RESUMO
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. Bladder function was assessed by cystometry in conscious rats treated by intravenous solifenacin (1 mg/kg). Subsequently, erectile function was assessed under anesthesia following electrical stimulation of the cavernous nerve in presence of intravenous sildenafil (0.3 mg/kg). GK rats displayed detrusor overactivity with a significant increase in frequency/amplitude of nonvoiding contractions during the filling phase, together with an increase in bladder capacity, intercontraction interval, voided volume, and maximal pressure of voiding contraction. Solifenacin significantly decreased parameters characterizing voiding contractions without modifying voiding efficiency. Erectile function in GK rats was markedly impaired and remained so after sildenafil treatment despite a significant improvement. GK rats display both bladder and erectile dysfunctions and respond at least partially to standard-of-care treatments for each disorder, thus representing a suitable model to investigate the pathophysiology and assess the efficacy of new therapeutic agents for Type 2 diabetes-associated bladder and erectile complications.
Assuntos
Complicações do Diabetes/fisiopatologia , Diabetes Mellitus Tipo 2/complicações , Disfunção Erétil/etiologia , Doenças da Bexiga Urinária/etiologia , Animais , Diabetes Mellitus Tipo 2/fisiopatologia , Masculino , Ereção Peniana/efeitos dos fármacos , Piperazinas/farmacologia , Purinas/farmacologia , Quinuclidinas/farmacologia , Ratos , Ratos Wistar , Citrato de Sildenafila , Succinato de Solifenacina , Sulfonas/farmacologia , Tetra-Hidroisoquinolinas/farmacologia , Bexiga Urinária/fisiologia , Doenças da Bexiga Urinária/tratamento farmacológico , Doenças da Bexiga Urinária/fisiopatologia , Micção/efeitos dos fármacos , Micção/fisiologia , Agentes Urológicos/farmacologia , Vasodilatadores/farmacologiaRESUMO
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).
Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Amidas/farmacologia , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Indóis/química , Pirrolidinas/química , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/metabolismo , Amidas/síntese química , Amidas/química , Animais , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Camundongos , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
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).
Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Amidas/química , Inibidores Enzimáticos/química , Compostos de Espiro/química , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/metabolismo , Amidas/farmacologia , Sítios de Ligação , Simulação por Computador , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Humanos , Compostos de Espiro/farmacologia , Relação Estrutura-AtividadeRESUMO
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).