Discovery of N-[Bis(4-methoxyphenyl)methyl]-4-hydroxy-2-(pyridazin-3-yl)pyrimidine-5-carboxamide (MK-8617), an Orally Active Pan-Inhibitor of Hypoxia-Inducible Factor Prolyl Hydroxylase 1-3 (HIF PHD1-3) for the Treatment of Anemia.

The discovery of novel 4-hydroxy-2-(heterocyclic)pyrimidine-5-carboxamide inhibitors of hypoxia-inducible factor (HIF) prolyl hydroxylases (PHD) is described. These are potent, selective, orally bioavailable across several species, and active in stimulating erythropoiesis. Mouse and rat studies showed hematological changes with elevations of plasma EPO and circulating reticulocytes following single oral dose administration, while 4-week q.d. po administration in rat elevated hemoglobin levels. A major focus of the optimization process was to decrease the long half-life observed in higher species with early compounds. These efforts led to the identification of 28 (MK-8617), which has advanced to human clinical trials for anemia.

Dihydro-pyrano[2,3-b]pyridines and tetrahydro-1,8-naphthyridines as CB1 receptor inverse agonists: synthesis, SAR and biological evaluation.

Synthesis and structure-activity relationships of cannabinoid-1 receptor (CB1R) inverse agonists based on dihydro-pyrano[2,3-b] pyridine and tetrahydro-1,8-naphtyridine scaffolds are presented. Rat food intake and pharmacokinetic evaluation of 13g, 13i, 13k and 17a revealed these compounds to be highly efficacious orally active modulators of CB1R.

Furo[2,3-b]pyridine-based cannabinoid-1 receptor inverse agonists: synthesis and biological evaluation. Part 1.

The synthesis, SAR and binding affinities of cannabinoid-1 receptor (CB1R) inverse agonists based on furo[2,3-b]pyridine scaffolds are described. Food intake, mechanism specific efficacy, pharmacokinetic, and metabolic evaluation of several of these compounds indicate that they are effective orally active modulators of CB1R.

Glutathione S-transferase catalyzed desulfonylation of a sulfonylfuropyridine.

MRL-1, a cannabinoid receptor-1 inverse agonist, was a member of a lead candidate series for the treatment of obesity. In rats, MRL-1 is eliminated mainly via metabolism, followed by excretion of the metabolites into bile. The major metabolite M1, a glutathione conjugate of MRL-1, was isolated and characterized by liquid chromatography/mass spectrometry and NMR spectroscopic methods. The data suggest that the t-butylsulfonyl group at C-2 of furopyridine was displaced by the glutathionyl group. In vitro experiments using rat and monkey liver microsomes in the presence of reduced glutathione (GSH) showed that the formation of M1 was independent of NADPH and molecular oxygen, suggesting that this reaction was not mediated by an oxidative reaction and a glutathione S-transferase (GST) was likely involved in catalyzing this reaction. Furthermore, a rat hepatic GST was capable of catalyzing the conversion of MRL-1 to M1 in the presence of GSH. When a close analog of MRL-1, a p-chlorobenzenesulfonyl furopyridine derivative (MRL-2), was incubated with rat liver microsomes in the presence of GSH, p-chlorobenzene sulfinic acid (M2) was also identified as a product in addition to the expected M1. Based on these data, a mechanism is proposed involving direct nucleophilic addition of GSH to sulfonylfuropyridine, resulting in an unstable adduct that spontaneously decomposes to form M1 and M2.

Adverse effect of increased left ventricular wall thickness on five year outcomes of patients with negative dobutamine stress.

BACKGROUND: To determine if patients without dobutamine induced left ventricular wall motion abnormalities (WMA) but an increased LV end-diastolic wall thickness (EDWT) exhibit a favorable cardiac prognosis. RESULTS: Between 1999 and 2001, 175 patients underwent a dobutamine stress cardiovascular magnetic resonance (DCMR) procedure utilizing gradient-echo cines. Participants had a LV ejection fraction >55% without evidence of an inducible WMA during peak dobutamine/atropine stress. After an average of 5.5 years, all participants were contacted and medical records were reviewed to determine the post-DCMR occurrence of cardiac death, myocardial infarction (MI), and unstable angina (USA) or congestive heart failure (CHF) warranting hospitalization.In a multivariate analysis, that took into account Framingham and other risk factors associated with cardiac events, a cine gradient-echo derived LV EDWT > or =12 mm was associated independently with an increase in cardiac death and MI (HR 6.0, p = 0.0016), and the combined end point of MI, cardiac death, and USA or CHF warranting hospitalization (HR 3.0, p = 0.0005). CONCLUSION: Similar to echocardiography, CMR measures of increased LV wall thickness should be considered a risk factor for cardiac events in individuals receiving negative reports of inducible ischemia after dobutamine stress. Additional prognostic studies of the importance of LV wall thickness and mass measured with steady-state free precession techniques are warranted.

