Synthesis and Anticonvulsant Properties of New N‐Mannich Bases Derived from 3,3‐Diphenyl‐ and 3‐Ethyl‐3‐methyl‐pyrrolidine‐2,5‐diones. Part III

Twenty‐four new N‐[(4‐phenylpiperazin‐1‐yl)‐methyl] derivatives of 3,3‐diphenyl‐ ( 7 – 18 ) and 3‐ethyl‐3‐methyl‐pyrrolidine‐2,5‐dione ( 19 – 30 ) were synthesized and evaluated for their anticonvulsant activity in the maximum electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) seizure tests. The acute neurological toxicity was determined using the rotorod screen. Eleven compounds were active and revealed protection only in electrically induced seizures (MES). In the whole series the most effective compound was N‐[{4‐(3‐trifluoromethylphenyl)‐piperazin‐1‐yl}‐methyl]‐3,3‐diphenyl‐pyrrolidine‐2,5‐dione ( 14 ) with an ED₅₀ value of 30.3 mg/kg (p.o. rats) in the MES test. To explain the possible mechanism of action, for chosen active derivatives 7 , 8 , 9 , 11 , 14 , 23 , and 26 , their influence on Na_V1.2 sodium channel currents was evaluated in vitro. The crystallographic structures for several molecules ( 8 , 10 , and 11 ) were solved.     

Novel Mannich Bases, 5‐Arylimidazolidine‐2,4‐dione Derivatives with Dual 5‐HT1A Receptor and Serotonin Transporter Affinity

A computer aided ligand design study of imidazolidine‐2,4‐dione derivatives was conducted in order to obtain compounds with dual 5‐HT_1A receptor and serotonin transporter (SERT) affinity. According to molecular modeling results, series of Mannich bases were chosen and synthesized. Investigated compounds were tested for 5‐HT_1A, 5‐HT_2A, α₁ and SERT affinity. Two selected compounds ( 5 , 9 ) were characterized in functional experiments and possessed a pharmacological profile which may enhance SERT blocking efficacy – 5‐HT_1A partial agonism and 5‐HT_2A antagonism in one molecule. Furthermore these compounds displayed satisfactory selectivity over adrenergic α₁ receptors. The most promising compounds, 5‐arylimidazolidine‐2,4‐dione derivatives with 4‐(3‐chlorophenyl)piperazinylmethyl moiety were tested for antidepressant and anxiolytic activity. In particular, compound 5 (5‐(2‐methoxyphenyl)‐3‐{1‐[4‐(3‐chlorophenyl)piperazin‐1‐yl]methyl}‐imidazolidine‐2,4‐dione), tested in the forced swim test in mice, exhibited a favorable antidepressant‐like profile without affecting spontaneous locomotor activity.     

Synthesis and anticonvulsant activity of new n-mannich bases derived from 5-cyclopropyl-5-phenyl-hydantoins

Synthesis, physicochemical and anticonvulsant properties of new N‐Mannich bases 3–24 derived from 5‐cyclopropyl‐5‐phenyl‐ and 5‐cyclopropyl‐5‐(4‐chlorophenyl)‐hydantoins were described here. Initial anticonvulsant screening was performed using intraperitoneal (i.p.) maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) seizures tests. Selected derivatives were also screened in the 6‐Hz test. The neurotoxicity was determined applying the rotorod test. The pharmacological results revealed that the majority of compounds were effective in MES and/or scPTZ tests. The quantitative studies after oral administration into rats showed that several molecules were more potent than phenytoin and ethosuximide which were used as reference antiepileptic drugs. From the whole series the most active was 3‐[(4‐phenylpiperazin‐1‐yl)‐methyl]‐5‐cyclopropyl‐5‐phenyl‐imidazolidine‐2,4‐dione ( 3 ) with the ED₅₀ value of 5.29 mg/kg in the MES test.     

