James J. McNally

Analytical and preparative high-performance liquid chromatographic separation of thienopyran enantiomers

Abstract The analytical and preparative enantiomeric resolution of a racemic substituted thienopyran was obtained with a β-cyclodextrin bonded-phase column using isocratic conditions. Baseline separations were obtained with short run times. The analytical method is accurate, reliable and reproducible for measuring enantiomeric excess. A semi-preparative high-performance liquid chromatographic method was used to obtain the enantiomers for pharmacological testing prior to developing an asymmetric synthesis of RWJ 26629.

Thiophene systems. 12. Analogues of ketanserin and ritanserin as selective 5-HT2 antagonists

Abstract A series of thieno[3,2-d]-, [3,4-d]- and [2,3-d]pyrimidinedione derivatives was prepared with N-3 substitution containing the side chains of ketanserin and ritanserin. The best of these thiophene analogues were the isosteres of ketanserin which were up to 20-fold more potent than the standards in 5-HT2 binding assays. More importantly, in addition to their increased potency, these derivatives were more selective than the standards in that they had less affinity for 5-HT1A and α1 binding sites. This selectivity is especially noted as the ratio of α 1 5-HT 2 wherein the most interesting thiophene isostere (2) in this study had a binding selectivity > 12-fold of ketanserin or ritanserin.

Tetrahydroindazole derivatives as potent and peripherally selective cannabinoid-1 (CB1) receptor inverse agonists.

A series of potent and receptor-selective cannabinoid-1 (CB1) receptor inverse agonists has been discovered. Peripheral selectivity of the compounds was assessed by a mouse tissue distribution study, in which the concentrations of a test compound in both plasma and brain were measured. A number of peripherally selective compounds have been identified through this process. Compound 2p was further evaluated in a 3-week efficacy study in the diet-induced obesity (DIO) mouse model. Beneficial effects on plasma glucose were observed from the compound-treated mice.

Novel thieno[2,3-b]- and [3,4-b]pyrans as potassium channel openers. Thiophene systems--XVII.

The syntheses and antihypertensive activity of the thieno[3,4-b]pyran and thieno[2,3-b]pyran isosteres of the potassium channel opener (PCO) RWJ 26629 (+/- 2a) are reported. While the unsubstituted thiophene derivatives were active at 20 mg/kg, introduction of a strong electron withdrawing group in the 2-position of the thieno[3,2-b] series increased potency. Similar substitution on the thieno[3,4-b] series significantly lowered potency. Compounds 26 and 30 are approximately 5-fold more potent than the prototypic PCO cromakalim (+/- 1).