redox cysteine/cystine, il a Ct C suggCrC que l'on pourrait rCpliquer l'action du rCcepteur de la phCnytoi'ne a l'aide d'un cyclod...

show abstract

Cyclic Ureides

Cited by 20 publications

References 120 publications

Crystal structure of (E)-1-(4-methoxyphenyl)ethanoneO-dehydroabietyloxime

Crystal structure of (E)-1-(4-methoxyphenyl)ethanoneO-dehydroabietyloxime

How did phenobarbital’s chemical structure affect the development of subsequent antiepileptic drugs (AEDs)?

Phenceptin: a biomimetic model of the phenytoin receptor

Contact Info

Product

Resources

About