Stereochemical preferences and requirement for the 3-hydroxyl group in novel anticonvulsant 4-fluorobenzoylamino benzopyrans

Brown, Thomas H.; Campbell, C. A.; Chan, Wai N.; Evans, John; Martin, Roger T.; Stean, Tania O.; Stemp, Geoffrey; Stevens, Nichola; Thompson, Mervyn; Upton, Neil; Vong, Antonio

doi:10.1016/0960-894x(95)00437-x

Cited by 10 publications

(5 citation statements)

References 5 publications

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“…Despite the fact that SB‐204269 is derived from a series of hypotensive agents related to cromakalim which exert their actions by opening ATP‐regulated K + channels (see Introduction), there is no evidence to suggest that this compound acts in a similar manner, as indicated by its inability to lower blood pressure in conscious rats at very high doses. However, the observation that the 4S stereochemistry is an absolute requirement for the anticonvulsant efficacy of SB‐204269 and related compounds, and that the 4R configuration (as in SB‐204268) is associated with predominantly hypotensive properties (Blackburn et al , 1995; Brown et al , 1995), provides some indication that the former agents may interact with a specific site with stringent conformational requirements. This has indeed proved to be the case and the accompanying paper describes the discovery of a unique stereospecific binding site for SB‐204269 in rat brain (Herdon et al , 1997).…”

Section: Discussionmentioning

confidence: 99%

Profile of SB‐204269, a mechanistically novel anticonvulsant drug, in rat models of focal and generalized epileptic seizures

Upton

Blackburn

Campbell

et al. 1997

British J Pharmacology

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1 Earlier optimization of structure-activity relationships in a novel series of 4-(benzoylamino)-benzopyrans, led to the discovery of SB-204269 (trans-(+)-6-acetyl-4S-(4-¯uorobenzoylamino)-3,4-dihydro-2,2-dimethyl-2H-benzo [b]pyran-3R-ol, hemihydrate), a potent orally-active anticonvulsant in the mouse maximal electroshock seizure threshold (MEST) test. 2 Studies have now been undertaken to determine the e ects of SB-204269 in a range of seizure models and tests of neurological de®cits in rats. In addition, the compound has been evaluated in a series of in vitro mechanistic assays. 3 SB-204269 proved to be an orally-e ective anticonvulsant agent, at doses (0.1 ± 30 mg kg 71 ) devoid of overt behavioural depressant properties, in models of both electrically (MEST and maximal electroshock (MES)) and chemically (i.v. pentylenetetrazol (PTZ) infusion)-evoked tonic extension seizures. However, the compound did not inhibit PTZ-induced myoclonic seizures at doses up to 30 mg kg 71 , p.o. 4 SB-204269 also selectively reduced focal electrographic seizure activity in an in vitro elevated K + rat hippocampal slice model at concentrations (0.1 ± 10 mM) that had no e ect on normal synaptic activity and neuronal excitability. 5 In all of these seizure models, SB-204269 was equivalent or better than the clinically established antiepileptic drugs carbamazepine and lamotrigine, in terms of anticonvulsant potency and e cacy. 6 Unlike SB-204269, the corresponding trans 3S,4R enantiomer, SB-204268, did not produce marked anticonvulsant e ects, an observation in accord with previous ®ndings for other related pairs of trans enantiomers in the benzopyran series. 7 In the rat accelerating rotarod test, a sensitive paradigm for the detection of neurological de®cits such as sedation and motor incoordination, SB-204269 was inactive even at doses as high as 200 mg kg 71 , p.o. This was re¯ected in the excellent therapeutic index (minimum signi®cantly e ective dose in the rotarod test/ED 50 in the MES test) for SB-204269 of 431, as compared to equivalent values of only 7 and 13 for carbamazepine and lamotrigine, respectively. 8 At concentrations (510 mM) well above those required to produce anticonvulsant activity in vivo (i.e. 0.1 mM in brain), SB-204269 did not interact with many of the well known mechanistic targets for established antiepileptic drugs (e.g. Na + channels or GABAergic neurotransmission). Subsequent studies have shown that the anticonvulsant properties of SB-204269 are likely to be mediated by a novel stereospeci®c binding site present in the CNS. 9 The overall e cacy pro®le in rodent seizure models, together with a minimal liability for inducing neurological impairment and an apparently unique mechanism of action, highlight the therapeutic potential of SB-204269 for the treatment of refractory partial and generalized tonic-clonic seizures.

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Section: Discussionmentioning

confidence: 99%

Profile of SB‐204269, a mechanistically novel anticonvulsant drug, in rat models of focal and generalized epileptic seizures

Upton

Blackburn

Campbell

et al. 1997

British J Pharmacology

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“…Optical purity was determined by HPLC on a Chiracel OD, P45SC (Daicel) column using phosphate buffer (pH 3)/methanol/acetonitrile as eluent. 3 (X-ray analysis of 5b also confirmed the absolute stereochemistry; data not presented. )…”

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confidence: 75%

“…The 3S,4R enantiomers additionally showed little anticonvulsant activity. A subsequent communication 3 confirmed that a 4S configuration of the fluorobenzamide is crucial in conferring anticonvulsant activity without antihypertensive activity. Although the 3-hydroxyl group appears essential for anticonvulsant activity, its stereochemistry is not important.…”

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confidence: 92%

“…Alternatively, the benzopyran epoxides 3 were converted directly into the benzamides 5a and 5e on treatment with the anion of 4-fluorobenzamide in tert -butyl alcohol at 40 °C (method B). Optical purity was determined by HPLC on a Chiracel OD, P45SC (Daicel) column using phosphate buffer (pH 3)/methanol/acetonitrile as eluent . (X-ray analysis of 5b also confirmed the absolute stereochemistry; data not presented.)…”

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Synthesis of Novel trans-4-(Substituted-benzamido)-3,4-dihydro-2H-benzo[b]pyran-3-ol Derivatives as Potential Anticonvulsant Agents with a Distinctive Binding Profile

et al. 1996

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“…Numerous methods for the synthesis of oxazolines have been reported. Among these are the use of thionyl chloride, SOCl 2 −AgOTf, PPh 3 /DEAD, sulfonyl chlorides, − BF 3 ·Et 2 O, Tf 2 O, Tf 2 O/Ph 2 SO, P 2 O 5 , Et 2 N−SF 3 , Burgess reagent, Ph 3 P/TEA/CCl 4 , Bu 2 SnCl 2 , POCl 3 , TMSF, 30% HBr, AcOH, o -chlorophenylphosphoro-bis-(1,2,4)-triazolide, and RN 3 /(PhO) 3 P . Each method has its advantages and disadvantages in any given situation; therefore, no one reagent has proven totally general.…”

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confidence: 99%

The Synthesis of Oxazolines Using the Vilsmeier Reagent

Wuts¹,

Northuis²,

Kwan³

2000

J. Org. Chem.

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Stereochemical preferences and requirement for the 3-hydroxyl group in novel anticonvulsant 4-fluorobenzoylamino benzopyrans

Cited by 10 publications

References 5 publications

Profile of SB‐204269, a mechanistically novel anticonvulsant drug, in rat models of focal and generalized epileptic seizures

Profile of SB‐204269, a mechanistically novel anticonvulsant drug, in rat models of focal and generalized epileptic seizures

Synthesis of Novel trans-4-(Substituted-benzamido)-3,4-dihydro-2H-benzo[b]pyran-3-ol Derivatives as Potential Anticonvulsant Agents with a Distinctive Binding Profile

The Synthesis of Oxazolines Using the Vilsmeier Reagent

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