Synthesis and evaluation of 5,7‐dichloro‐4‐(3‐{4‐[4‐(2‐[18F]fluoroethyl)‐piperazin‐1‐yl]‐phenyl}‐ureido)‐1,2,3,4‐tetrahydroquinoline‐2‐carboxylic acid as a potential NMDA ligand to study glutamatergic neurotransmission in vivo

The neurotransmitter glutamate is thought to be crucially involved in a huge number of neurological and psychiatric disorders, such as Morbus Parkinson, Alzheimer's disease and schizophrenia. Aiming at an improved diagnostic tool for PET a new [¹⁸F]fluorine labelled NMDA receptor ligand was developed that may potentially allow the in vivo visualization of glutama‐tergic neurotransmission. The ¹⁹F‐analogue trans‐5,7‐dichloro‐4‐(3‐{4‐[4‐(2‐fluoroethyl)‐piperazin‐1‐yl]‐phenyl}‐ureido)‐1,2,3,4‐tetrahydro quinoline‐2‐carboxylic acid was synthesised to determine the binding affinity, lipophilicity and biodistribution of the ligand. This substance exhibits a K_i of 12 nM for the glycine binding site using [³H]MDL‐105,519 assays on pig cortical membranes. A logD of 1.3 was determined for this compound according to the OECD guidelines employing the HPLC method. Radiosynthesis of this ligand was achieved by labelling the precursor trans‐5,7‐dichloro‐4‐[3‐(4‐piperazin‐1‐yl‐phenyl)‐ureido]‐1,2,3,4‐tetrahydroquinoline‐2‐carboxylic acid methyl ester with 2‐[¹⁸F]fluoroethyltosylate and subsequent cleaving of the methyl ester moiety, resulting in an overall decay corrected yield of 35% of the final product trans‐5,7‐dichloro‐4‐(3‐{4‐[4‐(2‐[¹⁸F]fluoroethyl)‐piperazin‐1‐yl]‐phenyl}‐ureido)‐1,2,3,4‐tetrahydroquinoline‐2‐carboxylic acid. The biodistribution kinetics of this compound were determined with Sprague Dawley rats ex vivo for brain, liver, kidney, and bone. The ligand showed a maximum brain uptake 30 min.p.i. of about 0.1% ID/g. Copyright © 2003 John Wiley & Sons, Ltd.     

Synthesis and evaluation of [O‐methyl‐11C]4‐[3‐[4‐(2‐methoxyphenyl)‐ piperazin‐1‐yl]propoxy]‐4‐aza‐tricyclo[5.2.1.02,6]dec‐8‐ene‐3,5‐dione as a 5‐HT1A receptor agonist PET ligand

4‐[3‐[4‐(2‐Methoxyphenyl)piperazin‐1‐yl]propoxy]‐4‐aza‐tricyclo[5.2.1.02,6]dec‐8‐ene‐3,5‐dione (4), a potent and selective 5‐HT_1A agonist, was labeled by ¹¹C‐methylation of the corresponding desmethyl analogue 3 with ¹¹C‐methyl triflate. The precursor molecule 3 was synthesized from commercially available endo‐N‐hydroxy‐5‐norbornene‐2,3‐dicarboximide in two steps with an overall yield of 40%. Radiosynthesis of ¹¹C‐4 was achieved in 35 min in 20±5% yield (n=6) at the end of synthesis with a specific activity of 2600±250 Ci/mmol. In vivo positron emission tomography (PET) studies in baboon revealed rapid uptake of the tracer into the brain. However, lack of specific binding indicates that ¹¹C‐4 is not useful as a 5‐HT_1A agonist PET ligand for clinical studies. Copyright © 2008 John Wiley & Sons, Ltd.     

Synthesis,anticonvulsant, and antinociceptive activity of new 3‐(3‐methyl‐2,5‐dioxo‐3‐phenylpyrrolidin‐1‐yl)propanamides and 3‐phenyl‐butanamides

A focused library of new 3‐(3‐methyl‐2,5‐dioxo‐3‐phenylpyrrolidin‐1‐yl)propanamides and their nonimide analogs were synthesized and tested for anticonvulsant activity. These compounds were obtained through the coupling reaction of the starting carboxylic acids with appropriate amines. The initial anticonvulsant screening was performed in mice (intraperitoneal administration) using the maximal electroshock seizure (MES) and the subcutaneous pentylenetetrazole (scPTZ) seizure models. The most promising compound 6 showed more potent protection in the MES and scPTZ tests than valproic acid, which is still recognized as one of the most relevant first‐line anticonvulsants. The structure–activity relationship analysis revealed that the presence of the pyrrolidine‐2,5‐dione ring is important but not indispensable to retain anticonvulsant activity. Additionally, compound 6 showed potent antinociceptive properties in the oxaliplatin‐induced neuropathic pain model in mice. The most plausible mechanism of action for compound 6 may result from its influence on the neuronal sodium channel (Site 2) and the high‐voltage‐activated L‐type calcium channel.     

