Pyrazole-based sulfonamide and sulfamides as potent inhibitors of mammalian 15-lipoxygenase.

A series of inhibitors of mammalian 15-lipoxygenase (15-LO) based on a 3,4,5-tri-substituted pyrazole scaffold is described. Replacement of a sulfonamide functionality in the lead series with a sulfamide group resulted in improved physicochemical properties generating analogs with enhanced inhibition in cell-based and whole blood assays.

(3R,5S,E)-7-(4-(4-fluorophenyl)-6-isopropyl-2-(methyl(1-methyl-1h-1,2,4-triazol-5-yl)amino)pyrimidin-5-yl)-3,5-dihydroxyhept-6-enoic acid (BMS-644950): a rationally designed orally efficacious 3-hydroxy-3-methylglutaryl coenzyme-a reductase inhibitor with reduced myotoxicity potential.

3-hydroxy-3-methylglutaryl coenzyme-A reductase (HMGR) inhibitors, more commonly known as statins, represent the gold standard in treating hypercholesterolemia. Although statins are regarded as generally safe, they are known to cause myopathy and, in rare cases, rhabdomyolysis. Statin-dependent effects on plasma lipids are mediated through the inhibition of HMGR in the hepatocyte, whereas evidence suggests that myotoxicity is due to inhibition of HMGR within the myocyte. Thus, an inhibitor with increased selectivity for hepatocytes could potentially result in an improved therapeutic window. Implementation of a strategy that focused on in vitro potency, compound polarity, cell selectivity, and oral absorption, followed by extensive efficacy and safety modeling in guinea pig and rat, resulted in the identification of compound 1b (BMS-644950). Using this discovery pathway, we compared 1b to other marketed statins to demonstrate its outstanding efficacy and safety profile. With the potential to generate an excellent therapeutic window, 1b was advanced into clinical development.

The Guinea pig as a preclinical model for demonstrating the efficacy and safety of statins.

Statins, because of their excellent efficacy and manageable safety profile, represent a key component in the current armamentarium for the treatment of hypercholesterolemia. Nonetheless, myopathy remains a safety concern for this important drug class. Cerivastatin was withdrawn from the market for myotoxicity safety concerns. BMS-423526 [{(3R,5S)-7-[4-(4-fluorophenyl)-6,7-dihydro-2-(1-methylethyl)-5H-benzo[6,7]cyclohepta[1,2-b]pyridin-3-yl]-3,5-dihydroxy-heptenoic acid} sodium salt], similar to cerivastatin in potency and lipophilicity, was terminated in early clinical development due to an unacceptable myotoxicity profile. In this report, we describe the guinea pig as a model of statin-induced cholesterol lowering and myotoxicity and show that this model can distinguish statins with unacceptable myotoxicity profiles from statins with acceptable safety profiles. In our guinea pig model, both cerivastatin and BMS-423526 induced myotoxicity at doses near the ED(50) for total cholesterol (TC) lowering in plasma. In contrast, wide differences between myotoxic and TC-lowering doses were established for the currently marketed, more hydrophilic statins, pravastatin, rosuvastatin, and atorvastatin. This in vivo model compared favorably to an in vitro model, which used statin inhibition of cholesterol synthesis in rat hepatocytes and L6 myoblasts as surrogates of potential efficacy and toxicity, respectively. Our conclusion is that the guinea pig is a useful preclinical in vivo model for demonstrating whether a statin is likely to have an acceptable therapeutic safety margin.

Discovery of selective imidazole-based inhibitors of mammalian 15-lipoxygenase: highly potent against human enzyme within a cellular environment.

A series of 2,4,5-tri-substituted imidazoles has proven to be highly potent in inhibiting mammalian 15-lipoxygenase (15-LO) with excellent selectivity over human isozymes 5- and P-12-LO. Non-symmetrical sulfamides (e.g., 21a-n) were found to be suitable replacements for the earlier arylsulfonamide-containing members of this series (e.g., 2, 14a-p). Several members of these series also demonstrated potent inhibition of human 15-LO in a cell-based assay.

A switch in enantiomer preference between mitochondrial F1F0-ATPase chemotypes.

The preferred absolute configuration of two series of F(1)F(0)-ATP synthase inhibitors was determined. Although the configuration of the active enantiomer in each series is different, each series presents the same 'triaryl' pharmacophore to the enzyme binding site.

Tryptamine and homotryptamine-based sulfonamides as potent and selective inhibitors of 15-lipoxygenase.

