Structure-based design of 7-azaindole-pyrrolidine amides as inhibitors of 11ß-hydroxysteroid dehydrogenase type I.

Indole-pyrrolidines were identified as inhibitors of 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) by high-throughput screening. Optimisation of the initial hit through structure-based design led to 7-azaindole-derivatives, with the best analogues displaying single digit nanomolar IC(50) potency. The modeling hypotheses were confirmed by solving the X-ray co-crystal structure of one of the lead compounds. These compounds were selective against 11ß-hydroxysteroid dehydrogenase type 2 (selectivity ratio >200) and exhibited good inhibition of 11ß-HSD1 (IC(50)<1µM) in a cellular model (3T3L1 adipocytes).

Discovery and structure-activity relationships of pentanedioic acid diamides as potent inhibitors of 11beta-hydroxysteroid dehydrogenase type I.

Benzylamides of pentanedioic acid were identified as inhibitors of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) by high-throughput screening. Optimisation to 2-adamantyl amides yielded inhibitors with single digit nanomolar IC(50)s on the 11beta-HSD1 human isoform. The hydroxy adamantyl amide lead compound was selective against 11beta-hydroxysteroid dehydrogenase type 2 (selectivity ratio >1000) and displayed good inhibition of 11beta-HSD1 (IC(50)<0.1microM) in a cellular model (3T3L1 adipocytes).

Discovery and structure-guided drug design of inhibitors of 11beta-hydroxysteroid-dehydrogenase type I based on a spiro-carboxamide scaffold.

Spiro-carboxamides were identified as inhibitors of 11beta-hydroxysteroid-dehydrogenase type 1 by high-throughput screening. Structure-based drug design was used to optimise the initial hit yielding a sub-nanomolar IC(50) inhibitor (0.5nM) on human 11beta-HSD1 with a high binding efficiency index (BEI of 32.7) which was selective against human 11beta-HSD2 (selectivity ratio>200000).

Cardiovascular vagosympathetic activity in rats with ventromedial hypothalamic obesity.

OBJECTIVE: Rats with ventromedial hypothalamic lesion (VMH) are massively obese with endogenous hyperinsulinemia, insulin resistance, low sympathetic activity, and high parasympathetic activity, which are likely to induce hypertension. The goal was to follow in this model the long-term hemodynamic changes and to investigate the role of autonomic nervous system and insulin resistance in these changes. RESEARCH METHODS AND PROCEDURES: Heart rate and blood pressure were monitored for 12 weeks after operation using a telemetric system in VMH and sham rats. Plasma catecholamines and heart beta-adrenoceptors were measured. Glucose tolerance was studied after an intravenous glucose injection and insulin sensitivity during a euglycemic hyperinsulinemic clamp test. RESULTS: A marked bradycardia and only a mild increase in blood pressure occurred in VMH rats compared with sham animals. Response to autonomic-acting drugs showed an increase in heart vagal tone and responsiveness to a beta-agonist drug. Plasma catecholamine levels were markedly increased, and the density and affinity of heart beta-adrenoceptors were similar in VMH, sham, and control rats. Muscle glucose use was reduced by 1 week after operation in VMH animals. DISCUSSION: These results show the following in this model of massively obese rats with sympathetic impairment: 1). adrenal medulla secretion is increased, probably as a result of hyperinsulinemia and increased vagal activity; 2). cardiac responsiveness to beta-agonist stimulation is increased; and 3). despite these changes and suspected resistance to the vasodilative effect of insulin, blood pressure does not increase. We conclude that high vagal activity may be protective against hypertension associated with obesity.