Martha Huntington

Use of an ephedrine alkoxide to mediate enantioselective addition of an acetylide to a prochiral ketone: asymmetric synthesis of the reverse transcriptase inhibitor L-743,726

Abstract The asymmetric synthesis of L-743,726 was achieved in six steps with an overall yield of 31%. The asymmetry was introduced using a lithiated ephedrine to mediate acetylide addition to a trifluoromethyl ketone with an enantiomeric excess of 96–98%.

A New Cyclooxygenase‐2 Inhibitor, Rofecoxib (VIOXX®), Did Not Alter the Antiplatelet Effects of Low‐Dose Aspirin in Healthy Volunteers

The present study examined whether rofecoxib (VIOXX®), a new specific inhibitor of cyclooxygenase‐2 (COX‐2), would interfere with the desired antiplatelet effects of aspirin. Thus, the effects of rofecoxib on inhibition of ex vivo serumgenerated thromboxane B2 (TXB2) and platelet aggregation by low doses (81 mg) of aspirin were examined in healthy volunteers. This was a double‐blind, randomized, placebo‐controlled, parallel study of two treatment groups (n = 12 per group) in which subjects received 50 mg of rofecoxib or placebo for 10 days in a blinded fashion. Subjects also received 81 mg aspirin once on each of days 4 through 10 in an open‐label fashion. Blood for measurement of serum TXB2 production and platelet aggregation studies was collected on day 1 (prior to rofecoxib/placebo), on day 4 (prior to aspirin), and on day 10 (before and 4 hours following the seventh dose of aspirin). Platelet‐derived serum TXB2 (COX‐1 assay) was measured in blood clotted for 1 hour at 37°C. Platelet aggregation was independently induced employing 1 mM arachidonic acid and 1 μg/mL collagen as agonists. Rofecoxib administered alone had no significant effect on serum TXB2 production or platelet aggregation (day 4). TXB2 production was inhibited 98.4% by aspirin coadministered with either rofecoxib or placebo (day 10). Similarly, platelet aggregation induced by arachidonic acid was inhibited 93.7% and 93.5% by aspirin coadministered with either rofecoxib or placebo, respectively (day 10). The comparable values for inhibition of collagen‐induced platelet aggregation were 86.8% and 90.8%, respectively. No important clinical or laboratory adverse experiences were observed. In conclusion, rofecoxib alone (50 mg QD for 4 days) did not inhibit serum TXB2 production or platelet aggregation. In addition, rofecoxib (50 mg QD for 10 days) did not alter the antiplatelet effects of low‐dose aspirin (inhibition of platelet aggregation and TXB2 production). Rofecoxib was generally well tolerated when administered alone or in combination with low‐dose aspirin.

Rhodium-carbenoid-mediated intermolecular O–H insertion reactions: a dramatic additive effect. Application in the synthesis of an ascomycin derivative

Abstract A catalyst system of Rh 2 (oct) 4 /DIPEA or TMU allows for the rapid construction of α-alkoxyketones from the corresponding α-diazo ketone and alcohol. This methodology was applied to the synthesis of immunoregulant 1 .

Efficacy and tolerability of the specific cyclooxygenase-2 inhibitor DFP compared with naproxen sodium in patients with postoperative dental pain

DFP [3-(2-propyloxy)-(4-methyl-sulfonylphenyl)-(5,5-dimethyl)-fu ranone] is a highly specific cyclooxygenase-2 inhibitor (>2500-fold selective in transfected Chinese hamster ovary cell assays) that has demonstrated efficacy in preclinical models of pain and inflammation. The present single-dose, randomized, double-masked, double-dummy, placebo-controlled, parallel-group study was undertaken to compare DFP 5, 25, and 50 mg with naproxen sodium 550 mg and with placebo in 196 patients (mean age, 25.8 years; 187 [95.4%] males) who experienced moderate-to-severe pain after surgical removal of > or =2 third molars. Overall analgesic effect, duration of effect, time to onset of analgesic effect, peak analgesic effect, and tolerability were assessed over a 24-hour postdose period. Both DFP 25 and 50 mg, as well as the active comparator, naproxen sodium 550 mg, were significantly more effective than placebo. The onset of analgesic effect in the DFP 25-mg, DFP 50-mg, and naproxen sodium 550-mg groups did not differ significantly. DFP was generally well tolerated in single doses up to 50 mg. DFP 50 mg was efficacious in the treatment of postoperative dental pain and was indistinguishable from the active comparator, naproxen sodium 550 mg.

MK-0966, a cyclooxygenase-2 (COX-2) specific inhibitor, had no effect on the anti-platelet activity of low-dose aspirin (ASA) measured by serum thromboxane B2 (TXB2) production and platelet aggregation.

Clinical Pharmacology & Therapeutics (1999) 65, 163–163; doi: