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Nonsteriodal anti-inflammatory drugs (NSAIDs) are efficacious for the treatment of pain associated with inflammatory disease. Clinical experience with marketed selective cyclooxygenase-2 (COX-2) inhibitors (celecoxib, rofecoxib, and valdecoxib) has confirmed the utility of these agents in the treatment of inflammatory pain with an improved gastrointestinal safety profile relative to NSAID comparators. These COX-2 inhibitors belong to the same structural class. Each contains a core heterocyclic ring with two appropriately substituted phenyl rings appended to adjacent atoms. Here, we report the identification of vicinally disubstituted pyridazinones as potent and selective COX-2 inhibitors. The lead compound in the series, ABT-963 [2-(3,4-difluoro-phenyl)-4-(3-hydroxy-3-methyl-butoxy)-5-(4-methanesulfonyl-phenyl)-2H-pyridazin-3-one], has excellent selectivity (ratio of 276, COX-2/COX-1) in human whole blood, improved aqueous solubility compared with celecoxib and rofecoxib, high oral anti-inflammatory potency in vivo, and gastric safety in the animal studies. After oral administration, ABT-963 reduced prostaglandin E2 production in the rat carrageenan air pouch model (ED50 of 0.4 mg/kg) and reduced the edema in the carrageenan induced paw edema model with an ED30 of 1.9 mg/kg. ABT-963 dose dependently reduced nociception in the carrageenan hyperalgesia model (ED50 of 3.1 mg/kg). After 14 days of dosing in the adjuvant arthritis model, ABT-963 had an ED(50) of 1.0 mg/kg in reducing the swelling of the hind paws. Magnetic resonance imaging examination of the diseased paws in the adjuvant model showed that ABT-963 significantly reduced bone loss and soft tissue destruction. ABT-963 is a highly selective COX-2 inhibitor that may have utility in the treatment of the pain and inflammation associated with arthritis.

A series of new and potent motilides, 8( R ),9( R )-9-deoxo-4''-deoxy-6,9-epoxyerythromycin A was designed, synthesized and evaluated for gastrointestinal prokinetic activity. These compounds were acid-stable with many demonstrating in vitro potency markedly superior to erythromycin.

A series of new, highly potent and orally active “motilactides”, 9-deoxo-4″-deoxy-6,9-epoxyerythromycin lactams was designed, synthesized, and evaluated for their gastrointestinal motor stimulating activity. These compounds were acid stable and showed good oral efficacy.

The oral absorption profile of a family of azole-based ET(A)-selective antagonists has been improved through a rational series of structural modifications which were suggested by analysis of the physicochemical parameter delta log P. Comparison of urea 2 with a series of well-absorbed compounds using delta log P analysis suggested that 2 has an excess capacity for forming hydrogen bonds with solvent. A series of urea modifications were explored as a means of reducing H-bonding capacity while maintaining affinity for the ET(A)-receptor. The correlation between delta log P values and absorption in an intraduodenal (id) bioavailability model was good; this strategy uncovered replacements for each of the urea NH groups which simultaneously improve both potency and drug absorption. A combination of these optimized modifications produces carbamate 16h, a highly-selective ET(A) antagonist with a potency/bioavailability profile consistent with an oral route of administration.

Purpose. A variety of methods exist which determine the rate and extent of intestinal absorption. The method described here employs an internal absorption reference probe and portal blood sampling in unanesthetized rat. Methods. Theophylline and tritiated water were selected as absorption reference probes since they are quantitatively absorbed in conscious rat. The fraction of an intestinal dose which reaches portal blood was determined from the resulting portal-systemic blood concentration gradients of the drug relative to the absorption probe. The absorption probes provide a means to calculate the drug mass reaching portal blood without the need of measuring the portal blood flow rate. The technique was evaluated with verapamil and a well-absorbed 5-lipoxygenase inhibitor, A-79035. Results. The fraction of an intrajejunal dose of A-79035 reaching the portal vein (FG) was 0.86 using theophylline as the absorption probe. Verapamil, which is susceptible to extensive hepatic first-pass elimination, was completely absorbed (FG = 0.98) within 1 hour, but was only 21.4% bioavailable. Absorption rate constants, estimated from initial appearance rates in portal blood, were used to monitor factors that affect drug absorption. For example, with a dose solution containing 30% PEG-400, the absorption rate constants of theophylline and A-79035 were significantly reduced. Anesthesia reduced the absorption rate constant for theophylline in rats by 40% compared to conscious animals. Conclusions. The technique detailed here allows reliable, direct measurement of intestinal absorption which may assist in characterizing oral dosing for novel therapeutic agents.

