Design and selection of DMP 850 and DMP 851: the next generation of cyclic urea HIV protease inhibitors.

BACKGROUND: Recent clinical trials have demonstrated that HIV protease inhibitors are useful in the treatment of AIDS. It is necessary, however, to use HIV protease inhibitors in combination with other antiviral agents to inhibit the development of resistance. The daunting ability of the virus to rapidly generate resistant mutants suggests that there is an ongoing need for new HIV protease inhibitors with superior pharmacokinetic and efficacy profiles. In our attempts to design and select improved cyclic urea HIV protease inhibitors, we have simultaneously optimized potency, resistance profile, protein binding and oral bioavailability. RESULTS: We have discovered that nonsymmetrical cyclic ureas containing a 3-aminoindazole P2 group are potent inhibitors of HIV protease with excellent oral bioavailability. Furthermore, the 3-aminoindazole group forms four hydrogen bonds with the enzyme and imparts a good resistance profile. The nonsymmetrical 3-aminoindazoles DMP 850 and DMP 851 were selected as our next generation of cyclic urea HIV protease inhibitors because they achieve 8 h trough blood levels in dog, with a 10 mg/kg dose, at or above the protein-binding-adjusted IC90 value for the worst single mutant--that containing the Ile84-->Val mutation. CONCLUSIONS: In selecting our next generation of cyclic urea HIV protease inhibitors, we established a rigorous set of criteria designed to maximize chances for a sustained antiviral effect in HIV-infected individuals. As DMP 850 and DMP 851 provide plasma levels of free drug that are sufficient to inhibit wild-type HIV and several mutant forms of HIV, they could show improved ability to decrease viral load for clinically significant time periods. The ultimate success of DMP 850 and DMP 851 in clinical trials might depend on achieving or exceeding the oral bioavailability seen in dog.

Design and synthesis of isoxazoline derivatives as factor Xa inhibitors. 2.

Intravascular clot formation is an important factor in a number of cardiovascular diseases. Therefore, the prevention of blood coagulation has become a major target for new therapeutic agents. One attractive approach is the inhibition of factor Xa (FXa), the enzyme directly responsible for thrombin activation. Herein we report a series of isoxazoline derivatives which are potent FXa inhibitors. Optimization of the side chain at the quaternary position of the isoxazoline ring led to SK549 which showed subnanomolar FXa potency (K(i) 0.52 nM). SK549 shows good selectivity for FXa compared to thrombin and trypsin, potent antithrombotic effect in the rabbit arterio-venous thrombosis model, and improved pharmacokinetics relative to other compounds evaluated from this series.

Nonsymmetric P2/P2' cyclic urea HIV protease inhibitors. Structure-activity relationship, bioavailability, and resistance profile of monoindazole-substituted P2 analogues.

Using the structural information gathered from the X-ray structures of various cyclic urea/HIVPR complexes, we designed and synthesized many nonsymmetrical P2/P2'-substituted cyclic urea analogues. Our efforts concentrated on using an indazole as one of the P2 substituents since this group imparted enzyme (Ki) potency as well as translation into excellent antiviral (IC90) potency. The second P2 substituent was used to adjust the physical and chemical properties in order to maximize oral bioavailability. Using this approach several very potent (IC90 11 nM) and orally bioavailable (F% 93-100%) compounds were discovered (21, 22). However, the resistance profiles of these compounds were inadequate, especially against the double (I84V/V82F) and ritonavir-selected mutant viruses. Further modification of the second P2 substituent in order to increase H-bonding interactions with the backbone atoms of residues Asp 29, Asp 30, and Gly 48 led to analogues with much better resistance profiles. However, these larger analogues were incompatible with the apparent molecular weight requirements for good oral bioavailability of the cyclic urea class of HIVPR inhibitors (MW < 610).

Discovery of 1-[3-(aminomethyl)phenyl]-N-3-fluoro-2'-(methylsulfonyl)-[1,1'-biphenyl]-4-yl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (DPC423), a highly potent, selective, and orally bioavailable inhibitor of blood coagulation factor Xa.

