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The discovery of a novel 2-aminotetrahydropyridine class of BACE1 inhibitors is described. Their pK a and lipophilicity were modulated by a pending sulfonyl group, while good permeability and brain penetration were achieved via intramolecular hydrogen bonding. BACE1 selectivity over BACE2 was achieved in the S3 pocket by a novel bicyclic ring system. An optimization addressing reactive metabolite formation, cardiovascular safety, and CNS toxicity is described, leading to the clinical candidate JNJ-67569762 ( 12 ), which gave robust dose-dependent BACE1-mediated amyloid β lowering without showing BACE2-dependent hair depigmentation in preclinical models. We show that 12 has a favorable projected human dose and PK and hence presented us with an opportunity to test a highly selective BACE1 inhibitor in humans. However, 12 was found to have a QT effect upon repeat dosing in dogs and its development was halted in favor of other selective leads, which will be reported in the future.

Kainate receptor antagonists have potential as therapeutic agents in a number of neuropathologies. Synthetic modification of the convulsant marine toxin neodysiherbaine A (NDH) previously yielded molecules with a diverse set of pharmacological actions on kainate receptors. Here we characterize three new synthetic analogs of NDH that contain substituents at the C10 position in the pyran ring of the marine toxin. The analogs exhibited high-affinity binding to the GluK1 (GluR5) subunit and lower affinity binding to GluK2 (GluR6) and GluK3 (GluR7) subunits in radioligand displacement assays with recombinant kainate and AMPA receptors. As well, the natural toxin NDH exhibited approximately 100-fold selectivity for GluK2 over GluK3 subunits, which was attributable to the C8 hydroxyl group in NDH. We used molecular dynamic simulations to determine the specific interactions between NDH and residues within the ligand-binding domains of these two kainate receptor subunits that contribute to the divergent apparent affinities for the compound. These data demonstrate that interactions with the GluK1 subunit are preserved in analogs with substitutions at C10 in NDH and further reveal the determinants of selectivity and pharmacological activity of molecules acting on kainate receptor subunits, which could aid in design of additional compounds that target these receptors., (Copyright 2009 Elsevier Ltd. All rights reserved.)

The physicochemical properties of aqueous solutions of novel anionic heterogemini surfactants (POH-n-ODAm) have been studied on the basis of static/dynamic surface tension, fluorescence, dynamic light scattering (DLS) and cryogenic transmission electron microscope (cryo-TEM) data. The surfactants are synthesized from oleic acid: the hydrocarbon chain (n=6, 8 and 10) is covalently bound to the terminal carbonyl group and a phosphate headgroup is introduced to the cis double bond of an oleic acid derivative. The static surface tension and fluorescence measurements demonstrate that the critical aggregation concentration (cac) is decreased significantly with increasing hydrocarbon chain length, resulting from the increased hydrophobicity and the increased degree of dissymmetry of the surfactants. As is generally seen for gemini surfactants, the measured cac is much lower than that of the monomeric phosphate-type surfactant reported previously. At concentrations well above the cac, the heterogemini surfactants spontaneously form vesicular assemblies in bulk solution, which is confirmed with DLS and cryo-TEM measurements.

A variety of polymerized assemblies of cationic gemini surfactants has been demonstrated as a function of the electrolyte concentration in aqueous solution. The gemini surfactant consists of two cationic monomeric surfactants linked with an ethylene spacer at the level of the quaternary ammonium groups. Polymerizable methacryloxy groups are covalently attached to the terminal of the hydrocarbon chains. In the lower electrolyte concentration region, radical polymerization results in the formation of spherical aggregates [Langmuir 22 (2006) 8293]. However, in the higher electrolyte concentration region, elongated tubular hollow assemblies are observed with transmission electron microscopy, as a result of polymerization of vesicular hollow assemblies spontaneously formed in the aqueous solution. These experimental results suggest that it is possible to prepare different shapes of polymerized assemblies by changing the electrolyte concentration.