A series of new, highly potent and orally active “motilactides”, 9-deoxo-4″-deoxy-6,9-epoxyerythromycin lactams was designed, synthesized, and evaluated for their gastrointestinal motor stimulating activity. These compounds were acid stable and showed good oral efficacy.

A series of new and potent motilides, 8( R ),9( R )-9-deoxo-4''-deoxy-6,9-epoxyerythromycin A was designed, synthesized and evaluated for gastrointestinal prokinetic activity. These compounds were acid-stable with many demonstrating in vitro potency markedly superior to erythromycin.

The effects of an antibacterially effective IV dose of erythromycin on gastrointestinal motor activity were investigated in eight normal healthy human volunteers in the fasted state and the fed state. Motor activity was recorded by a multilumen manometric tube. Data were analyzed visually and by a computer method. Blood samples were obtained for erythromycin and motilin assays. In the gastric antrum, erythromycin significantly increased the total duration, amplitude, and area under contractions from 0 to 60 minutes and frequency of contractions from 0 to 30 minutes from the start of its infusion in the fasted state. A similar response in the fed state occurred mostly from 0 to 30 minutes after the start of erythromycin infusion. By contrast, erythromycin inhibited the frequency and decreased the duration of small intestinal contractions in the fed state but had no effect in the fasted state. The gastric motor response was related to the plasma concentration of erythromycin, but not to plasma motilin. Erythromycin significantly shortened the duration of migrating motor complex disruption by a meal. Erythromycin also induced symptoms of upper abdominal pain, bloating, and nausea. Abdominal pain was related to strong antral contractions in both fasted and fed states; bloating occurred only in the fed state. Nausea occurred in both fasted and fed states, but it was not related to any specific pattern of motor activity. It is concluded that the strong antral contractions induced by erythromycin may accelerate the rate of gastric emptying, but they may also be responsible for causing the sensations of upper abdominal pain and bloating. The motor response to erythromycin is less during the fed than during the fasted state. The strong antral contractions induced by erythromycin are not mediated by the release of motilin.

The significance of the paracellular pathway in both the absorption and secretion of therapeutic compounds by the intestine has received little attention to date. A growing body of literature firmly documents the importance of this aqueous pathway as a major contributor to the transepithelial flow of water and solutes in a wide spectrum of epithelia, including both the small and large intestine. The relative contributions of the paracellular and cellular pathways to intestinal absorption are discussed with respect to both diffusion and convective flow of water. Emphasis is placed on the interaction of convective flow with net intestinal absorption. The discussion of convective flow is extended to the intriguing observations that the permeability of the paracellular tight junction may be under active regulation by glucose and amino acids through cytoskeletal connections to the perijunctional actomyosin complex. The review cites studies from other epithelia, suggesting the universal character of the importance of the transport between, as well as through, cells and attempts to establish physiological criteria for assessing the contribution of paracellular transport to the intestinal absorption of therapeutic compounds, including peptides and peptidomimetics.

Inhibition of the prosurvival members of the Bcl-2 family of proteins represents an attractive strategy for the treatment of cancer. We have previously reported the activity of ABT-737, a potent inhibitor of Bcl-2, Bcl-XL, and Bcl-w, which exhibits monotherapy efficacy in xenograft models of small-cell lung cancer and lymphoma and potentiates the activity of numerous cytotoxic agents. Here we describe the biological activity of A-385358, a small molecule with relative selectivity for binding to Bcl-XL versus Bcl-2 (Ki's of 0.80 and 67 nmol/L for Bcl-XL and Bcl-2, respectively). This compound efficiently enters cells and co-localizes with the mitochondrial membrane. Although A-385358 shows relatively modest single-agent cytotoxic activity against most tumor cell lines, it has an EC50 of