Factor Xa (fXa) plays a critical role in the coagulation cascade, serving as the point of convergence of the intrinsic and extrinsic pathways. Together with nonenzymatic cofactor Va and Ca2+ on the phospholipid surface of platelets or endothelial cells, factor Xa forms the prothrombinase complex, which is responsible for the proteolysis of prothrombin to catalytically active thrombin. Thrombin, in turn, catalyzes the cleavage of fibrinogen to fibrin, thus initiating a process that ultimately leads to clot formation. Recently, we reported on a series of isoxazoline and isoxazole monobasic noncovalent inhibitors of factor Xa which show good potency in animal models of thrombosis. In this paper, we wish to report on the optimization of the heterocyclic core, which ultimately led to the discovery of a novel pyrazole SN429 (2b; fXa K(i) = 13 pM). We also report on our efforts to improve the oral bioavailability and pharmacokinetic profile of this series while maintaining subnanomolar potency and in vitro selectivity. This was achieved by replacing the highly basic benzamidine P1 with a less basic benzylamine moiety. Further optimization of the pyrazole core substitution and the biphenyl P4 culminated in the discovery of DPC423 (17h), a highly potent, selective, and orally active factor Xa inhibitor which was chosen for clinical development.

Methods for the analysis of enantiomers of racemic drugs application to pharmacological and pharmacokinetic studies.

Although the existence and differences in biological behavior of optical isomers have long been appreciated, there has been an apparent reluctance to address these differences in pharmacology and the pharmaceutical sciences. At least part of this reluctance arises from the belief that the separation of enantiomers requires highly specialized analytical equipment and expertise. The purpose of this review is to present general principles that allow the separation of stereoisomers and demonstrate that these procedures can be accomplished using available and convenient chromatography techniques.

Possible role of the intestinal P-450 enzyme system in a cyclosporine-clarithromycin interaction.

Clarithromycin is a macrolide antibiotic similar in structure to erythromycin, but suggested to have fewer drug interactions. Although a pharmacokinetic interaction between clarithromycin and cyclosporine was recently reported, its magnitude and mechanism have not been explored. A 43-year-old renal transplant recipient receiving cyclosporine was treated with clarithromycin because of pneumonia. A cyclosporine pharmacokinetic study was performed 8 days after the initiation of the clarithromycin and 14 days after stopping the drug. Clarithromycin coadministration caused an approximately 2-fold increase in the area under the whole blood concentration versus time curve of cyclosporine. The oral clearance of cyclosporine was halved by clarithromycin, but the terminal elimination rate constant decreased only 15% and mean residence time 20%. These observations suggest that clarithromycin inhibits not only the hepatic metabolism but also the intestinal metabolism of cyclosporine. Caution is advised when administering the two drugs concurrently, and additional studies are necessary to elucidate the mechanism of this interaction.

Dose-dependency of flurbiprofen enantiomer pharmacokinetics in the rat.

Flurbiprofen is a chiral 2-arylpropionate used clinically as a racemate. Previously a significant pharmacokinetic interaction between the enantiomers of flurbiprofen has been reported in both rats and humans. The possible mechanism for this interaction was believed to involve competitive protein binding between the enantiomers. In addition, the saturable binding of flurbiprofen enantiomers in vitro in human plasma has been demonstrated. In this study different doses of racemic flurbiprofen were administered to rats to create differing extents of competition for protein binding sites between the enantiomers. There was a statistically significant dose-dependent increase in total body clearance and volume of distribution of both the R and S enantiomers. However, there was no change in either the S/R AUC ratio or the elimination rate constants for (R)- or (S)-flurbiprofen with increasing dose. These results are consistent with the hypothesis that the increasing amount of (R)- and (S)-flurbiprofen in the body causes displacement of flurbiprofen enantiomers from their protein binding sites, resulting in their increased total body clearance and volume of distribution. Further, the data suggest that previously reported extents of R to S enantiomeric inversion for other 2-arylpropionates may not be accurate if the enantiomers exhibit nonlinear kinetics or there is a significant kinetic interaction between the enantiomers.