Identification of NQO1 and ferrochelatase as interaction partners for neuroprotective N‐{[2‐(4‐phenyl‐piperazin‐1‐yl)‐ethyl]‐phenyl}‐arylamides

Affinity chromatography was used to identify potential cellular targets that are responsible for neuroprotective activity of N‐{[2‐(4‐phenyl‐piperazin‐1‐yl)‐ethyl]‐phenyl}‐arylamides. Active and inactive representatives of N‐{[2‐(4‐phenyl‐piperazin‐1‐yl)‐ethyl]‐phenyl}‐arylamides bearing an extended linker were synthesized and immobilized on an agarose‐based matrix. This was followed by the identification of specifically bound proteins isolated out of the whole rat brain extract. Inducible flavoprotein NAD(P)H:quinone oxidoreductase (NQO1) was identified as candidates for cellular targets.     

Synthesis and preliminary in vivo evaluation of 4‐[18F]fluoro‐N‐{2‐[4‐(6‐trifluoromethylpyridin‐2‐yl)piperazin‐1‐yl]ethyl}benzamide,a potential PET radioligand for the 5‐HT1A receptor

4‐Fluoro‐N‐{2‐[4‐(6‐trifluoromethylpyridin‐2‐yl)piperazin‐1‐yl]ethyl}benzamide is a full 5‐HT_1A agonist with high affinity (pK_i=9.3), selectivity and a c log P of 3.045. The corresponding PET radioligand 4‐[¹⁸F]fluoro‐N‐{2‐[4‐(6‐trifluoromethylpyridin‐2‐yl)piperazin‐1‐yl]ethyl}benzamide was synthesized by nucleophilic aromatic substitution on the nitro precursor. The fluorinating agent K[¹⁸F]F/Kryptofix 2.2.2 was both dried (9 min, 700 W) and incorporated in the precursor (5 min, 700 W) using a commercially available microwave oven. In a total synthesis time of 60 min, an overall radiochemical yield of 18% (SD=5, n=7, EOS) was obtained. Radiochemical purity was always higher than 99% and specific activity always higher than 81.4 GBq/µmol (2.2 Ci/µmol). Initial brain uptake in mice was 2.19% ID (5.47% ID/g, 2 min) but decreased rapidly (0.17% ID, 0.45% ID/g (60 min)). During the first 20 min p.i., radioactivity concentration of the brain was significantly higher than that of blood demonstrating good brain entry of the tracer. Copyright © 2004 John Wiley & Sons, Ltd.     

Synthesis and Evaluation of a Series of Piperidine‐2,6‐dione‐piperazine (piperidine) Derivatives as Multireceptor Atypical Antipsychotics

In this paper, we report the discovery and the synthesis of novel, potential antipsychotic piperidine‐2,6‐dione derivatives combining potent dopamine D₂, D₃ and serotonin 5‐HT_1A, 5‐HT_2A, 5‐HT_2C receptor properties. We describe the structure–activity relationships that led us to the promising derivative: 1‐(4‐(4‐(6‐fluorobenzo[d]isoxazol‐3‐yl)piperidin‐1‐yl)butyl)‐4‐(4‐chlorophenyl)‐piperidine‐2,6‐dione 5 . The unique pharmacological features of compound 5 are a high affinity for dopamine D₂, D₃ and serotonin 5‐HT_1A, 5‐HT_2A, 5‐HT_2C receptors, together with a low affinity for the H₁ receptor (to reduce the risk of obesity under chronic treatment). In a behavioral model predictive of positive symptoms, compound 5 inhibited apomorphine‐induced climbing behavior and MK‐801‐induced hyperactivity with no extrapyramidal symptoms liability in mice. In particular, compound 5 was more potent than clozapine.     