In our quest toward the discovery of highly potent and acid-stable motilides, novel 4"-deoxy derivatives of 9-deoxo-6, 9-epoxyerythromycin were designed, synthesized, and evaluated for their gastrointestinal prokinetic activities. These compounds, in their 9R configuration, were more potent than their 6,9-enol ether homologues in inducing well-coordinated smooth muscle contractions in an in vitro rabbit duodenal assay: e.g., (9R), (8S)-9-deoxo-4"-deoxy-3'-N-desmethyl-3'-N-ethyl-6, 9-epoxyerythromycin A (10) and (9R), (8S)-9-deoxo-4"-deoxy-3'-N-desmethyl-3'-N-ethanol-6, 9-epoxyerythromycin A (15) had a pED50 of 8.54 and 8.11 compared to a pED50 of 7.22 for compound 2 (ABT-229). Reduction of the 6,9-enol ether, which was aimed at improving the acid stability, afforded the most stable motilides to date with t1/2 of 5.5 h for 10 and 15. Compounds 10 and 15 bind specifically to rabbit antral smooth muscle motilin receptors with pIC50 values of 8.52 and 8.70.

As an approach to discovering highly potent motilides with oral activity, novel 4''-deoxy derivatives of 8,9-anhydroerythromycin 6,9-hemiacetal were designed, synthesized, and evaluated for their gastrointestinal prokinetic activities. These compounds were orders of magnitude more potent than their 4''-hydroxy analogs in inducing smooth muscle contractions in an in vitro rabbit duodenal assay. Removal of the 12-hydroxy group, which was aimed at improving oral bioavailability, also afforded further potentiation in in vitro activity, leading to the identification of 8,9-anhydro-4''-deoxy-3'-N-desmethyl-3'-N-ethylerythromycin B 6,9-hemiacetal (ABT-229) as a potential prokinetic drug. ABT-229 was >300 000 times more potent than erythromycin in vitro and had 39% oral bioavailability in dog compared to its 4'',12-dihydroxy congener (EM-523), which was only 400 times more potent than erythromycin and had relatively low (1.4%) oral bioavailability

The relation between active transepithelial Na transport across rabbit ileum and 42K exchange from the serosal solution across the basolateral membranes has been explored. Although 42K influx across the basolateral membranes is inhibited by ouabain and by complete depletion of cell Na, it is not affected when transepithelial Na transport is abolished (i.e. in the presence of an Na-free mucosal solution) or stimulated (i.e. when glucose or alanine is added to the mucosal solution). We are unable to detect any relation between the ouabain-sensitive Na-K exchange mechanism responsible for the maintenance of intracellular Na and K concentrations and active transcellular Na transport. In addition, the maintenance of cell volume (water content) does not appear to be dependent upon transepithelial Na transport or the ouabain-sensitive Na-K exchange pump. Although the results of these studies cannot be considered conclusive, they raise serious questions regarding the role of the Na-K exchange pump, located at the basolateral membranes, in active transepithelial Na transport and the maintenance of cell volume.

Escherichia coli may produce a heat-labile enterotoxin (LT) or two heat-stable enterotoxins (STa, STb). STb consistently causes secretion in vivo in 5-hr weaned-pig intestinal loops (P less than .0001). In Ussing chambers in vitro, crude culture filtrates of STb initiate a prompt increase in short circuit current (SCC; P less than or equal to .0001) and potential difference (P less than or equal to .0001) when compared with nontoxigenic culture filtrates. In bidirectional in vitro studies of ion flux (22Na and 36Cl), STb did not alter 22Na or 36Cl unidirectional or net fluxes. The calculated residual ion flux increased significantly (P less than .03), however, in tissues treated with STb and fully accounted for the STb-induced increase in SCC. Measurement of the electrolyte content of ligated intestinal segments in vivo further suggested that STb stimulated bicarbonate secretion. Relative to controls, significant accumulation of Na and Cl also occurred intraluminally in vivo. These data indicate that STb is a unique enterotoxin that causes net secretion in pig jejunum in vivo. In vitro and in vivo studies show that STb stimulates active secretion of nonchloride anion. We postulate that STb causes active bicarbonate secretion in weaned-piglet jejunum.

A synthetic method has been developed for the iterative preparation of unlabelled and 3H-polyethylene glycol (PEG) oligomers. The strategy involved alkylating the sodium anion of mono-tritylated ethylene glycol oligomers (Ph3C[OCH2CH2]nOH, n=1−28) with O-tosyl-O-allyl-triethylene glycol or O-tosyl-O-allyl-pentaethylene glycol. Subsequent ozonolysis of the terminal olefin followed by reduction with NaBH4 or NaB[3H]4 provided the next higher mono-tritylated ethylene glycol oligomer which could be deprotected to the final glycol oligomer (H[OCH2CH2]nOH, n=4−34) or carried on in the iterative process. The method provides discrete PEG oligomers of high specific activity (20.6–48.6 mCi/mmoL) in 96–98% radiochemical purity.

