Colin P. Dell

Preparation of some new benzylidenemalononitriles by an SNAr reaction: application to naphtho[1,2-b]pyran synthesis

The reaction of 4-fluoro-3-nitrobenzylidene malononitrile (3) with piperidine and 1-naphthol yields the addition-elimination product (9) rather than the expected naphtho[1,2-b]pyran (7). This reaction is extended to produce other 3,4-disubstituted benzylidenemalononitriles (10)-(13). These compounds are then reacted with 1-naphthol and 4-methylmorpholine producing the naphtho[1,2-b]pyrans (14)-(17)

ARL 17477, a selective nitric oxide synthase inhibitor, with neuroprotective effects in animal models of global and focal cerebral ischaemia

In the present studies, we have evaluated the effects of N-[4-(2-¿[(3-Chlorophenyl)methyl]amino¿ethyl)phenyl]-2-thiophenecarbo ximidamide dihydrochloride (ARL 17477) on recombinant human neuronal NOS (nNOS) and endothelial NOS (eNOS). We then carried out pharmacokinetic studies and measured cortical nitric oxide synthase (NOS) inhibition to determine that the compound crossed the blood brain barrier. Finally, the compound was evaluated in a model of global ischaemia in the gerbil and two models of transient focal ischaemia in the rat. The IC(50) values for ARL 17477 on human recombinant human nNOS and eNOS were 1 and 17 microM, respectively. ARL 17477 (50 mg/kg i.p.) produced a significant reduction in the ischaemia-induced hippocampal damage following global ischaemia when administered immediately post-occlusion, but failed to protect when administration was delayed until 30 min post-occlusion. In the endothelin-1 model of focal ischaemia, ARL 17477 (1 mg/kg i.v.) significantly attenuated the infarct volume when administered at either 0, 1 or 2 h post-endothelin-1 (P<0.05). In the intraluminal suture model, ARL 17477 at both 1 and 3 mg/kg i.v. failed to reduce the infarct volume measured at 1, 3 or 7 days post-occlusion. These results demonstrate that ARL 17477 protects against global ischaemia in gerbils and provides some reduction in infarct volume following transient middle cerebral artery occlusion in rats, indicating that nNOS inhibition may be a useful treatment of ischaemic conditions.

The anti-rheumatic potential of a series of 2,4-di-substituted-4H-naphtho[1,2-b]pyran-3-carbonitriles

Abstract A new series of naphtho[1,2-b]pyran-3-carbonitriles with enhanced stability under acid conditions has been synthesised and examined for antiproliferative and anti-inflammatory activity. 4-(3-nitrophenyl)-2-(N-succinimido)-4H-naphtho[1,2-b]pyran-3-carbonitrile, 10, has proved to be acid stable and still retains biological activity.

LY290181, an Inhibitor of Diabetes-Induced Vascular Dysfunction, Blocks Protein Kinase C—Stimulated Transcriptional Activation Through Inhibition of Transcription Factor Binding to a Phorbol Response Element

Previous studies have shown that high glucose levels and diabetes induce an elevation in protein kinase C (PKC) activity in vascular cells and tissues susceptible to diabetic complications. In addition, PKC activation has been shown to modulate vascular cell growth, permeability, and gene expression, processes thought to be involved in the development of vascular complications. Using two in vivo model systems, we have identified a novel inhibitor of diabetic vascular dysfunction, LY290181. LY290181 prevented glucose-induced increases in blood flow and permeability in rat granulation tissue and corresponding vascular changes in the retina, sciatic nerve, and aorta of diabetic rats. Tested for its ability to inhibit PKC-regulated processes, LY290181 inhibited phorbol ester–stimulated plasminogen activator activity in a dose-dependent manner in bovine retinal endothelial cells and in human dermal fibroblasts. In addition, LY290181 inhibited phorbol ester–stimulated activation of the porcine urokinase plasminogen activator (uPA) promoter (−4600/+398) linked to the chloramphenicol acetyltransferase (CAT) reporter gene (p4660CAT). More detailed analysis of the uPA promoter revealed that LY290181 inhibited phorbol ester–stimulated activation of the uPA phorbol response element (−2458/−2349) located upstream of the thymidine kinase promoter (puPATKCAT). LY290181 appears to inhibit uPA promoter activation by blocking phorbol ester–stimulated binding of nuclear proteins to the uPA PEA3/12-O-tetradecanoylphorbol 13-acetate responsive element (TRE). These results suggest that LY290181 may inhibit diabetes-induced vascular dysfunction by inhibiting transcription factor binding to specific PKC-regulated genes involved in vascular function.

Evaluation of glycine site antagonists of the NMDA receptor in global cerebral ischaemia.