Synthesis and preliminary characterization of radioiodinated benzofuran‐3‐yl‐(indol‐3‐yl)maleimide derivatives as potential SPECT imaging probes for the detection of glycogen synthase kinase‐3β (GSK‐3β) in the brain

We report on the synthesis and preliminary characterization of two radioiodinated benzofuran‐3‐yl‐(indol‐3‐yl)maleimides, 3‐(benzofuran‐3‐yl)‐4‐(5‐[¹²⁵I]iodo‐1‐methyl‐1H‐indol‐3‐yl)‐1H‐pyrrole‐2,5‐dione ([¹²⁵I]5), and 3‐(5‐[¹²⁵I]iodo‐1‐methyl‐1H‐indol‐3‐yl)‐4‐(6‐methoxybenzofuran‐3‐yl)‐1H‐pyrrole‐2,5‐dione ([¹²⁵I]6), as the first potential SPECT imaging probes targeting glycogen synthase kinase‐3β (GSK‐3β). In this study, we used ¹²⁵I as a surrogate of ¹²³I because of its ease of use. The radioiodinated ligands were prepared from the corresponding tributyltin precursors through an iododestannylation reaction using hydrogen peroxide as an oxidant with a radiochemical yield of 10–30%. In vitro binding experiments suggested that both compounds show high affinity for GSK‐3β at a level similar to a known GSK‐3β inhibitor. Biodistribution studies with normal mice revealed that the radioiodinated compounds display sufficient uptake into (1.8%ID/g at 10 min postinjection) and clearance from the brain (1.0%ID/g at 60 min postinjection). These preliminary results suggest that the further optimization of radioiodinated benzofuran‐3‐yl‐(indol‐3‐yl)maleimide derivatives may facilitate the development of clinically useful SPECT imaging probes for the in vivo detection of GSK‐3β.     

Synthesis and Anticonvulsant Activity of N‐(2‐Hydroxy‐ethyl)amide Derivatives

A series novel of N‐(2‐hydroxyethyl)amide derivatives was synthesized and screened for their anticonvulsant activities by the maximal electroshock (MES) test, and their neurotoxicity was evaluated by the rotarod test (Tox). The maximal electroshock test showed that N‐(2‐hydroxyethyl)decanamide 1g , N‐(2‐hydroxyethyl)palmitamide 1l , and N‐(2‐hydroxyeth‐yl)stearamide 1n were found to show a better anticonvulsant activity and also had lower toxicity than the marked anti‐epileptic drug valproate. In the anti‐MES potency test, these compounds exhibited median effective doses (ED₅₀) of 22.0, 23.3, 20.5 mg/kg, respectively, and median toxicity doses (TD₅₀) of 599.8, >1000, >1000 mg/kg, respectively, resulting in a protective index (PI) of 27.5, >42.9, >48.8, respectively. This is a much better protective index than that of the marked anti‐epileptic drug valproate (PI = 1.6). To further investigate the effects of the anticonvulsant activity in several different models, compounds 1g , 1l , and 1n were tested having evoked convulsions with chemical substances, including pentylenetetrazloe, isoniazide, 3‐mercaptopropionic acid, bicuculline, thiosemicarbazide, and strychnine.     

Anticonvulsant and Neurotoxicity Evaluation of Some Novel Kojic Acids and Allomaltol Derivatives

A series of new 3‐hydroxy‐6‐hydroxymethyl/methyl‐2‐substituted 4H‐pyran‐4‐ones were synthesized and prepared by the reaction of kojic acid or allomaltol with piperidine derivatives and formaline as potential anticonvulsant compounds. The structure of the synthesized compounds was confirmed using the elemental analysis results and the spectroscopic techniques such as IR, ¹H‐NMR, and ESI‐MS. Anticonvulsant activities were examined by maximal electroshock (MES) and subcutaneous Metrazol (scMet)‐induced seizure tests. Neurotoxicity was determined by the rotorod toxicity test. All these tests were performed in accordance with the procedures of the Antiepileptic Drug Development (ADD) program. According to the activity studies and at all doses, 3‐hydroxy‐2‐[(4‐hydroxy‐4‐phenylpiperidin‐1‐yl)methyl]‐6‐methyl‐4H‐pyran‐4‐one (compound 1 ), 2‐{[4‐(4‐chlorophenyl)‐3,6‐dihydropyridin‐1(2H)‐yl]methyl}‐3‐hydroxy‐6‐methyl‐4H‐pyran‐4‐one (compound 6 ), 2‐[(4‐acetyl‐4‐phenylpiperidin‐1‐yl)methyl]‐3‐hydroxy‐6‐(hydroxymethyl)‐4H‐pyran‐4‐one (compound 11 ), and 2‐{[4‐(4‐chlorophenyl)‐3,6‐dihydropyridin‐1(2H)‐yl] methyl}‐3‐hydroxy‐6‐hydroxymethyl‐4H‐pyran‐4‐one (compound 12 ) were found to have anticonvulsant activity against MES‐induced seizures at 4 h. Also, 2‐{[4‐(4‐bromophenyl)‐4‐hydroxypiperidin‐1‐yl]methyl}‐3‐hydroxy‐6‐(hydroxymethyl)‐4H‐pyran‐4‐one (compound 8 ) was determined to be the most active compound against scMet‐induced seizures at all doses at 0.5 and 4 h. In the rotorod neurotoxicity screening, all compounds showed no toxicity at all doses.     

