Discovery of a potent and orally bioavailable benzolactam-derived inhibitor of Polo-like kinase 1 (MLN0905).

This article describes the discovery of a series of potent inhibitors of Polo-like kinase 1 (PLK1). Optimization of this benzolactam-derived chemical series produced an orally bioavailable inhibitor of PLK1 (12c, MLN0905). In vivo pharmacokinetic-pharmacodynamic experiments demonstrated prolonged mitotic arrest after oral administration of 12c to tumor bearing nude mice. A subsequent efficacy study in nude mice achieved tumor growth inhibition or regression in a human colon tumor (HT29) xenograft model.

Design and optimization of potent and orally bioavailable tetrahydronaphthalene Raf inhibitors.

Inhibition of mutant B-Raf signaling, through either direct inhibition of the enzyme or inhibition of MEK, the direct substrate of Raf, has been demonstrated preclinically to inhibit tumor growth. Very recently, treatment of B-Raf mutant melanoma patients with a selective B-Raf inhibitor has resulted in promising preliminary evidence of antitumor activity. This article describes the design and optimization of tetrahydronaphthalene-derived compounds as potent inhibitors of the Raf pathway in vitro and in vivo. These compounds possess good pharmacokinetic properties in rodents and inhibit B-Raf mutant tumor growth in mouse xenograft models.

Outcome of extreme prematurity: a prospective comparison of 2 regional cohorts born 20 years apart.

OBJECTIVE: To determine changes that have occurred over the past 20 years in perinatal characteristics, neonatal treatments, morbidities, and early neurodevelopmental outcomes of infants born at < or =30 weeks' gestation. METHODS: This was a prospective regional study including all live-born infants < or =30 weeks' gestation born between July 1985 and June 1986 (cohort 1) and July 2005 and June 2006 (cohort 2). Sociodemographically matched term controls were recruited for each cohort. Perinatal characteristics, mortality rates, and survival with and without impairments at 24 months' corrected age were compared. RESULTS: There was a 35% increase in the number of live-born preterm births (138 in cohort 1 and 187 in cohort 2) despite a >10% decline in total births in the region (P < .001). Assisted fertility (rarely available for mothers in cohort 1) was responsible for 20% of pregnancies in cohort 2. Survival to hospital discharge increased over 20 years from 82% to 93% (P = .002), primarily because of higher survival for infants born at <27 weeks' gestation (63% vs 88%; P = .004). Changes in management in cohort 2 included the use of surfactant (62% of infants) and increased use of postnatal steroids (39% vs 9%; P < .001), that were associated with a shorter median duration of mechanical ventilation (13 vs 21 days; P < .001); however, the incidence of bronchopulmonary dysplasia was higher in cohort 2 (56% vs 35%; P < .001). There was a significant decrease in incidence of severe ultrasound abnormalities from 17% in cohort 1 to 7% in cohort 2 (P = .008). At 24 months of age, 7% of cohort 1 and 5% of cohort 2 had an abnormal neurologic exam. Bayley cognitive scores were improved in cohort 2 (significantly closer to the mean of their controls). As a result, survival without severe neurodevelopmental impairment increased from 62% in cohort 1 to 81% in cohort 2 (P < .001). CONCLUSION: Over 20 years, there has been a significant increase in live births at < or =30 weeks' gestational age, with a greater percentage of these neonates surviving without severe neurodevelopmental impairment at 24 months.

Synthesis and biological evaluation of imidazole-based small molecule antagonists of the melanocortin 4 receptor (MC4-R).

A novel series of imidazole-based small molecule antagonists of the melanocortin 4 receptor (MC4-R) is reported. Members of this series have been identified, which exhibit sub-micromolar binding affinity for the MC4-R, functional potency <100nM, and good oral exposure in rat. Antagonists of the MC4-R are potentially useful in the therapeutic treatment of involuntary weight loss due to advanced age or disease (e.g. cancer or AIDS), an area of large, unmet medical need.

Identification of 2-[2-[2-(5-bromo-2- methoxyphenyl)-ethyl]-3-fluorophenyl]-4,5-dihydro-1H-imidazole (ML00253764), a small molecule melanocortin 4 receptor antagonist that effectively reduces tumor-induced weight loss in a mouse model.

The melanocortin 4 receptor (MC4R) plays an important role in body weight regulation and energy homeostasis. Administration of peptidic MC4R antagonists (usually by intracerebro ventricular injection) has been shown in the literature to increase body weight and/or food intake in several rodent models. We report here the identification of a novel nonpeptidic MC4R antagonist and its effects on tumor-induced weight loss in mice following peripheral administration.