Synthesis and structure–activity relationships of potential anticonvulsants based on 2-piperidinecarboxylic acid and related pharmacophores

Ho, Bin; Crider, A. Michael; Stables, James P.

doi:10.1016/s0223-5234(00)01206-x

Cited by 147 publications

(50 citation statements)

References 27 publications

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“…First of all we tested the effect of the substitution of the proline cycle with the less planar piperidine ring. The substitution is of interest as several local anesthetics used in therapy such as mepivacaine, bupivacaine and ropivacaine are alkyl-substituted 2-piperidine carboxanilides, structurally related to our compounds [28]. Furthermore a piperidine ring is also present in many natural occurring alkaloids and synthetic drugs, which reinforced the interest in establishing its potential role in modulating pharmacophore requirement for further search of potential candidates in existing pharmacopeia.…”

Section: Discussionmentioning

confidence: 99%

Searching for novel anti-myotonic agents: Pharmacophore requirement for use-dependent block of skeletal muscle sodium channels by N-benzylated cyclic derivatives of tocainide

A¹,

Bellis²,

Corbo³

et al. 2012

Neuromuscular Disorders

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Drug screening on sodium currents of native myofibers by means of voltage-clamp recordings is predictive of pre-clinical anti-myotonic activity in vivo and ex vivo. By this approach we identified the N-benzylated beta-proline derivative of tocainide (To10) as the most potent use-dependent blocker of Nav1.4 so far. We tested novel analogs with modifications on the pharmacophore groups of To10. The substitution of the proline cycle with less planar piperidine or piperazine rings disclosed the importance of a two carbon atom distance and/or an additional nitrogen atom for potency. Structural changes on the xylididic group corroborated the role of a proper electronic cloud for hydrophobic interactions with the binding site. The N-benzylated moiety lead to a stereoselective behavior only in the rigid alpha-proline analog To11 vs. To10 and N-benzylated tocainide (To12). The results confirm the strict structural requirements of Nav1.4 blockers and allow to refine the drug design toward novel anti-myotonic drugs.

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Section: Discussionmentioning

confidence: 99%

Searching for novel anti-myotonic agents: Pharmacophore requirement for use-dependent block of skeletal muscle sodium channels by N-benzylated cyclic derivatives of tocainide

A¹,

Bellis²,

Corbo³

et al. 2012

Neuromuscular Disorders

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“…Using N-(2,6-dimethyl)phenyl-2-piperidinecarboxyamide 35 and N(α-methylbenzyl)-2-piperidinecarboxamide 36 as structural leads (Fig. 13), a variety of analogues have been synthesized and evaluated for anticonvulsant activity in the MES test in mice [87]. The following modifications led to an increase in MES activity: replacement of the piperidine ring with pyridine and movement of the carboxamide group to the 4-position, then opening the piperidine ring.…”

Section: 6-dimethylanilides Carboxamidesmentioning

confidence: 99%

New Anticonvulsant Agents

Malawska

2005

CTMC

145

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The search for antiepileptic compounds with more selective activity and lower toxicity continues to be an area of intensive investigation in medicinal chemistry. This review describes new anticonvulsant agents representing various structures for which the precise mechanism of action is still not known. Many of the compounds presented in this review have been tested according to the procedure established by the Antiepileptic Drug Development Program of the Epilepsy Branch of the National Institute of Neurological Disorders and Stroke, National Institute of Health, USA. The newer agents include sulfonamides, amino acids, amides (analogs of gamma-vinyl GABA, N-benzylamides, 2,6-dimethylanilides, carboxyamides, hydroxyamides, alkanoamides); heterocyclic agents ((arylalkyl)imidazoles, pyrrolidin-2,5-diones, lactams, semi- thiosemicarbazones, thiadiazoles, quinazolin-4(3H)-ones, 2,5-disubstituted 1,2,4-thadiazoles, xanthones, derivatives of isatin) and enaminones. These new structural classes of compounds can prove useful for the design of future targets and development of new drugs.

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“…1c,d,6 Recently, an Ugi type reaction between 3,4-dihydroisoquinoline N-oxides and isocyanides in the presence of TMSCl, has been used to synthesize THIQ-1-carboxamides. 7 In the second method (method B), substituted phenethylamines are coupled with glyoxylate derivatives to yield the corresponding THIQ-1-carboxlic acid; here, the piperidine ring of the THIQ moiety is formed as a result of PicteteSpengler or BischlereNapieralski reactions. 8 The intermediate substituted 3,4-dihydroisoquinoline derivative is eventually reduced to afford the THIQ-1-carboxamide derivative.…”

Section: Introductionmentioning

confidence: 99%

Palladium-catalyzed double carbonylation-based diversity-oriented synthesis of 3,4-dihydroisoquinoline-1-carboxamides

et al. 2015

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Synthesis and structure–activity relationships of potential anticonvulsants based on 2-piperidinecarboxylic acid and related pharmacophores

Cited by 147 publications

References 27 publications

Searching for novel anti-myotonic agents: Pharmacophore requirement for use-dependent block of skeletal muscle sodium channels by N-benzylated cyclic derivatives of tocainide

Searching for novel anti-myotonic agents: Pharmacophore requirement for use-dependent block of skeletal muscle sodium channels by N-benzylated cyclic derivatives of tocainide

New Anticonvulsant Agents

Palladium-catalyzed double carbonylation-based diversity-oriented synthesis of 3,4-dihydroisoquinoline-1-carboxamides

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