Enamine Prodrugs

Caldwell, Henry C.; Adams, H.J.; Jones, Russell G.; Mann, W.; Dittert, Lewis W.; Chong, Clifford W.; Swintosky, Joseph V.

doi:10.1002/jps.2600601207

Cited by 12 publications

(7 citation statements)

References 12 publications

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“…Enamines [ 96 ], ( α,β -unsaturated amines), just like imines, are generally unstable particularly at low pH, which make them unsuitable for the preparation of prodrugs for oral delivery. Nevertheless, an enamine prodrug of ampicillin was found to promote the rectal absorption of the drug [ 97 ].…”

Section: Prodrugs That Rely Mostly On Chemical Activationmentioning

confidence: 99%

Prodrugs for Amines

2008

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The purpose of this work is to review the published strategies for the production of prodrugs of amines. The review is divided in two main groups of approaches: those that rely on enzymatic activation and those that take advantage of physiological chemical conditions for release of the drugs. A compilation of the most important approaches is presented in the form of a table, where the main advantages and disadvantages of each strategy are also referred.

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Section: Prodrugs That Rely Mostly On Chemical Activationmentioning

confidence: 99%

Prodrugs for Amines

2008

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“…Research in our laboratories has disclosed a series of highly potent anticonvulsant enaminones (Edafiogho et al, 1992). Enaminones, enamines of P-dicarbonyl compounds, have been shown to be quite stable and have been used as prodrugs with variable results (Caldwell et al, 1971; Jensen et al, 1980; Murakami et al, 1981a,b;Fedor, 1984; Naringrekar and Stella, 1990). Structureactivity studies in our laboratories have shown that for maximum anticonvulsant activity enaminones should be derived from primary arylamines (which are substituted in the para posi-tion with a strong electron withdrawing group) and that a chiral ester function (e.g., carbomethoxy) in position 1 provides sustained duration of action.…”

mentioning

confidence: 99%

Profile of Anticonvulsant Activity and Minimal Toxicity of Methyl 4‐[(p‐Chlorophenyl)amino]‐6‐Methyl‐2‐Oxo‐Cyclohex‐3‐En‐l‐Oate and Some Prototype Antiepileptic Drugs in Mice and Rats

Mulzac¹,

Scott²

1993

Epilepsia

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The anticonvulsant and toxic properties of methyl 4-[(p-chlorophenyl)amino]-6-methyl-2-oxocyclohex-3-en-1-oate (ADD 196022), were compared with those of phenytoin (PHT), carbamazepine (CBZ), and valproate (VPA). These compounds were evaluated in mice and rats using well-standardized anticonvulsant testing procedures. Results indicate that ADD 196022 is a very potent anticonvulsant in the maximal electroshock seizure (MES) model. The compound was effective in nontoxic doses after intraperitoneal (i.p.) administration in mice and oral administration in rats. In mice, i.p. administration of ADD 196022 resulted in an ED50 value of 26.2 mg/kg as compared with a value of 6.48 mg/kg for PHT in the same assay. ADD 196022 was more potent that PHT in the oral rat model, having an ED50 value of 5.79 mg/kg as compared to 23.2 mg/kg for PHT. ADD 196022 was ineffective in nontoxic doses against all other seizure models evaluated and thus has a pharmacologic profile similar to that of PHT.

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“…4.5 ± 0.5 (5) 5.1 ± 0.1 (7) 4.9 ± 0.4 (5) hypothalamus (Hypo) (8) 1.5 ± 0.1 (7) 1.4 ± 0.6 (5) FC 1.0 ± 0.1 (8) 0.9 ± 0.1 (7) 0.8 ± 0.2 (5) PC 0.9 ± 0.1 (8) 1.0 ± 0.1 (7) 0.8 ± 0.1 ( 5)…”

Section: Resultsmentioning

confidence: 99%

(R)-(-)-10-Methyl-11-hydroxyaporphine: a highly selective serotonergic agonist

et al. 1988

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Prior work in these laboratories identified (+/-)-5-hydroxy-6-methyl-2- (di-n-propylamino)tetralin as a dopaminergic agonist prodrug. The ortho methyl hydroxy aromatic substitution pattern in this molecule has now been incorporated into the aporphine ring system to give a congener of the dopaminergic agonist apomorphine in which the position 10 OH group has been replaced by methyl. Preparation of the target compound involved acid-catalyzed rearrangement of the 3-(1-phenyltetrazolyl) ether of morphine and subsequent molecular modification of the product, the 10-(1-phenyltetrazolyl) ether of (R)-(-)-apomorphine. Surprisingly, the target compound elicited no responses in any assays for effects at dopamine receptors, but rather it displayed pharmacological properties consistent with its being a serotonergic agonist with a high degree of selectivity for 5-HT1A receptors similar to the serotonergic agonist 8-hydroxy-2-(di-n-propylamino)tetralin.

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Enamine Prodrugs

Cited by 12 publications

References 12 publications

Prodrugs for Amines

Prodrugs for Amines

Profile of Anticonvulsant Activity and Minimal Toxicity of Methyl 4‐[(p‐Chlorophenyl)amino]‐6‐Methyl‐2‐Oxo‐Cyclohex‐3‐En‐l‐Oate and Some Prototype Antiepileptic Drugs in Mice and Rats

(R)-(-)-10-Methyl-11-hydroxyaporphine: a highly selective serotonergic agonist

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