A novel polymerizable anionic gemini surfactant has been synthesized and the physicochemical properties in aqueous solution have been studied with a combination of various analytical techniques. The surfactant (PA12-2-12) contains two anionic monomeric parts linked with an ethylene spacer and polymerizable methacryloxy groups covalently bound to the terminal of the hydrocarbon chains. The static surface tension data suggest that, when compared with a conventional (non-polymerizable) anionic gemini surfactant (A12-2-12), (i) the interfacial adsorption of PA12-2-12 occurs more effectively from low surfactant concentrations, whereas (ii) a weak interaction of the polymerizable terminal groups with water molecules (and/or the steric hindrance of the polymerizable groups) plays a significant role in the subsequent molecular packing at the air/aqueous solution interface. The latter effect (as well as the electrostatic repulsion between the anionic headgroups) results in a relatively less packed monolayer film, overcoming the strong intermolecular attractive interaction that is frequently seen for gemini surfactant systems. In the region of low added electrolyte concentrations, PA12-2-12 spontaneously forms spherical micelles in aqueous solution, which is confirmed with the Corrin-Harkins analysis (critical micelle concentration (cmc) vs. total counter-ion concentration) and cryogenic transmission electron microscopy (cryo-TEM). The spherical micelles have been polymerized under UV light irradiation in the absence of added electrolytes. Cryo-TEM measurements confirm that no significant change in the original micelle morphology occurs during the polymerization. This offers a possibility that the polymerizable anionic gemini surfactant should be useful as nano-structural organic templates and/or interfacial stabilizers in aqueous solution.

A rapid and efficient total synthesis of dysiherbaine (1), a potent and subtype-selective agonist for ionotropic glutamate receptors, has been accomplished. A key intermediate 15 was synthesized by two approaches. The first synthetic route utilized compound 9, an advanced intermediate in our previous total synthesis of neodysiherbaine A, as the starting point, and the cis-oriented amino alcohol functionality on the tetrahydropyran ring was installed by using an intramolecular S(N)2 cyclization of N-Boc-protected amino alcohol 20. An alternative and even more efficient synthetic approach to 15 featured stereoselective introduction of an amino group at C8 by iodoaminocyclization prior to constructing the bicyclic ether skeleton. The amino acid appendage was efficiently constructed by a catalytic asymmetric hydrogenation of enamide ester 36. The synthetic route developed here provided access to several dysiherbaine analogues, including 9-epi-dysiherbaine (38), 9-deoxydysiherbaine (39), 9-methoxydysiherbaine (40), and N-ethyldysiherbaine (41). The preliminary structure-activity relationship studies revealed that the presence and stereochemistry of the C9 hydroxy group in dysiherbaine is important for high-affinity and selective binding to glutamate subtype receptors.

To enable studies to elucidate the detailed biological function of dysiherbaine and neodysiherbaine A, potent and subunit-selective agonists for ionotropic glutamate receptors, the derivative with a hydroxymethyl substituent at the C10 position has been developed. Preliminary biological evaluation of the analogue showed that a C10 hydroxymethyl substituent produced significant alterations in binding affinities for the ionotropic glutamate receptor subtypes.

A polymerizable cationic gemini surfactant, [CH(2)=C(CH(3))COO(CH(2))(11)N(+)CH(3))(2)CH(2)](2).2Br(-), 1 has been synthesized and its basic interfacial properties were investigated (in water and in the presence of 0.05 M NaBr). For comparison, the properties of monomeric surfactant corresponding to 1, CH(2)=C(CH(3))COO(CH(2))(11)N(+)(CH(3))(3).Br(-), 2, were also investigated. Parameters studied include cmc (critical micelle concentration), C(20) (required to reduce the surface tension of the solvent by 20 mN/m), gamma(cmc) (the surface tension at the cmc), Gamma(cmc) (the maximum surface excess concentration at the air/water interface), A(min) (the minimum area per surfactant molecule at the air/water interface), and cmc/C(20) ratio (a measure of the tendency to form micelles relative to adsorb at the air/water interface). For the polymerizable gemini surfactant, 1, the methacryloxy groups at the terminal of each hydrophobic group in a molecule have no contact with the air/water interface in the monolayer, whereas for the corresponding monomeric surfactant, 2, the methacryloxy group contacts at the interface forming a looped configuration like a bolaamphiphile. Polymerized micelles of the gemini surfactant are fairly small monodisperse and spherical particles with a mean diameter of 3 nm.

