1 This manuscript presents the preclinical profile of lumiracoxib, a novel cyclooxygenase-2 (COX-2) selective inhibitor. 2 Lumiracoxib inhibited purified COX-1 and COX-2 with K i values of 3 and 0.06 mM, respectively. In cellular assays, lumiracoxib had an IC 50 of 0.14 mM in COX-2-expressing dermal fibroblasts, but caused no inhibition of COX-1 at concentrations up to 30 mM (HEK 293 cells transfected with human COX-1). 3 In a human whole blood assay, IC 50 values for lumiracoxib were 0.13 mM for COX-2 and 67 mM for COX-1 (COX-1/COX-2 selectivity ratio 515). 4 Lumiracoxib was rapidly absorbed following oral administration in rats with peak plasma levels being reached between 0.5 and 1 h. 5 Ex vivo, lumiracoxib inhibited COX-1-derived thromboxane B 2 (TxB 2 ) generation with an ID 50 of 33 mg kg À1, whereas COX-2-derived production of prostaglandin E 2 (PGE 2 ) in the lipopolysaccharidestimulated rat air pouch was inhibited with an ID 50 value of 0.24 mg kg À1 . 6 Efficacy of lumiracoxib in rat models of hyperalgesia, oedema, pyresis and arthritis was dosedependent and similar to diclofenac. However, consistent with its low COX-1 inhibitory activity, lumiracoxib at a dose of 100 mg kg À1 orally caused no ulcers and was significantly less ulcerogenic than diclofenac (Po0.05). 7 Lumiracoxib is a highly selective COX-2 inhibitor with anti-inflammatory, analgesic and antipyretic activities comparable with diclofenac, the reference NSAID, but with much improved gastrointestinal safety. British Journal of Pharmacology (2005) 144, 538-550. doi:10.1038/sj.bjp.0706078 Published online 17 January 2005 Keywords: Lumiracoxib; COX-2; cyclooxygenase-2 selective inhibitor; preclinical Abbreviations: AUC, area-under-curve of the concentration vs time curve; C max , maximum drug plasma concentration; CFA, complete Freund's adjuvant; 51 Cr-EDTA, chromium-51 labelled EDTA; COX, cyclooxygenase; D 30 , dose at which 30% inhibition was achieved; DMSO, dimethyl sulphoxide; F 0 , fraction of uninhibited enzyme at equilibrium; GI, gastrointestinal; HEK, human embryonic kidney; IL-1, interleukin-1; K i , inhibitor constant; k on , second-order rate constant representing speed at which an inhibitor binds to an enzyme; I, inhibitor concentration; LC/MS/MS, liquid chromatography/mass spectrometry/mass spectrometry; LPS, lipopolysaccharide; NSAID, nonsteroidal anti-inflammatory drug; O 2 , oxygen; PGE 2 , prostaglandin E 2 ; s, arachidonic acid concentration; t 1/2 , half-life; t opt , time to optimal velocity; TxB 2 , thromboxane B 2 ; V 0 , velocity in the absence of inhibitor; V obs , observed velocity in the presence of inhibitor; V opt , highest observed O 2 consumption velocity; V max , Michaelis-Menten constant for the maximal calculated velocity

In a survey of 504 college students examining predictors of violence in heterosexual relationships, over half of both men and women had committed at least one physically violent act, and men more often than women reported having been the victims of such acts. Most respondents who reported some experience with violence had both committed and received it, were involved in relatively few different types of violence, and first experienced violence when a relationship had moved beyond the casual dating stage. Modest associations between physical violence and sexual aggression were uncovered. In a series of discriminant analyses, men who abused their partners were not readily distinguished from men who did not, but tended to be young, low in family income, traditional in attitudes toward women, abused as children, currently living with a woman, and from Appalachian areas. Women who abused were more readily discriminated and scored low in social desirability, were abused as children, and were from non-Appalachian areas. Men who were abused were likely to be living with a woman and tended to be low in family income; similarly, cohabitation was related among women to being a target of violence, as were having been abused as a child and scoring low in social desirability. Findings are related to those of other studies of dating abuse, as well as to the family violence and aggression literatures.

The synthesis of three series of dicarboxylic acid dipeptide neutral endopeptidase 24.11 (NEP) inhibitors is described. In particular, the amino butyramide 21a exhibited potent NEP inhibitory activity (IC50 = 5.0 nM) in vitro and in vivo. Blood levels of 21a were determined using an ex vivo method by measuring plasma inhibitory activity in conscious rats, mongrel dogs, and cynomolgus monkeys. Free drug concentrations were 10-1500 times greater than the inhibitory constant for NEP over the course of a 6 h experiment. A good correlation of free drug concentrations was obtained when comparing values determined by the ex vivo analysis to those calculated from direct HPLC measurements. Plasma atrial natriuretic factor (exogenous) levels were elevated in rats and dogs after oral administration of 19a. Urinary volume and urinary sodium excretion were also potentiated in anesthetized dogs treated with 21a.