A series of inhibitors of mammalian 15-lipoxygenase based on tryptamine and homotryptamine scaffolds is described. Compounds with aryl substituents at C-2 of the indole core of tryptamine and homotryptamine sulfonamides (e.g., 37a-p) proved to be potent inhibitors of the isolated enzyme. Selected compounds also demonstrated desirable inhibition selectivities over isozymes 5- and P-12-LO.

Benzodiazepine-based selective inhibitors of mitochondrial F1F0 ATP hydrolase.

A series of benzodiazepine-based inhibitors of mitochondrial F(1)F(0) ATP hydrolase were prepared and evaluated for their ability to selectively inhibit the enzyme in the forward direction. Compounds from this series showed excellent potency and selectivity for ATP hydrolase versus ATP synthase, suggesting a potentially beneficial profile useful for the treatment of ischemic heart disease.

N-[1-Aryl-2-(1-imidazolo)ethyl]-guanidine derivatives as potent inhibitors of the bovine mitochondrial F1F0 ATP hydrolase.

A series of substituted guanidine derivatives were prepared and evaluated as potent and selective inhibitors of mitochondrial F(1)F(0) ATP hydrolase. The initial thiourethane derived lead molecules possessed intriguing in vitro pharmacological profiles, though contained moieties considered non-drug-like. Analogue synthesis efforts led to compounds with maintained potency and superior physical properties. Small molecules in this series which potently and selectivity inhibit ATP hydrolase and not ATP synthase may have utility as cardioprotective agents.

The effects of interferon alpha-2b in combination with ribavirin on health related quality of life and work productivity.

BACKGROUND/AIMS: Interferon plus ribavirin is the most effective therapy for chronic hepatitis C. The aim of this study was to evaluate the effect of chronic hepatitis C and therapy on health-related quality of life and work functioning. METHODS: Nine hundred and twelve patients with hepatitis C infection were randomized in a controlled trial of Interferon alpha 2b 3 MU tiw for 24 or 48 weeks plus ribavirin 1000-1200 mg or placebo. Questionnaire-based assessments of health-related quality of life and work functioning were performed before, during, and after treatment. Outcome measures included the SF-36 Health Survey and additional generic and specific scales. Work functioning was assessed as missed days, shorter hours or less productivity at work. RESULTS: Pre-treatment, patients had significant impairment in five of eight SF-36 concepts compared to matched population norms. Sustained responders had a return to normal for four of these five concepts. Quality of life did not improve in non-responders. Improvements in histology, viral load or ALT values predicted improvements in quality of life. Sustained responders also had improvements in work functioning and productivity. CONCLUSIONS: Hepatitis C patients had impaired quality of life. After combination therapy, sustained virologic responders achieved benefits in their quality of life and work functioning.

Sustained virologic response is associated with improved health-related quality of life in relapsed chronic hepatitis C patients.

Although evidence of virologic elimination, normalization of serum alanine aminotransferase levels, and reduction in liver inflammation are the principal therapeutic outcome goals in chronic hepatitis C patients, improvement in health-related quality of life (HQL) is also an important aspect of therapeutic outcome. In a recent report of chronic hepatitis C patients treated for 24 weeks with interferon, sustained virologic response (24 weeks post-treatment) was associated with improvement in HQL compared with nonresponse. We report on the relationship between sustained virologic response and Hepatitis Quality-of-Life Questionnaire (HQLQ) survey results of patients who relapsed after a previous course of interferon alfa who were subsequently treated with recombinant interferon alfa-2b (rIFN-alpha 2b) either alone or in combination with ribavirin. The HQLQ was administered at baseline, at treatment Weeks 12 and 24, and at follow-up Weeks 12 and 24. All patients received rIFN-alpha 2b 3 million International Units by subcutaneous injection three times weekly plus either oral ribavirin (1,000 or 1,200 mg) or placebo daily for 24 weeks. At baseline, patients scored lower than adjusted population norms in HQL. Relative to patients treated with rIFN-alpha 2b monotherapy, patients receiving combination therapy showed better HQL in 6 of 13 domains. Furthermore, sustained virologic response in either treatment group was associated with improvement in the scores of both generic and hepatitis-specific HQL survey domains. These results indicate that successful therapeutic resolution of hepatitis C infection improves HQL as assessed by generic and hepatitis C-specific measures of functional health and well-being. Furthermore, improvements in HQL outcome measures may predict reduced demand for health care resources and greater productivity in the workplace.