Dysiherbaine (1) and its congener neodysiherbaine A (2) are naturally occurring excitatory amino acids with selective and potent agonistic activity for ionotropic glutamate receptors. We describe herein the total synthesis of 2 and its structural analogues 3-8. Advanced key intermediate 16 was employed as a branching point to assemble a series of these analogues 3-8 with respect to the C8 and C9 functionalities, which would not have been accessible through manipulations of the natural product itself. The synthesis of key intermediate 16 features (i) stereocontrolled C-glycosylation to set the C6 stereocenter, (ii) concise synthesis of the bicyclic ether skeleton through chemo- and stereoselective dihydroxylation of the exo-olefin and stereoselective epoxidation of the endo-olefin, followed by epoxide ring opening/5-exo ring closure, and (iii) catalytic asymmetric hydrogenation of enamide ester to construct the amino acid appendage. A preliminary biological evaluation of analogues for their in vivo toxicity against mice and binding affinity for glutamate receptors showed that both the type and stereochemistry of the C8 and C9 functional groups affected the subtype selectivity of dysiherbaine analogues for members of the kainic acid receptor family.

A study of the equilibrium surface properties (in water and in the presence of 0.01 M NaCl) of a novel series of anionic gemini surfactants, alkanediyl-alpha,omega-bis(sodium N-acyl-beta-alaninates), is described. Parameters studied include cmc (critical micelle concentration), C20 (required to reduce the surface tension of the solvent by 20 mN/m), gamma(cmc) (the surface tension at the cmc), Gamma(max) (the maximum surface excess concentration at the air/aqueous solution interface), Amin (the minimum area per surfactant molecule at the air/water interface), and the cmc/C20 ratio (a measure of the tendency to form micelles relative to adsorb at the air/water interface). The geminis with a spacer consisting of two methylene groups show premicellar self-aggregation, both in water and in 0.01 M NaCl, when the N-acyl group contains more than 12 carbon atoms; geminis with a spacer consisting of four methylene groups show no premicellar aggregation even when the N-acyl group contains 16 carbon atoms. For the acyl chain lengths where premicellar aggregation does not occur, the values of the cmc of the geminis with a two-methylene spacer are lower than those for the corresponding analogous geminis with a four-methylene spacer. The premicellar formation for the geminis with a two-methylene spacer is due to the short-chain linkage. The geminis show little or no break in their specific conductance-surfactant molar concentration plots and an increase in the pH at the cmc. This is attributed to protonation of the carboxylate group and strong Na+ release during micellization.

The interaction in two mixtures of an anionic gemini surfactant having N ,N -dialkylamide and carboxylate groups in a molecule, (CH2)2[N(COC11H23)CH(CO2H)CH2(CO2H)]2. 2NaOH (GA), and conventional anionic surfactants have been investigated in 0.1 M NaCl at pH 5.0. The two mixtures are GA/sodium dodecylsulfate (SDS) and GA/sodium N -dodecanoylglutamate (AGS) at a molar fraction of GA, alphaGA = 0.25 . Mixtures of both GA/SDS and GA/AGS exhibit synergism in surface tension reduction effectiveness. The GA/SDS mixture also exhibits synergism in surface tension reduction efficiency and mixed micelle formation, whereas the GA/AGS mixture does not. The interaction in mixed adsorption film formation is stronger than that in mixed micelle formation for the two mixtures. The interaction in the formation of the mixed adsorption film and the mixed micelle for the GA/SDS mixture is stronger in both formations than that for the GA/AGS mixture. The stronger interaction for the GA/SDS mixture may be caused by the combination of the smaller minimum area per molecule at the air/water interface (Amin) of the head groups in the GA molecule and the larger Amin in the SDS molecule.

