A novel class of cyclic beta-dicarbonyl leaving groups and their use in the design of benzisothiazolone human leukocyte elastase inhibitors.

Human leukocyte elastase (HLE) has been proposed to be a primary mediator of pulmonary emphysema, and inhibitors of this enzyme should be effective in the treatment of emphysema and other pulmonary diseases. We have discovered a novel class of alicyclic and heterocyclic leaving groups which share one common structural feature, a cyclic beta-dicarbonyl. This design concept for leaving groups has not been previously reported. A structure-activity relationship has been developed and the concept extended to several types of alicyclic and heterocyclic beta-dicarbonyl systems. This work led to the identification of a potent (K*i of 0.066 nM) and tissue stable (in vitro: blood t1/2 = 160 min, liver t1/2 > 240 min) benzisothiazolone HLE inhibitor, WIN 65936 (13b).

Aminoalkylindoles: structure-activity relationships of novel cannabinoid mimetics.

Aminoalkylindoles (AAIs) are a novel series of cannabinoid receptor ligands. In this report we disclose the structural features of AAIs which are important for binding to this receptor as measured by inhibition of binding of [3H]Win 55212-2 (5). Functional activity in the mouse vas deferens is also noted and used to distinguish agonists from potential antagonists. The key structural features for potent cannabinoid activity in this series are a bicyclic (naphthyl) substituent at the 3-position, a small (H) substituent at the 2-position, and an aminoethyl (morpholinoethyl) substituent at the 1-position. A 6-bromo analog, Win 54461 (31), has been identified as a potential cannabinoid receptor antagonist. Modeling experiments were done to develop a pharmacophore and also to compare AAI structures with those of classical cannabinoids. The fact that the cannabinoid AAIs arose out of work on a series of cyclooxygenase inhibitors make sense now that an endogenous cannabinoid ligand has been identified which is a derivative of arachidonic acid. Because of their unique structures and physical properties, AAIs provide useful tools to study the structure and function of the cannabinoid receptor(s).

Androgen receptor affinity of 5'-acyl furanosteroids.

Syntheses of 5'-acyl furanosteroids are described from the corresponding unsubstituted [3,2-b]furanosteroids using acid anhydrides and acid chlorides in the presence or absence of Lewis acids. New methods have been developed to prepare 5'-acetyl derivatives: reduction of a 5'-trichloroacetyl intermediate either by sodium formaldehyde sulfoxylate or with 10% Pd/C. Most of these 5'-acyl derivatives bind to the rat ventral prostate androgen receptor. However the antiandrogenic activity was diminished when compared with 4,5'-methylsulfonyl furanosteroid. Biological studies revealed that 5'-acyl furanosteroids were either androgens or modest antiandrogens. The electrostatic potential maps of the substructures of 3, 4, and 5'-acetyl syn- and anti-furanosteroids showed striking differences which may explain, to some extent, the lack of significant antiandrogenic activity of 5'-acyl furanosteroids.

Antiandrogenic steroidal sulfonylpyrazoles.

The steroidal sulfonylpyrazole 1 bound to the rat ventral prostate androgen receptor in vitro; it inhibited testosterone propionate induced increases in ventral prostate weight in vivo in the castrated, immature male rat with an ED50 of 15 mg/kg po. Compound 1 lacked androgenic activity in vivo in contrast to the parent steroidal pyrazole 5, which was both androgenic and antiandrogenic. The 2'- and 5'-methylsulfonyl isomers 6 and 6a did not bind to the androgen receptor. Introduction of an alkylsulfonyl at the N-1'-position has served, therefore, to isolate the intrinsic antiandrogenic properties of the steroidal heterocycle free of apparent hormone agonist properties. Structure-activity relationship studies revealed that a methylsulfonyl group at N-1' together with a C-17 alpha-substituent were the optimal combination for in vitro androgen receptor binding, in vivo antiandrogenic potency, and a lack of androgenic activity.

Iosulamide: a new intravenous cholangiocholecystographic medium.

Iosulamide is a bis-benzoic analogue of metrizoate that shows clear advantages in animal tests over meglumine iodipamide. The intravenous toxicity of iosulamide meglumine is considerably lower than that of iodipamide (Cholografin) in the mouse and rat. The LD50 in mice for iosulamide meglumine is 11,500 +/- 844 mg free acid/kg and for iodipamide is 2380 +/- 290 mg free acid/kg. A threefold difference in toxicity was seen in rats; the LD50 for iosulamide meglumine is 13,600 +/- 1710 mg free acid kg and for iodipamide is 4430 +/- 310 mg free acid/kg. Iosulamide is a highly effective contrast agent for cholangiocholecystographic visualization in cats and monkeys. speed and degree of opacification are equivalent to that of iodipamide at equimolar doses. Studies of biliary and urinary excretion patterns indicate iosulamide is rapidly excreted compared to iodipamide, while at the same time providing equal concentrations in bile on an mg/ml bile basis. A more efficient blood to bile clearance rate and a shorter blood half-life for iosulamide may account for the lower circulating blood levels and rapid total excretion compared to iodipamide. Iosulamide's rapid blood-bile clearance coupled with its extremely low toxicity may allow rapid administration of high doses, affording superior visualization and safety compared to iodipamide. It may also provide visualization of the liver parenchyma with computerized axial tomography, due to the pharmacokinetic profile that provides for high liver clearance but low blood levels. The emetic potential of iosulamide meglumine is quite low compared to iodipamide. Iosulamide meglumine also lacks hypotensive activity. Little or no effect on blood pressure was seen with iosulamide meglumine in cats or monkeys, whereas iodipamide caused marked transient, or sustained, reductions. Iosulamide meglumine did not produce significant toxic effects when administered as single daily intravenous injections to albino rats for three weeks, or in 10-minute intravenous infusions to rhesus monkeys 10 times in 14 days. Clinical trials with iosulamide are under way.