Synthesis of Novel 2,5‐Disubstituted 1,3,4‐Thiadiazoles for Their Potential Anticonvulsant Activity: Pharmacophoric Model Studies

A series of novel N¹‐[5‐(4‐substituted phenyl)‐1,3,4‐thiadiazol‐2‐yl]‐N⁴‐(4‐substituted benzaldehyde)‐semicarbazone 1 – 12 , N¹‐[5‐(4‐substituted phenyl)‐1,3,4‐thiadiazol‐2‐yl]‐N⁴‐[1‐(4‐substituted phenyl)ethanone]‐semicarbazone 13 ‐ 16 , and N¹‐[5‐(4‐substituted phenyl)‐1,3,4‐thiadiazol‐2‐yl]‐N⁴‐[1‐(4‐substituted phenyl) (phenyl) methanone]‐semicarbazone 17 – 20 were synthesized for their anticonvulsant activity. The chemical structures of the compounds were proved by elemental and spectral (IR, ¹H‐NMR, ¹³C‐NMR, and MS) analysis. The anticonvulsant potential of the compounds was investigated using maximal electroshock seizure (MES) and subcutaneous pentylenetrtrazole (scPTZ) models. Compound 19 was found to possess significant anticonvulsant activity in both the models employed for anticonvulsant evaluation. Compounds 8 , 13 , 15 , and 16 also demonstrated a marked anticonvulsant property. The results of the present study validated that the pharmacophore model with four binding sites is essential for anticonvulsant activity. The efforts were also made to establish structure‐activity relationships among the synthesized compounds.     

Synthesis of pyrimido[1,4]diazepin‐2‐one analogs and their evaluation as anticonvulsant agents

5‐Benzyloxycarbonylaminomethylcarbonyl(N‐methyl)amino‐4‐[2‐chloro(2‐fluoro or 2‐hydrogen)benzoyl]pyrimidines (compound 14 ) in which the chlorophenyl moiety of dipeptidoaminochlorobenzophenones ( 1 ) is replaced by a pyrimido ring, and 1,3‐dihydro‐1‐methyl‐5‐[2‐chloro (2‐fluoro or 2‐hydrogen)phenyl]‐2H‐pyrimido[5,4‐e][1,4]diazepin‐2‐ones ( 16 ) in which the chlorophenyl moiety of 7‐chloro‐5‐aryl‐benzo[1,4]diazepin‐2‐one ( 3 ) is replaced by a pyrimido ring, were synthesized and evaluated as anticonvulsants by using the subcutaneous metrazol‐ (Met) and maximal electroshock– (MES) induced seizure screening tests. Structure‐activity studies showed these two classes of compounds ( 14, 16 ) are generally more potent in the Met screen relative to the MES screen. The effect which the nature of the benzoyl C‐4 ortho‐substituent (Cl, F, H) in compound 14 , or the ortho‐phenyl C‐5 substituent (Cl, F. H) in compounds 16 , has upon anticonvulsant activity was small with the potency profile generally being Cl ≅ F > H. It is proposed that 5‐benzyloxycarbonylaminocarbonyl(N‐methyl)amino‐4‐(2‐fluorobenzoyl)pyrimidine ( 14b ) may act as a prodrug, at least in part, to 1,3‐dihydro‐1‐methyl‐5‐(2‐fluorophenyl)‐2H‐pyrimido[5,4‐e][1,4]diazepin‐2‐one ( 16b ), because 14b does not bind to the benzodiazepine receptor binding site(s), yet it is approximately equipotent to 16b in the Met and MES screens. Compounds 14b and 16b are less active than clonazepam but more active than valproic acid in the Met screen, and less active than phenytoin but more active than clonazepam and valproic acid in the MES screen. Drug Dev. Res. 46:155–162, 1999. © 1999 Wiley‐Liss, Inc.     

