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Ro 63-1908, 1-[2-(4-hydroxy-phenoxy)-ethyl]-4-(4-methyl-benzyl)-piperidin-4-ol, is a novel subtype-selective N-methyl-D-aspartate (NMDA) antagonist that has been characterized in vitro and in vivo. Ro 63-1908 inhibited [ 3 H]dizocilpine ( 3 H-MK-801) binding in a biphasic manner with IC 50 values of 0.002 and 97 M for the high-and low-affinity sites, respectively. Ro 63-1908 selectively blocked recombinant receptors expressed in Xenopus oocytes containing NR1C ϩ NR2B subunits with an IC 50 of 0.003 M and those containing NR1C ϩ NR2A subunits with an IC 50 of Ͼ100 M, thus demonstrating greater than 20,000-fold selectivity for the recombinant receptors expressing NR1C ϩ NR2B. Ro 63-1908 blocked these NMDA NR2B-subtype receptors in an activity-dependent manner. Ro 63-1908 was neuroprotective against glutamate-induced toxicity and against oxygen/glucose deprivation-induced toxicity in vitro with IC 50 values of 0.68 and 0.06 M, respectively. Thus, the in vitro pharmacological characterization demonstrated that Ro 63-1908 was a potent and highly selective antagonist of the NR2B subtype of NMDA receptors. Ro 63-1908 was active against sound-induced seizures (ED 50 ϭ 4.5 mg/kg i.p. when administered 30 min beforehand) in DBA/2 mice. The dose required to give a full anticonvulsant effect did not produce a deficit in the Rotarod test. NMDA-induced seizures were also inhibited by Ro 63-1908 with an ED 50 of 2.31 mg/kg i.v. when administered 15 min before testing. Ro 63-1908 gave a dose-related neuroprotective effect against cortical damage in a model of permanent focal ischemia. Maximum protection of 39% was seen at a plasma concentration of 450 ng/ml. There were, however, no adverse cardiovascular or CNS side-effects seen at this dosing level.Native NMDA receptors are composed of an NR1 subunit (can occur as eight different splice variants), which combines with NR2A-D subunits to form heteromeric receptors (for reviews see McBain and Mayer, 1994;Kemp and Kew, 1998). NMDA receptors are thought to be tetramers that are composed of two NR1 and two NR2 subunits (Laube et al., 1998), which is compatible with earlier electrophysiological evidence demonstrating that NMDA receptor activation requires occupation of two independent glycine binding sites and two independent glutamate sites (Benveniste and Mayer, 1991;Clements and Westbrook, 1991). The glutamate and glycine binding sites are believed to be located on the NR2 and NR1 subunits, respectively (Wafford et al., 1995;Hirai et al., 1996;Laube et al., 1997;Anson et al., 1998). However, the proposed tetrameric stoichiometry of NMDA receptor remains controversial because evidence also exists for a pentameric structure (for review see Kemp and Kew, 1998).In the adult rodent and human brain the NR1 subunit is widely distributed throughout the brain, whereas the NR2 subunits are expressed in a distinct spatio-temporal manner (Watanabe et al., 1993;Monyer et al., 1994;Rigby et al., 1996;Wenzel et al., 1997). The predominant NR2 subunits in the forebrain are NR2A and NR2...