Dobutamine cardiac magnetic resonance results predict cardiac prognosis in women with known or suspected ischemic heart disease.

OBJECTIVES: The purpose of this study was to determine the prognostic utility of dobutamine cardiac magnetic resonance (DCMR) stress test results in women. BACKGROUND: To date, the preponderance of studies reporting the utility of DCMR stress results for predicting cardiac prognosis have been performed in men. We sought to determine the utility of DCMR results for predicting cardiac prognosis in women. METHODS: Two hundred sixty-six consecutively referred women underwent DCMR in which left ventricular wall motion (LVWM) was assessed at rest and after intravenous dobutamine and atropine. Inducible LVWM abnormalities were identified during testing. Women were contacted to determine the post-DCMR occurrence of a cardiac event. All events were substantiated according to defined criteria and then were verified after a thorough medical record review by individuals blinded to testing data. RESULTS: Women were contacted an average of 6.2 +/- 1.6 (median 6.2, range 0.8 to 10.4) years after DCMR; 27% of the women experienced an inducible LVWM abnormality during testing. In those with and without inducible LVWM abnormalities, the proportion of women with cardiac events were 63% versus 30%, respectively, (hazard ratio [HR]: 2.7; 95% confidence interval [CI]: 1.8 to 4.3 for the presence of inducible LVWM abnormalities p < 0.0001). The proportion of women with myocardial infarction (MI) and cardiac death were 33.3% and 7.5%, respectively. This resulted in a HR for MI and cardiac death of 4.1 (95% CI: 2.2 to 9.4) for those with versus those without inducible LVWM abnormalities; p < 0.0001. A subgroup analysis was performed in women without a history of coronary artery disease and in those with LVWM abnormalities, DCMR remained an adverse predictor of cardiac events (HR: 4.0, 95% CI: 1.8 to 9.0, p = 0.003). CONCLUSIONS: Inducible LVWM abnormalities during DCMR predict cardiac death and MI in women. Similar to men, these results indicate that DCMR is a valuable noninvasive stress imaging modality for identifying cardiac risk in women with known or suspected ischemic heart disease.

Pyridopyrimidine based cannabinoid-1 receptor inverse agonists: Synthesis and biological evaluation.

The synthesis, SAR and binding affinities are described for cannabinoid-1 receptor (CB1R) specific inverse agonists based on pyridopyrimidine and heterotricyclic scaffolds. Food intake and pharmacokinetic evaluation of several of these compounds indicate that they are effective orally active modulators of CB1R.

Pharmacological evaluation of LH-21, a newly discovered molecule that binds to cannabinoid CB1 receptor.

LH-21 (5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-3-hexyl-1H-1,2,4-triazole) was previously reported as a neutral antagonist at the cannabinoid CB1 receptor which, despite its reported poor ability to penetrate into the brain, suppressed food intake and body weight in rats by intraperitoneal administration. In the present study, we studied the mechanism of action of LH-21 by characterizing its in vitro pharmacological properties and in vivo efficacy. LH-21 inhibited the binding of [3H]CP55940 to cloned human and rat CB1 receptors with IC50 values of 631+/-98 nM, and 690+/-41 nM, respectively, and acted as an inverse agonist in a cAMP functional assay using cultured cells expressing human, rat or mouse CB1 receptor. The compound was shown to be brain-penetrant in rats by intravenous administration. Importantly, a single dose of LH-21 (60 mg/kg, i.p.) caused a similar suppression of overnight food intake and body weight gain in wild-type and CB1 receptor knockout mice. Our results suggest that LH-21 is a low affinity inverse agonist for the CB1 receptor and does not act on the CB1 receptor to inhibit food intake in mice.

Whole grain intake and cardiovascular disease: a meta-analysis.