Lichen planus (LP), common mucocutaneous disorder, involves not only oral mucosa and skin but genitalia membrane. LP is frequently seen in patients with HCV infection. This study evaluated patients with HCV-associated oral lichen planus (OLP) for vulvar and vaginal LP involvement, and the possible intraspousal transmission of HCV. We examined a total of 24 female Japanese patients with OLP for genitalia LP: 14 OLP-HCV positive and 10 OLP-HCV negative. All subjects were evaluated for genital LP by a gynecologist. All 24 subjects and 10 of the husbands were tested for anti-HCV and serum HCV RNA. Vulvar LP was observed in 10 (41.7%) of 24 patients with OLP. Vulvar LP in 14 (OLP-HCV positive) and 10 patients (OLP-HCV negative) were observed in 42.9 and 40%, respectively. There were no significant differences (age, sites of OLP, blood transfusion, HCV infection, and degree of liver diseases) between the vulvar LP and non-vulvar LP patients. Two spouses of 10 married couples were shown to be infected with HCV. In one couple with HCV infection, the wife and husband had also erosive OLP, the wife had erosive vulvar LP. In conclusion, the majority of OLP patients suffered from genitalia LP in Japan. Clinicians should follow the OLP patients with sufficient attention to the presence of extraoral manifestations. These data may suggest the occurrence of intraspousal transmission of HCV through erosive vulvar LP.

The chelating abilities of phosphobetaines [2-(N,N,N-trialkylammonio)alkyl hydrogen phosphates; 1] for divalent cations (e.g., calcium ion, zinc ion, copper ion, and cadmium ion) were investigated to elucidate the correlation between the antimicrobial activity and the chelating ability. The maximal chelating ability was obtained with the compound having a dimethylene bridge as an intercharge distance between the phosphate and quaternary ammonium group; in contrast, the minimum was obtained with the compound with a trimethylene bridge. These behaviors paralleled the antimicrobial activity of these compounds. The antimicrobial activities, in terms of log (1/MIC) (minimum inhibitory concentration, mumol/L) of homologues of 1 against Candida albicans and Propionibacterium acnes were found to correlate linearly with the chelating ability for the calcium ion. This linear relationship is discussed with respect to the structure of the phosphobetaine moiety in the molecule of 1.

A series of phosphobetaines [2-(N,N,N-trialkylammonio)alkyl hydrogen phosphates], having different alkyl chains and a methylene bridge separating the phosphate and ammonio group, was investigated in order to provide a new antimicrobial agent. Maximal activity was obtained with the compound having a hexadecyl group as a long-chained alkyl group, two methyl groups as short-chained alkyl groups, and a dimethylene bridge as an intercharge distance. In contrast, sodium 2-(N-hexadecyl-N-methylamino)ethyl hydrogen phosphate, 2-(N-hexadecyl-N,N-dimethylammonio)-1-hydroxyethyl iodide, and N-octadecyl-N,N-dimethylammonio acetate showed decreased activity, indicating that the presence of a phosphobetaine moiety was essential for activity. Thus, 2-(N-hexadecyl-N,N-dimethylammonio)ethyl hydrogen phosphate has been found to possess strong antimicrobial activity and a broad antimicrobial spectrum against nine kinds of bacteria (e.g., fungi, yeast, gram-negative and gram-positive bacteria), which are comparable with those of chlorhexidine digluconate.

A case is reported of a 71-year-old female with cervical myelopathy caused by calcified nodules in the cervical ligamentum flavum and improved by en bloc laminectomy. The calcified nodules were formed by the deposition of two crystals, hydroxyapatite (HAP) and calcium pyrophosphate dihydrate (CPPD). Light microscopy, scanning electron microscopy, energy dispersive X-ray microanalysis and X-ray diffraction study disclosed that the larger nodule located on the right was composed mainly of HAP in the central part and CPPD in the circumference. On the other hand, the smaller nodule located on the left was composed mainly of CPPD crystal. These findings support the hypothesis that calcification of the ligamentum flavum and CPPD crystal deposition disease in the cervical region are the same entity and the both are merely different aspects of the same entity at different chronological stages.