Inhibitors of the zinc protease neutral endopeptidase (NEP, EC 3.4.24.11) offer significant therapeutic interest as antihypertensives due to their ability to potentiate the biological action of the circulating natriuretic hormone ANF (atrial natriuretic factor). N-Phosphonomethyl dipeptides bearing a central (4-phenyl)phenylalanine residue have been designed to exert potent and selective NEP inhibition. In particular, (S)-3-[N-[2- [(phosphonomethyl)amino]-3-(4-biphenylyl)propionyl]amino]propionic acid (10a) (CGS 24592) displayed high inhibitory potency in vitro (IC50 = 1.9 +/- 0.1 nM) and a long plasma half-life in rats but lacked oral bioavailability. This drawback was overcome by using esterase-sensitive (acyloxy)alkyl phosphonates. More remarkable, several diaryl phosphonate derivatives of 10a also performed as effective prodrugs. Specifically, the structurally simple diphenyl phosphonate 18 (CGS 25462) induced potent inhibition of NEP ex vivo for at least 8 h after oral administration to rats (30 mg/kg). Its antihypertensive effect was demonstrated in DOCA-salt rats. At 30 mg/kg orally, 18 caused a significant reduction in mean arterial pressure measuring -35 +/- 7 mmHg at 5-h postdosing. The alpha-aminomethyl phosphonate 18 represents a new generation of selective NEP inhibitors that combine high potency, long duration of action, and oral bioavailability. Therefore, it holds promise as a novel therapeutic agent for the treatment of human hypertension and congestive heart failure.

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A potent macrocyclic inhibitor of neutral endopeptidase (NEP) 24.11 was designed using a computer model of the active site of thermolysin. This 10-membered ring lactam represents a general mimic for any hydrophobic dipeptide in which the two amino acid side chains bind to an enzyme in a contiguous orientation. The parent 10-membered ring lactam was synthesized and exhibited excellent potency as an NEP 24.11 inhibitor (IC50 = 3 nM). In order to improve oral bioavailability, various functionality was attached to the macrocycle. These modifications lead to CGS 25155, an orally active NEP 24.11 inhibitor that slows down the degradation of the cardiac hormone atrial natriuretic factor, producing a lowering of blood pressure in the DOCA-salt rat model of hypertension.

We have monitored the plasma concentrations of products of the transsulfuration pathway in 11 undernourished noncirrhotic patients, and in 10 cachectic cirrhotic subjects, before and during nasoenteral nutrition with Vivonex (Norwich-Eaton Pharmaceuticals, Norwich, NY) or total parenteral nutrition (TPN) with FreAmine III (American McGaw, Irvine, CA). In the cirrhotic cases eating a mixed diet, levels of taurine, cysteine, plasma glutathione, and free choline were subnormal. During nasoenteral hyperalimentation, methionine was elevated while cysteine, glutathione, and free choline levels remained depressed. During TPN, levels of taurine, cysteine, protein-bound cysteine, glutathione, free choline, and phosphatidyl choline were depressed and methionine was elevated. In the noncirrhotic cases eating a mixed diet, only the free choline concentration was low. During nasoenteral hyperalimentation, the plasma levels of both free choline and total carnitine were depressed. During TPN, plasma levels of cystine, protein-bound cysteine, total carnitine, free choline, and phosphatidyl choline were subnormal. These data suggest that biosynthesis of several products of the transsulfuration pathway may be inadequate in both cirrhotic and noncirrhotic patients during TPN with FreAmine III.

Dual inhibitors of the two zinc metallopeptidases, neutral endopeptidase (NEP, EC 3.4.24.11) and angiotensin-I converting enzyme, have been the focus of much clinical interest for the treatment of hypertension and congestive heart failure. A novel series of alpha-thio dipeptides containing central cyclic non-natural amino acids were prepared and were evaluated for their ability to inhibit these two metallopeptidases in vitro and in vivo. Most of these compounds were found to be excellent dual inhibitors of ACE and NEP in vitro and several were also found to inhibit angiotensin-I (AI) pressor response in conscious rats when given by intravenous administration. Compound 6n, one of our most potent dual inhibitors in vitro, was found to be more efficacious than captopril in the AI pressor experiment when administered orally to conscious rats. This compound was also found to inhibit plasma NEP activity following oral administration to conscious rats and was more efficacious than acetorphan. The structure-activity relationships and biological activity of these dual inhibitors will be discussed.