13C‐ and 14C‐labelling of N‐[1‐(4‐chlorophenyl)‐1H‐pyrrol‐2‐yl‐methyleneamino] guanidinium acetate

N‐[1‐(4‐chlorophenyl)‐1H‐pyrrol‐2‐yl‐¹³C₄‐methyleneamino]guanidinium acetate has been synthesized by a four‐step procedure. This involved reduction of the Weinreb amide N,N′‐dimethyl‐N,N′‐dimethyloxybutane‐1,4‐diamide‐1,2,3,4‐¹³C₄ by Dibal‐H to give the corresponding unstable dialdehyde which is reacted in situ with 4‐chloroaniline to form 1‐(4‐chlorophenyl)‐1H‐pyrrole‐¹³C₄. This pyrrole analogue underwent a Vilsmeyer acylation with POCl₃/DMF followed by final reaction with aminoguanidine bicarbonate to produce the desired labelled compound with 99% atom ¹³C. By using DMF [α‐¹⁴C] a radio‐labelled analogue was synthesized with a specific activity of 60 mCi/mmol. Copyright © 2005 John Wiley & Sons, Ltd.     

Synthesis,In Vitro Protoporphyrinogen Oxidase Inhibition,and Herbicidal Activity of N‐(Benzothiazol‐5‐yl)hexahydro‐1H‐isoindole‐1,3‐diones and N‐(Benzothiazol‐5‐yl)hexahydro‐1H‐isoindol‐1‐ones

Protoporphyrinogen oxidase ( EC 1.3.3.4 ) is one of the most significant targets for a large family of herbicides. As part of our continuous efforts to search for novel protoporphyrinogen oxidase‐inhibiting herbicides, N‐(benzothiazol‐5‐yl)tetrahydroisoindole‐1,3‐dione was selected as a lead compound for structural optimization, leading to the syntheses of a series of novel N‐(benzothiazol‐5‐yl)hexahydro‐1H‐isoindole‐1,3‐diones ( 1a – o ) and N‐(benzothiazol‐5‐yl)hexahydro‐1H‐isoindol‐1‐ones ( 2a – i ). These newly prepared compounds were characterized by elemental analyses, ¹H NMR, and ESI‐MS, and the structures of 1h and 2h were further confirmed by X‐ray diffraction analyses. The bioassays indicated that some compounds displayed comparable or higher protoporphyrinogen oxidase inhibition activities in comparison with the commercial control. Very promising, compound 2a , ethyl 2‐((6‐fluoro‐5‐(4,5,6,7‐tetrahydro‐1‐oxo‐1H‐isoindol‐2(3H)‐yl)benzo[d]thiazol‐2‐yl)‐sulfanyl)acetate, was recognized as the most potent candidate with K_i value of 0.0091 μm . Further greenhouse screening results demonstrated that some compounds exhibited good herbicidal activity against Chenopodium album at the dosage of 150 g/ha.     

Synthesis and Anticonvulsant Activity of 5‐Phenyl‐[1,2,4]‐triazolo[4,3‐a]quinolines

A series of novel 5‐phenyl‐[1,2,4]‐triazolo[4,3‐a]quinoline derivatives was synthesized by the cyclization of 2‐chloro‐4‐phenyl‐1,2‐dihydronaphthalene with formohydrazide. The starting material 2‐chloro‐4‐phenyl‐1,2‐dihydronaphthalene was synthesized from ethyl‐3‐oxo‐3‐phenylpropanoate and substituted aniline. Their anticonvulsant activities were evaluated by the maximal electroshock (MES) test and their neurotoxicity was evaluated by the rotarod neurotoxicity test (Tox). The maximal electroshock test showed that 7‐hexyloxy‐5‐phenyl‐[1,2,4]‐triazolo[4,3‐a]quinoline 4f was found to be the most potent compound with an ED₅₀ value of 6.5 mg/kg and a protective index (PI = ED₅₀ / TD₅₀) value of 35.1, which was much higher than the PI of the reference drug phenytoin.     