The computerized tomography (CT) findings were analyzed in five cases of subdural tension pneumocephalus following surgery for chronic subdural hematoma. They were compared with CT scans in 14 cases of asymptomatic subdural pneumocephalus. In this study, two new CT findings were identified that suggest increased tension of the subdural air. Subdural air separates and compresses the frontal lobes, creating a widened interhemispheric space between the tips of the frontal lobes that mimics the silhouette of Mt. Fuji. The presence of air between the frontal tips associated with massive air inclusion over the frontal lobes presumably indicates increased tension of the subdural air. The "Mt. Fuji sign" was seen in four of the five cases with subdural tension pneumocephalus. The other finding was the presence of multiple small air bubbles scattered through several cisterns ("air bubble sign"). It is postulated that these air bubbles enter the subarachnoid space through a tear in the arachnoid membrane caused by increased tension of air in the subdural space. This finding was seen in four cases with subdural tension pneumocephalus. These two CT findings are helpful in making a diagnosis of subdural tension pneumocephalus following surgery for chronic subdural hematoma.

Subdural tension pneumocephalus (TP) following surgery for chronic subdural hematoma was analyzed in 5 cases from clinical standpoints of view, especially from CT findings. The cases were compared with 14 cases of subdural asymptomatic pneumocephalus (AP). The TP tends to complicate elderly patients who showed a poor re-expansion of the brain after irrigation of bilateral chronic subdural hematoma. In such patients, it is difficult to make an exact diagnosis of TP because of residual mass effect of the evacuated hematoma. Significance of mass effect caused by subdural air has been discussed in the literature only little. In this study, we found two new CT findings suggesting increased tension of subdural air. First, the subdural tensive air separates and compresses the frontal lobes. The compressed frontal lobes with widened interhemispheric space between the frontal poles mimic the silhouette of Mt. Fuji. We called this CT finding "Mt. Fuji" sign. The presence of air between the frontal poles associated with massive air over the frontal lobes presumably indicates an increased tension of the subdural air. "Mt. Fuji" sign was seen in 4 cases out of 5 TP cases. Another sign is the presence of multiple small air bubbles in the subarachnoid space, especially in the cisterns. We proposed that these air bubbles were trapped in the subarachnoid space through a tear of the arachnoid membrane which is caused by increased tension of air in the subdural space. This finding was present in 4 cases with TP. We emphasize that these two CT signs are helpful to make an accurate diagnosis of TP following surgery for chronic subdural hematoma.

The technique of percutaneous transluminal angioplasty (PTA) that was introduced initially by Dotter and Judkins in 1964 has been applied to various arterial stenoses and some occlusive lesions and has advanced dramatically with the development of the Grüntzig catheter in the treatment of peripheral vascular disease. However, the application to occlusive disease in brachiocephalic arteries is still considered to be disputable and has been made only in selective cases, especially in Japan. We report here a case with stenosis of the left subclavian artery successfully treated with PTA. The patient was 66 year-old man, who had been suffering from transient attacks of vertigo, ataxia, visual disturbance and the left arm claudication. Blood pressure was 150/92 mmHg in the right arm and 110 mmHg in systole in the left arm. Diagnostic arteriography identified the right carotid artery occlusion at its origin and significant stenosis in the proximal left subclavian artery. PTA under fluoroscopic control was performed by passing dilating catheter in antegrade fashion by Seldinger method through the left femoral artery. Anatomic correction was achieved without hemorrhagic or embolic complications. Systolic blood pressure gradient measured at the brachial artery level disappeared immediately after PTA and symptomatic relief was obtained completely. One month later, wide patency of the left subclavian artery and sufficient antegrade flow in the vertebral artery were confirmed angiographically. During follow-up period of 4 months, the patient was asymptomatic. We reviewed the literature reporting PTA for occlusive disease in brachiocephalic arteries and discussed its problems and possibilities, especially for the treatment of subclavian artery stenosis.