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500J. Org. Chem. during t h e esterification step. Both 4e and 4t proved t o be optically pure.T h e synthesis presented here is very convenient, owing t o t h e simplicity of t h e different steps, avoiding in particular use of protection and deprotection operations, which are often a real problem with fluoro amino acids.20p21 T h e enzymatic conversion leads directly t o the desired optically pure products in very high yield. Experimental SectionGeneral Methods. Melting points were measured with a Kofler hot-stage apparatus and are uncorrected. 'H NMR and lgF NMR spectra were recorded at 90 MHz on a JEOL FX9OQ spectrometer. Optical rotations were determined with a Perkin-Elmer Model 141 polarimeter with 10 cm path length cells.Chemicals. Ethyl fluoroacetate was purchased from Fluka, boron tribromide was purchased from Merck, and ethyl bromoacetate and diethyl oxalate were purchased from Prolabo. Glutamate dehydrogenase (from beef liver) and NAD+ (100%) were obtained from Boehringer; yeast alcohol dehydrogenase was from Sigma. Dowex resins were purchased from Fluka. Diethyl Fluorooxaloacetate Sodium Salt (1). Compound 1 was obtained in 82% yield from ethyl fluoroacetate and diethyl oxalate according to Bergmann et al.,8 mp 175-177 "C dec. The protonated form of 1 was recovered by acidification to pH 1 with sulfuric acid and extraction with diethyl ether: 'H NMR (CDC13, TMS) 6 1.37 (6 H, m, 2 OCH2CH3), 4.37 (4 H, m, 2 OCHzCH3), Hz, CHF).Diethyl 2-0xo-3-carbethoxy-3-fluoroglutarate ( 2 ) . Ethyl bromoacetate (25.5 mL, 0.23 mol) was added dropwise within 1 h to a solution of 1 (35 g, 0.153 mol) in dry dimethylformamide (125 mL) cooled at 0 "C. After the mixture was stirred at room temperature overnight, the sodium bromide was filtered, and the solvent was eliminated under vacuum, the product was taken up in ethyl acetate, washed with water, dried, and evaporated to dryness (47 g). Chromatography on silica gel with ethyl acetate-hexane (1:l) as solvent of 15 g of this crude product yielded 2 (7.5 g, 52%): 'H NMR (CDCl,, TMS) 6 1.30 (9 H, m, 3 OCHzCH3), 2.35-3.88 (2 H, m, CH2), 4.25 (6 H, m, 3 OCH2CH3); JAx + JBx = 49.6 Hz), -108.9 (X part of an ABX spectrum, JG + JBx = 47.3 Hz); mass spectrum (positive chemical ionization), m/z 310 ((M + NHJ+), 290 ((M + NH4 -HF)+ and 2' (5.5 g, 48%); 'H NMR (CDC13, TMS) 6 1.35 (9 H, m, 3 OCH2CH3), 4.35 (6 H, m, 3 OCHzCH3), 4.63 + 4.67 (2 H, CHz); 19F NMR (CDC13, CF,C6H5) 6 -88.0; mass spectrum (positive chemical ionization), m / z 310 ((M + NH4)+).

Background: The prognostic significance of coexisting deep vein thrombosis (DVT) in acute pulmonary embolism (PE) is controversial. This study aimed to provide routine patient care data on the impact of this association on PE severity and 3-month outcomes in a population presenting with symptomatic venous thromboembolism (VTE) from the REMOTEV registry. Methods and Results: REMOTEV is a prospective, non-interventional study of patients with acute symptomatic VTE, treated with direct oral anticoagulants (DOACs) or standard anticoagulation (vitamin K antagonists (VKA) or parenteral heparin/fondaparinux alone) for at least 3 months. From 1 November 2013 to 28 February 2018, among 1241 consecutive patients included, 1192 had a follow-up of at least 3 months and, among them, 1037 had PE with (727) or without DVT (310). The median age was 69 (55–80, 25th–75th percentiles). Patients with PE-associated DVT had more severe forms of PE (p < 0.0001) and, when DVT was present, proximal location was significantly correlated to PE severity (p < 0.01). However, no difference in all-cause mortality rate (hazard ratio (HR) 1.36 (CI 95% 0.69–2.92)), nor in the composite criterion of all-cause mortality and recurrence rate (HR 1.56 (CI 95% 0.83–3.10)) was noted at 3 months of follow-up. Conclusion: In REMOTEV, coexisting DVT was associated with a higher severity of PE, with no impact on short-term prognosis.