Effect of the enantiomers of flurbiprofen, ibuprofen, and ketoprofen on intestinal permeability.

Numerous studies have demonstrated that the administration of nonsteroidal anti-inflammatory drugs (NSAIDs) increases small intestinal permeability, and this has been suggested to be a prerequisite to enteropathy. It is believed that the inhibitory effect of chiral NSAIDs on the synthesis of prostaglandins and hence their efficacy and toxicity are mainly due to the S enantiomer. Using the urinary excretion of [51Cr]-EDTA, we have investigated the effects of three nonsteroidal anti-inflammatory drugs (flurbiprofen, ibuprofen, and ketoprofen) on small intestinal permeability in rats. Single doses of each NSAID were administered orally as either the racemate or the R or S enantiomer, the enantiomer dose being half that of the racemate. Each treatment caused a significant increase in intestinal permeability above that seen in untreated animals. The R enantiomers of all three NSAIDs increased small intestinal permeability significantly above base line, which was expected for (R)-ketoprofen and (R)-ibuprofen due to substantial chiral R to S inversion. The intestinal permeability for (R)-flurbiprofen, although minimal and likely due to 10% inversion, may also suggest prostaglandin-independent involvement. Furthermore, (S)-flurbiprofen, used at one-half the dose of the racemate, increased permeability to a similar magnitude as the racemate. This observation was similar to that previously reported for etodolac. A stereochemically pure enantiomer does not necessarily offer a safer alternative than its racemic form.

The male aesthetic patient.

Just like their female counterparts, men are increasingly turning to facial plastic surgery, but male patients bring to the surgeon an array of unexplored motivations and expectations along with unresolved emotional conflicts. These feelings of ambivalence, emotional instability, and sometimes even hostility toward the surgeon make the male aesthetic patient more of a psychological risk than the female aesthetic patient. This article focuses on how the surgeon can recognize and control the male patient's emotional disturbances and, consequently, better serve his patient and protect himself.

Surgical addiction. A complication of modern surgery?

Today the concept of surgery has changed dramatically. No longer is surgery limited to emergency or lifesaving procedures. We now have surgery by choice, which, despite marked advantages, may well encourage a certain type of individual to have surgery for reasons for which it is not intended. This article discusses the underlying characteristics of the patient who seeks repetitive surgery. The author points out that it is the surgeon's, not the patient's, responsibility to prevent unnecessary surgery.

The elective surgeon's personality and role confusion.

This study explores the interrelationships of certain characteristics associated with the elective surgeon's personality. Findings indicate that the very characteristics that distinguish the surgeon's expertise also make it difficult for him to accept the changes that have occurred in the spectrum of modern medicine and the resulting role confusion. Rather than reacting defensively or negatively, this work recommends that the surgeon take an affirmative, assertive approach to the problem.

Glucuronidation in the chimpanzee (Pan troglodytes): studies with acetaminophen, oestradiol and morphine.