BACKGROUND AND AIMS: Whole grain food sources have been associated with lowered risk of cardiovascular disease (CVD). Studies in recent years have strengthened this observation and elucidated potential mechanisms for this association. This study sought to quantitate the available observational evidence on whole grain intake and clinical cardiovascular events. METHODS AND RESULTS: Seven prospective cohort studies with quantitative measures of dietary whole grains and clinical cardiovascular outcomes were identified from MEDLINE searches and a review of the literature. Based on event estimates adjusted for cardiovascular risk factors, greater whole grain intake (pooled average 2.5 servings/d vs. 0.2 servings/d) was associated with a 21% lower risk of CVD events [OR 0.79 (95% CI: 0.73-0.85)]. Similar estimates were noted for different CVD outcomes (heart disease, stroke, fatal CVD) and in sex-specific analyses. Conversely, refined grain intake was not associated with incident CVD events [1.07 (0.94-1.22)]. CONCLUSIONS: There is a consistent, inverse association between dietary whole grains and incident cardiovascular disease in epidemiological cohort studies. In light of this evidence, policy-makers, scientists, and clinicians should redouble efforts to incorporate clear messages on the beneficial effects of whole grains into public health and clinical practice endeavors.

Assessment of ventricular function with cardiovascular magnetic resonance.

The high spatial and temporal resolution of cardiovascular magnetic resonance (CMR) images makes it well-suited for use in the assessment of right ventricular and left ventricular function in patients who have cardiovascular disorders. This article reviews CMR methods used to assess regional and global ventricular function.

Assessment of ventricular function with cardiovascular magnetic resonance.

The high spatial and temporal resolution of cardiovascular magnetic resonance (CMR) images makes it well-suited for use in the assessment of right ventricular and left ventricular function in patients who have cardiovascular disorders. This article reviews CMR methods used to assess regional and global ventricular function.

Lead optimization of 5,6-diarylpyridines as CB1 receptor inverse agonists.

Optimization of the biological activity for 5,6-diarylpyridines as CB1 receptor inverse agonists is described. Food intake and pharmacokinetic evaluation of 3f and 15c indicate that these compounds are effective orally active modulators of CB1.

Synthesis of functionalized 1,8-naphthyridinones and their evaluation as novel, orally active CB1 receptor inverse agonists.

Synthesis, SAR, and binding affinities are described for a new class of 1,8-naphthyridinone CB1 receptor specific inverse agonists. Food intake, knockout mouse, and pharmacokinetic evaluation of 14 indicate that this compound is an effective orally active modulator of CB1.

Design and syntheses of melanocortin subtype-4 receptor agonists. Part 2: discovery of the dihydropyridazinone motif.

Optimization of the biological activity of a new class of non-peptidyl, pyridazinone derived human melanocortin subtype-4 receptor agonists is disclosed.

Synthesis and SAR of 5,6-diarylpyridines as human CB1 inverse agonists.

Structure-activity relationship studies for two series of 2-benzyloxy-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)pyridines having either a 3-cyano or 3-carboxamide moiety resulted in the preparation of the 2-(3,4-difluorobenzyloxy)-3-nitrile analog 10d and the 2-(3,4-difluorobenzyloxy)-3-(N-propylcarboxamide) analog 16c, (hCB1 IC(50)=1.3 and 1.7 nM, respectively) as potent and selective hCB1 inverse agonists. Their synthesis and biological activities are described herein.

Identification of neutral 4-O-alkyl quinolone nonpeptide GnRH receptor antagonists.

A series of neutral, nonbasic quinolone GnRH antagonists were prepared via Mitsunobu alkylation of protected and unprotected 4-hydroxy quinolone intermediates. The synthetic route was improved by utilization of unique reactivity and convergency afforded by the use of mono and bis-trimethylsilylethyl protected quinolones. Potent neutral GnRH antagonists were identified, including ether and lactam derivatives, that show similar in vitro binding affinity and functional activity as compared to the earlier basic 4-aminoalkyl quinolone series of nonpeptide GnRH antagonists.

Design and syntheses of melanocortin subtype-4 receptor agonists: evolution of the pyridazinone archetype.

The discovery and optimization of a new class of non-peptidyl, pyridazinone derived melanocortin subtype-4 receptor agonists is disclosed.

2-Arylindoles as gonadotropin releasing hormone (GnRH) antagonists: optimization of the tryptamine side chain.

A series of 2-arylindoles containing novel heteroaromatic substituents on the tryptamine tether, based on compound 1, was prepared and evaluated for their ability to act as gonadotropin releasing hormone (GnRH) antagonists. Successful modifications of 1 included chain length variation (reduction) and replacement of the pyridine with heteroaromatic groups. These alterations culminated in the discovery of compound 27kk which had excellent in vitro potency and oral efficacy in rodents.