One-pot in situ formation and reaction of trimethyl(trichloromethyl)silane: application to the synthesis of 2,2,2-trichloromethylcarbinols.

2,2,2-Trichloromethylcarbinols are 1 are valuable synthetic intermediates with a multitude of uses. A scalable procedure for the synthesis of TMS-protected-2,2,2-trichloromethylcarbinols and 2,2,2-trichloromethylcarbinols 1 was developed that employs the in situ generation and reaction of trimethyl(trichloromethyl)silane (CCl(3)-TMS). The procedure avoids the exposure of the carbonyl compounds to the strongly basic conditions typically used for this transformation and also avoids isolation of the difficult-to-handle CCl(3)-TMS. This procedure was applied to diastereoselective trichloromethyl additions to 2-substituted 4-piperidinones and to reactions with a variety of structurally diverse aldehydes and ketones.

The Effect of Exercise on Oxygen Content in Anemic Patients With Chronic Obstructive Pulmonary Disease.

BACKGROUND: Anemia is reported in one-third of the patients with chronic obstructive pulmonary disease (COPD). Anemia, by decreasing oxygen content, can be a contributing factor for hypoxemia. We determined to find whether anemia causes more prominent hypoxia by decreasing the total oxygen content after exercise in anemic patients with COPD. METHODS: Stable moderate-to-severe COPD patients with and without anemia were recruited. Arterial blood gas analyses were performed on room air before and after a 6-minute walking test (6MWT). Walking distance, oxygen saturation, and heart rate were recorded in each case before and after the 6MWT. Pulmonary function test measurements and other data were obtained from the chart. The mean and standard deviations were calculated for continuous variables. The independent t-test and Kruskal-Wallis test were performed for numerical covariate and univariate analyses. The paired t-test was used for the analyses of data before and after exercise. RESULTS: A total of 24 male patients were included in the study; 12 of which were anemic. The oxygen content was decreased in the anemic group (15.22 ± 1.28 vs 15.07 ± 1.22) after exercise, but it was not significant. In the non-anemic group, no oxygen content decrease was observed after exercise (18.83 ± 1.41 vs 18.9 ± 1.37). Interestingly, the Spo2, but not Sao2, was significantly lower after exercise in anemic patients with COPD (93.46% ± 5.06% vs 88.20% ± 6.35% before and after exercise, respectively). CONCLUSIONS: Anemia does not cause more prominent hypoxemia after exercise in patients with COPD. However, the recorded Spo2 levels were significantly lower after exercise in the anemic patients with COPD.

Utilizing structures of CYP2D6 and BACE1 complexes to reduce risk of drug-drug interactions with a novel series of centrally efficacious BACE1 inhibitors.

In recent years, the first generation of ß-secretase (BACE1) inhibitors advanced into clinical development for the treatment of Alzheimer's disease (AD). However, the alignment of drug-like properties and selectivity remains a major challenge. Herein, we describe the discovery of a novel class of potent, low clearance, CNS penetrant BACE1 inhibitors represented by thioamidine 5. Further profiling suggested that a high fraction of the metabolism (>95%) was due to CYP2D6, increasing the potential risk for victim-based drug-drug interactions (DDI) and variable exposure in the clinic due to the polymorphic nature of this enzyme. To guide future design, we solved crystal structures of CYP2D6 complexes with substrate 5 and its corresponding metabolic product pyrazole 6, which provided insight into the binding mode and movements between substrate/inhibitor complexes. Guided by the BACE1 and CYP2D6 crystal structures, we designed and synthesized analogues with reduced risk for DDI, central efficacy, and improved hERG therapeutic margins.

Maximizing lipophilic efficiency: the use of Free-Wilson analysis in the design of inhibitors of acetyl-CoA carboxylase.

This paper describes the design and synthesis of a novel series of dual inhibitors of acetyl-CoA carboxylase 1 and 2 (ACC1 and ACC2). Key findings include the discovery of an initial lead that was modestly potent and subsequent medicinal chemistry optimization with a focus on lipophilic efficiency (LipE) to balance overall druglike properties. Free-Wilson methodology provided a clear breakdown of the contributions of specific structural elements to the overall LipE, a rationale for prioritization of virtual compounds for synthesis, and a highly successful prediction of the LipE of the resulting analogues. Further preclinical assays, including in vivo malonyl-CoA reduction in both rat liver (ACC1) and rat muscle (ACC2), identified an advanced analogue that progressed to regulatory toxicity studies.

Concise synthesis of (S)-N-BOC-2-hydroxymethylmorpholine and (S)-N-BOC-morpholine-2-carboxylic acid.

An operationally simple synthesis of N-BOC-2-hydroxymethylmorpholine (1) and N-BOC-morpholine-2-carboxylic acid (2) from epichlorohydrin has been developed. No chromatography is required in the processing, which allows high process throughput.

A practical synthesis of cabergoline.

Cabergoline is an N-acylurea derived from 9,10-dihydrolysergic acid, which is a potent prolactin inhibitor. It is marketed by Pharmacia as Dostinex for the treatment of hyperprolactinemia and is currently under active development for the treatment of a variety of CNS disorders. In the existing process, the N-acylurea is formed by the reaction of an amide with a large excess of ethyl isocyanate at elevated temperatures. An improved process was developed that eliminates this hazardous reaction. The amide is reacted with phenyl chloroformate and then with ethylamine, which provides a mild and efficient means of forming the unsymmetrical N-acylurea.