The chimpanzee has recently been characterized as a surrogate for oxidative drug metabolism in humans and as a pharmacokinetic model for the selection of drug candidates. In the current study, the glucuronidation of acetaminophen, morphine and oestradiol was evaluated in the chimpanzee to extend the characterization of this important animal model. Following oral administration of acetaminophen (600 mg) to chimpanzees (n=2), pharmacokinetics were comparable with previously reported human values, namely mean oral clearance 0.91 vs. 0.62+/-0.05 l h-1 kg-1, apparent volume of distribution 2.29 vs. 1.65+/-0.25 l kg-1, and half-life 1.86 vs. 1.89+/-7h, for chimpanzee vs. human, respectively. Urinary excretions (percentage of dose) of acetaminophen, acetaminophen glucuronide and acetaminophen sulfate were also similar between chimpanzees and humans, namely 2.3 vs. 5.0, 63.1 vs. 54.7, and 25.0 vs. 32.3%, respectively. Acetaminophen, oestradiol and morphine glucuronide formation kinetics were investigated using chimpanzee (n=2) and pooled human liver microsomes (n=10). V(max) (app) and K(m)(app) (or S(50)(app)) for acetaminophen glucuronide, morphine 3- and 6-glucuronide, and oestradiol 3- and 17-glucuronide formation were comparable in both species. Eadie-Hofstee plots of oestradiol 3-glucuronide formation in chimpanzee microsomes were characteristic of autoactivation kinetics. Western immunoblot analysis of chimpanzee liver microsomes revealed a single immunoreactive band when probed with anti-human UGT1A1, anti-human UGT1A6, and anti-human UGT2B7. Taken collectively, these data demonstrate similar glucuronidation characteristics in chimpanzees and humans.

When collecting on unpaid balances, phone calls can produce the right answers.

Healthcare organizations trying to resolve aged patient accounts often find more success in personal contact by telephone. The approach allows payers to respond directly and allows collection employees to work on problem solving.

Body image satisfaction in adolescent girls and boys: A longitudinal study.

In a longitudinal developmental study, 90 girls and boys participated in a psychological investigation, and were medically examined when they were 11, 13, 15, and 18 years old. Their satisfaction with the various parts of their body was assessed by means of a questionnaire. Satisfaction was highest at age 18, with males on average more satisfied than females at all age levels. There was a fairly constant pattern of "critical body features" for each of the sexes. However, individual satisfaction varied greatly as a function of age and developmental level, with late maturers tending to be more satisfied than early matures at ages 11 and 18. The correlations between body image satisfaction and other variables varied as a function of the age and sex of the subjects, and are discussed in relation to the growth process.

Marcella O'Grady Boveri (1863-1950): her three careers in biology.

The career of Marcella O'Grady Boveri (1863-1950), a nineteenth-century Catholic woman educated in biology at MIT and Bryn Mawr, is discussed both in the biological context of the times and with regard to the position of women in science. The thesis is that her life pattern differed strikingly from that of other woman biologists of her generation and that the character of her contributions to biology varied with that pattern. Perhaps it is in consequence that the significance of her considerable achievement has been hidden. Boveri's circumstances led her to collaboration rather than independence in research: she worked with skill and interest, but without formal recognition, on her husband's theoretically important and already established research program in Germany (1900-1915). She thought it a privilege to do so. Earlier (1889-1896), at Vassar College, and later (1927-1943), at the newly established Albertus Magnus College, she was an innovator who introduced and developed new curricula in biology, a stimulating and influential teacher, a mentor, and a role model. In addition, she did much to promote international communication, as exemplified both by her English translation of Theodor Boveri's prescient theory of cancer and by her influence in bringing important scientists to the United States.

How to recognize and control the problem patient.

All surgery has a psychological impact, but nowhere does the patient's psyche come into play more prominently than in the field of elective surgery. Psychological manifestations related to elective surgery must be recognized and controlled preoperatively, lest they control the operative outcome. This article discusses the personality characteristics associated with the potential problem patient; counseling and evaluative techniques; common psychogenic conditions; cause and management of patient dissatisfaction; and psychology of the terminal patient.

Self-perception of the elective surgeon and some patient perception correlates.

This study investigated the personality characteristics of the elective surgeon, the realism of the surgeon's role concept, and the relationships between these variables and the occurrence of litigation. Data obtained from 125 surgeons and 65 of these surgeons' patients were computer analyzed to answer three specific questions. The surgeon's personality needs were found to differ significantly from those of the general population. Both the surgeons and the patients viewed the surgeon's role unrealistically. No specific physician-patient interaction variable was found to be related significantly to the occurrence of litigation. Findings showed that the elective surgeon is aware of the documented causes for litigation but unaware of how his own personality may affect his vulnerability to litigation.