Three cases of communicating hydrocephalus after subarachnoid hemorrhage are reported that underwent ventriculoperitoneal shunt and suffered from delayed intracerebral hemorrhage along the ventricular catheter. Ventricular catheters were inserted into the posterior horn with minimal brain damage by our method, in case 1 and 2, 3 times try of ventriculostomy, in case 3, replacement along the same route on the shunt revision. Blood pressure control after the operation was good and bleeding tendency was not observed. Vascular anomaly was not found in preoperative angiography in any case. In case 1, 60 year-old man, intracerebral hemorrhage occurred on the 7th-9th postoperative day as the result of respiratory acidosis and generalized convulsion which needed assisted ventilation for two days. In case 2, 54 year-old man and case 3, 59 year-old woman, headache and hemiparesis suddenly developed immediately after micturition 4 days after operation. Postoperative CT scan revealed that cranioplasty, performed at the same time as shunt operation, caused mass effect on the shunted side of the brain in case 2. In case 3, VP shunt system revised did not seem to function so well. These conditions might predispose the shunted brain to bleed, in addition to the increased intracranial pressure or blood pressure probably produced by Valsalva effect at micturition. These cases indicate that the small surgical wound in the brain induced by shunt procedure could cause progressive degenerative vascular change and bring about delayed intracranial hemorrhage under some predisposing factors.

A case of a 20-year-old woman who survived respiratory quadriplegic state and then became to be a candidate for rehabilitation is reported. The patient was injured in an automobile accident and immediately developed cardiopulmonary arrest, quadriplegia and maximum mydriasis bilaterally. She was transferred to our hospital six minutes after the accident. Immediate and appropriate resuscitation could bring restoration of only cardiac contractions without spontaneous breathing and minimal movement of extremities. Skull and cervical spine x-rays showed anterior atlanto-axial dislocation with a fracture of dens in addition to a linear skull fracture in the right temporoparietal region. Traction by Glisson's method was applied initially three and a half hours after the accident under controlled ventilation with a respirator. Five days after the onset, her consciousness became clear and she displayed an onionskin pattern of anesthesia with sensory preservation around her mouth and nose. Subsequently quadriplegia gradually improved from the lower extremities to the upper, however the proximal muscles of the upper extremities remained to be involved for a long period of time. The authors speculated that such a peculiar pattern of paralysis was due to the injury of the rostral part of the pyramidal decussation and to the acute central cord injury at the C2 level of the spinal cord. Halo-vest immobilization technique was applied and active postural drainage was done as the treatment of the respiratory quadriplegia. She could wean off the respirator four months after the onset and became independent in her active daily living six months after the accident.(ABSTRACT TRUNCATED AT 250 WORDS)

A case of spontaneous cervical epidural hematoma associated with long-term cervical spondylosis is presented. A 69-year-old man was admitted with a 3-day history of sudden onset of severe neck pain radiating to both upper extremities followed by impossibility in standing. Neurological examination on admission revealed paralysis below C7, total anesthesia below the T4 level and urinary incontinence. Initially, he was diagnosed as cervical cord injury caused by a violent fall. Subsequently, skeletal traction with tongs of the Crutchfield design was carried out. Nevertheless, he developed spinal shock 6 days after admission. A metrizamide myelogram followed by CT scanning 5 days after admission demonstrated an extradural isodensity mass displacing dura forward. The mass lesion was confirmed as spontaneous epidural hematoma by laminectomy from C4 to C7. Sudden onset of neck pain with radiation into both upper extremities should be differentiated cervical epidural hematoma from other cervical spinal lesions. Metrizamide CT is helpful to diagnose cervical epidural hematoma.