In the present studies we have investigated the effects of a range of glycine site antagonists of the N-methyl-d-aspartate (NMDA) receptor in the gerbil model of global cerebral ischaemia. The compounds tested were (+)-3-amino-1-hydroxy-2-pyrrolidone (HA 966, 15 mg/kg), 7-chloro-4-hydroxy-3-(3-phenoxy)phenyl-2(H)-quinolinone) (L-701,324, 40 mg/kg), 7-chloro-3-(cyclopropylcarbonyl)-4-hydroxy-2(1H)-quinolinone) (L-701, 252, 50 mg/kg), (3-(3-hydroxyphenyl)prop-2-ynyl 7-chloro-4 hydroxy-2(1H)-quinolone-3-carboxylate) (L-701,273, 50 mg/kg), 5-nitro-6,7-dichloro-2,3-quinoxalinedione (ACEA 1021, 25 mg/kg) and [(E)-3[(phenylcarbamoyl) ethenyl]-4,6-dichloroindole-2-carboxylic acid sodium salt (GV 150526A, 40 mg/kg). All compounds were administered via the i.p. route 30 min before and again at 2 h 30 min after 5 min bilateral carotid artery occlusion (BCAO) in the gerbil. For comparison we also evaluated a non-competitive NMDA antagonist, (5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a, d]cyclohepten-5,10-imine (MK-801, 2 mg/kg) and an alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) antagonist, (3S,4aR, 6R, 8aR)-6-[2-(1(2)H-tetrazole-5-yl)]decahydroisoquinoline-3-car boxylic acid (LY293558, 20 mg/kg). In the present studies L-701,252, L-701, 324 and L-701,273 provided a small degree of neuroprotection. ACEA 1021, GV 150526A and HA 966 failed to provide any neuroprotection, while MK-801 provided significant (20%) protection. In contrast LY293558 provided good (55%) neuroprotection. These results indicate that glycine site antagonists and competitive NMDA antagonists provide a small degree of neuroprotection in global cerebral ischaemia. In contrast, AMPA receptor antagonists provide more robust neuroprotection in global cerebral ischaemia.

Direct fluorination of the anthraquinone nucleus: scope and application to the synthesis of novel rhein analogues

Abstract Direct fluorination of the functionalised anthraquinone dimethyl rhein methyl ester with Selectfluor TM proceeds regioselectively, providing a concise approach to fluorinated compounds of potential medicinal interest. This represents a new use for Selectfluor TM which hitherto has only been used for fluorinating relatively activated compounds.

Use of functionalised ynamines in a hetero-Diels–Alder approach to dihydronaphtho[1,2-b]pyrans and indeno[1,2-b]pyrans

Reaction of the ynamine ester methyl 3-(pyrrolidin-1-yl)prop-2-ynoate 5 with 2-(4-nitrobenzylidene)1-tetralone 1 results in a very poor yield of the chromatographically labile 4-aryl-5, 6-dihydro-4H-naphtho[1,2-b]pyran 8 along with the α-pyrone 10. Increasing the reactivity of the 4π component by using the 2-arylidene indan-1,3-diones 11–13 results in moderate to good yields of the 4-aryl-5-oxo-4H-indeno[1,2-b]pyran-3-carboxylates 14–19. An ynamine nitrile 24, generated in situ, also reacts with 12 and 13, furnishing rather lower yields of the adducts 20 and 21.

Chapter 6. Neuronal Calcium Channels

Publisher Summary The understanding of the biology of neuronal calcium channels has developed significantly in recent times with the recognition of at least six subtypes of voltage-dependent calcium channels (VDCCs) found in the central nervous system (CNS). VDCC belong to a class of proteins that mediate ionic movements across excitable cell membranes in response to the changes in membrane potential. The subtypes of VDCC are commonly referred to as L, N, P, Q, R, and T that are divided into two groups, low voltage activated (LVA) and high voltage activated (HVA), on the basis of requirement of depolarization for activation. Molecular biology studies are revealing the subunit composition of these individual VDCC subtypes and allowing the development of cloned cell lines, expressing single populations of neuronal VDCCs. The chapter discusses the neuronal VDCCs of the N and P-Q families, because of their likely relevance to the neurotransmitter release. N-type channels are uniquely blocked by nanomolar concentrations of a peptide toxin, ω-CgTx-GVIA, found in the venom of a fish hunting mollusc, Conus geographus . Inhibition of a calcium channel by this toxin is widely accepted as being indicative of N type pharmacology. The inhibition is practically irreversible whereas that by another selective toxin, ω-CmTx-MVIIA from Conus magus, is readily reversible. There are known to be at least six a1 genes coding for the pore-forming proteins of HVA VDCCs. Expression of the cloned subunits in oocytes and mammalian cell lines is allowing comparison of the biophysics and pharmacologies of native and engineered channels. All cloned a1 subunits give rise to HVA channels. Expression of α 1A and α 1B gives rise to slowly inactivating channels whereas those expressed by α 1E genes are rapidly inactivating and more akin to R channels. Like R channels, α 1E expression leads to VDCCs that are insensitive to ω-CgTx-GVIA, ω-CmTx-MVIIC, and ω-Aga-IVA.

Reaction of 3-aryl-2-cyanothioacrylamides with electron-deficient alkynes: synthesis of 4-aryl-4H-thiopyrans

The 3-aryl-2-cyanothioacrylamides 2–4 react well with methyl propiolate and dimethyl acetylenedicarboxylate yielding the thiopyrans 8–13. Reactions with less activated alkynes proceed sluggishly, if at all.