Synthesis of C‐14 and C‐13, H‐2‐labeled IKK inhibitor: [14C] and [13C4,D3]‐N‐(6‐chloro‐7‐methoxy‐9H‐pyrido[3,4‐b]indol‐8‐yl)‐2‐methyl‐3‐pyridinecarboxamide

[¹⁴C]‐N‐(6‐Chloro‐7‐methoxy‐9H‐pyrido [3,4‐b]indol‐8‐yl)‐2‐methyl‐3‐pyridinecarboxamide (5B ), an IKK inhibitor, was synthesized from [¹⁴C]‐barium carbonate in two steps in an overall radiochemical yield of 41%. The intermediate, [carboxyl‐¹⁴C]‐2‐methylnicotinic acid, was prepared by the lithiation and carbonation of 3‐bromo‐2‐methylpyridine. [¹³C₄,D₃]‐N‐(6‐chloro‐7‐methoxy‐9H‐pyrido [3,4‐b]indol‐8‐yl)‐2‐methyl‐3‐pyridinecarboxamide (5C ) was synthesized from [1,2,3,4‐¹³C₄]‐ethyl acetoacetate and [D₄]‐methanol in six steps in an overall yield of 2%. [¹³C₄]‐2‐methylnicotic acid, was prepared by condensation of [¹³C₄]‐ethyl 3‐aminocrotonate and acrolein, followed by hydrolysis with lithium hydroxide. Copyright © 2006 John Wiley & Sons, Ltd.     

Synthesis and Positive Inotropic Evaluation of (E)‐2‐(4‐Cinnamylpiperazin‐1‐yl)‐N‐(1‐substituted‐4,5‐dihydro‐[1,2,4]triazolo[4,3‐a]quinolin‐7‐yl)acetamides

A series of (E)‐2‐(4‐cinnamylpiperazin‐1‐yl)‐N‐(1‐substituted‐4,5‐dihydro‐[1,2,4]triazolo[4,3‐a]quinolin‐7‐yl)acetamides were synthesized and evaluated for their positive inotropic activity by measuring the left atrium stroke volume on isolated rabbit heart preparations. This class of compounds presented favorable in vitro activity compared with the standard drug, milrinone, among which N‐(1‐(3‐chlorophenyl)‐4,5‐dihydro‐[1,2,4]triazolo[4,3‐a]quinolin‐7‐yl)‐2‐(4‐cinnamylpiperazin‐1‐yl)acetamide 5e was found to be the most potent with 16.58 ± 0.11% increased stroke volume (milrinone: 2.46 ± 0.07%) at a concentration of 3 × 10^?5 M. The chronotropic effects of the compounds having inotropic effects were also evaluated.     

Synthesis of the tritiated isotopomers of enzastaurin and its N‐des‐pyridylmethyl metabolite for use in ADME studies

Enzastaurin (3‐(1‐methyl‐1H‐indol‐3‐yl)‐4‐[1‐[1‐(2‐pyridinylmethyl)‐4‐piperidinyl]‐1H‐indol‐3‐yl]‐1H‐pyrrole‐2,5‐dione, 1), an agent with potential utility in the treatment of solid tumors, is currently in phase II clinical trials. Enzastaurin undergoes metabolism in vitro and in vivo to several products of oxidative metabolism, the major one of which is 3‐(1‐methyl‐1H‐indol‐3‐yl)‐4‐(1‐piperidin‐4‐yl‐1H‐indol‐3‐yl)‐1H‐pyrrole‐2,5‐dione (2). In a model study, the attempted synthesis 1‐[²H] by reaction of 1 with deuterium gas in the presence of Ir[(COD)(Cy₃P)pyr]PF₆ (Crabtree's catalyst) was unsuccessful. Alternatively, it was decided to prepare tritiated 2 as both a final product and the starting material for the tritiation of 1. We have reported herein a route that was developed for use in the preparation of tritium‐labeled 2‐[³H] and its successful conversion to 1‐[³H]. Copyright © 2008 John Wiley & Sons, Ltd.