The electrophysiologic properties of rabbit colonic epithelial cells were investigated employing microelectrode techniques. Under open-circuit conditions, the transepithelial electrical potential difference (PD) averaged 20 mV, serosa positive, and the intracellular electrical potential (psimc) averaged -32 mV, cell interior negative with respect to the mucosal solution; under short-circuit conditions, psimc averaged -46 mV. The addition of amiloride to the mucosal solution abolishes the transepithelial PD and active Na transport, and psimc is hyperpolarized to an average value of -53 mV. These results indicate that Na entry into the mucosal cell is a conductive process which, normally, depolarized psimc. The data obtained were interpreted using a double-membrane equivalent electrical circuit model of the "active Na transport pathway" involving two voltage-independent electromotive forces (emf's) and two voltage-independent resistances arrayed in series. Our observations are consistent with the notions that: (a) The emf's and resistances across the mucosal and baso-lateral membranes are determined predominantly by the emf (64 mV) and resistance of the Na entry process and the emf (53 mV) and resistance of the process responsible for active Na extrusion across the baso-lateral membranes: that is, the electrophysiological properties of the cell appear to be determined solely by the properties and processes responsible for transcellular active Na transport. The emf of the Na entry process is consistent with the notion that the Na activity in the intracellular transport pool is approximately one-tenth that in the mucosal solution or about 14 mM. (b) In the presence of amiloride, the transcellular conductance is essentially abolished and the total tissue conductance is the result of ionic diffusion through paracellular pathways. (c) The negative intracellular potential (with respect to the mucosal solution) is due primarily to the presence of a low resistance paracellular "shunt" pathway which permits electrical coupling between the emf at the baso-lateral membrane and the potential difference across the mucosal membrane; in the absence of this shunt, the "well-type" electrical potential profile characteristic of rabbit colonic cells would be 'converted' into a "staircase-type" profile similar to those reported for frog skin and toad urinary bladder by some investigators.

An equivalent electrical circuit model for “Na-transporting” epithelia is described which provides a consistent framework for the interpretation of transepithelial and intracellular bioelectric parameters under steady-state conditions. The predictions of this model are qualitatively consistent with electrophysiologic data on amphibian skin and urinary bladder. In addition, these predictions suggest experimental approaches by which the resistances and driving forces of the “active Na transport pathway” across the mucosal and baso-lateral membranes can be defined quantitatively in terms of equivalent electrical analogues.

Synthese d'α-aminoacides N-proteges (le N etant l'azote de benzyl-3 benzyloxycarbonyl-3 oxo-2 pyrrolidine ou -piperidine) a partir de benzyl-4 Z-3 oxazolidones-5; couplage C- ou N-terminal de ces composes

Basic hydrolysis of the oxazolidinone (I) followed by N-protection produces the allylic alcohol (IIb) which is converted to the diol (IV) by hydroboration.

Azidomethyl-substituted 1,2- and 1,3-diols were prepared from Boc-cyclohexylalanal and evaluated as transition state analogue renin inhibitors, leading to the development of a small (MW less than 600), nanomolar inhibitor. Remarkable aqueous solubility enhancement followed the incorporation of an N-terminal urea functionality. Evaluation of selected compounds both in vivo and in vitro demonstrated that while transport across the intestine occurred upon id administration, extensive liver extraction resulted in low systemic levels.

1. 1. Unidirectional influxes of Na+, Cl−, alanine, 3-O-methylglucose and mannitol across brush border of ileum and of iron across brush border of duodenum were determined in normal and cycloheximide-pretreated rabbits. 2. 2. Unidirectional influx of all solutes, with the exception of mannitol, was significantly reduced by cycloheximide administration. Mannitol influx was unaffected. 3. 3. The inhibitory effect of cycloheximide on alanine influx was attributable, almost exclusively, to a 70% reduction in maximal alanine influx. 4. 4. These results are consistent with the notion that cycloheximide inhibits the synthesis of protein(s) directly or indirectly involved in carrier-mediated transport across the brush border of mature, villus absorptive cells.