Discovery and optimization of oxadiazole-based FLAP inhibitors.

Structure activity relationship (SAR) investigation of an oxadiazole based series led to the discovery of several potent FLAP inhibitors. Lead optimization focused on achieving functional activity while improving physiochemical properties and reducing hERG inhibition. Several compounds with favorable in vitro and in vivo properties were identified that were suitable for advanced profiling.

Highly enantioselective imine cinnamylation with a remarkable diastereochemical switch.

The first general method for the enantioselective cinnamylation of aldimines is reported. The method utilizes a simple chiral cinnamylsilane reagent and is characterized by experimental simplicity and extraordinarily high levels of enantioselectivity. Further, a remarkable and unprecedented diastereochemical reversal has been realized whereby either diastereomer may be accessed from the same trans-cinnamylsilane based upon a subtle change to the imine, thus obviating the usual requirement for both the trans- and cis-cinnamylsilanes.

A high-throughput scintillation proximity assay for sphingosine-1-phosphate lyase.

The emergence of sphingosine-1-phosphate lyase (SPL) as a promising therapeutic target for inflammatory diseases has heightened interest in the identification of small molecules that modulate its activity. The enzymatic activity of SPL is typically measured using radiometric or fluorescence-based assays that require a lipid extraction step, or by direct quantitation of reaction products using mass spectrometry (MS). To facilitate testing large numbers of compounds to identify SPL modulators, we developed a robust scintillation proximity assay (SPA) that is compatible with high-throughput screening (HTS). This assay employs recombinant human full-length SPL in insect cell membrane preparations to catalyze the conversion of biotinylated aminosphingosine-1-[(33)P]phosphate (S1(33)P-biotin) to trans-2-hexadecenal-biotin and ethanolamine [(33)P]phosphate. To validate the SPA and confirm the fidelity of its measurement of SPL enzyme activity, we developed a Rapid-Fire MS method that quantitates nonradiolabeled S1P-biotin. In addition, we developed a simple, scalable method to produce S1(33)P-biotin in quantities sufficient for HTS. The optimized SPA screen in 384-well microplates produced a mean plate-wise Z'-statistic of 0.58 across approximately 3,000 plates and identified several distinct structural classes of SPL inhibitor. Among the inhibitors that the screen identified was one compound with an IC50 of 1.6 µM in the SPA that induced dose-dependent lymphopenia in mice.

Identification of a potent sodium hydrogen exchanger isoform 1 (NHE1) inhibitor with a suitable profile for chronic dosing and demonstrated cardioprotective effects in a preclinical model of myocardial infarction in the rat.

Sodium-hydrogen exchanger isoform 1 (NHE1) is a ubiquitously expressed transmembrane ion channel responsible for intracellular pH regulation. During myocardial ischemia, low pH activates NHE1 and causes increased intracellular calcium levels and aberrant cellular processes, leading to myocardial stunning, arrhythmias, and ultimately cell damage and death. The role of NHE1 in cardiac injury has prompted interest in the development of NHE1 inhibitors for the treatment of heart failure. This report outlines our efforts to identify a compound suitable for once daily, oral administration with low drug-drug interaction potential starting from NHE1 inhibitor sabiporide. Substitution of a piperidine for the piperazine of sabiporide followed by replacement of the pyrrole moiety and subsequent optimization to improve potency and eliminate off-target activities resulted in the identification of N-[4-(1-acetyl-piperidin-4-yl)-3-trifluoromethyl-benzoyl]-guanidine (60). Pharmacological evaluation of 60 revealed a remarkable ability to prevent ischemic damage in an ex vivo model of ischemia reperfusion injury in isolated rat hearts.

Topical imiquimod treatment for nodular basal cell carcinomas: an open-label series.

BACKGROUND: Imiquimod has been used for basal cell carcinomas (BCCs). This is the first open-label series using imiquimod for nodular BCC with Mohs surgery resection for confirmation of treatment. OBJECTIVE: To evaluate the efficacy of topical imiquimod in patients with biopsy-proven nodular BCC. RESULTS: After 12 weeks for three times a week application, treatment sites at week 15 were surgically excised using Mohs micrographic surgery. All 15 treatment subjects were clear of BCC. At the 18-month follow-up, no patients had recurrent tumor. CONCLUSION: Imiquimod 5% cream may be another treatment modality for nodular BCC.