Bladder and erectile dysfunctions in the Type 2 diabetic Goto-Kakizaki rat.

Despite the fact that urogenito-sexual complications significantly impact the quality of life of diabetic patients, a robust in vivo experimental model is lacking. Bladder and erectile function in the Type 2 diabetic Goto-Kakizaki (GK) rat and responses to standard-of-care treatments for each disorder have been assessed. GK rats (n = 25, 18-wk-old, GK/Par colony) and age-matched Wistar rats (n = 23), characterized for their metabolic parameters, were used.

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

Indole-pyrrolidines were identified as inhibitors of 11β-hydroxysteroid dehydrogenase type 1 (11β-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.

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.

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.