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. These compounds were selective against 11β-hydroxysteroid dehydrogenase type 2 (selectivity ratio >200) and exhibited good inhibition of 11β-HSD1 (IC(50)<1μM) in a cellular model (3T3L1 adipocytes).
Merck-Serono S.A., 9, Chemin des Mines, 1202 Geneva, Switzerland.
Eric
E
Valeur
Serge
S
Christmann-Franck
Franck
F
Lepifre
Denis
D
Carniato
Daniel
D
Cravo
Christine
C
Charon
Sophie
S
Bozec
Djordje
D
Musil
Per
P
Hillertz
Liliane
L
Doare
Fabien
F
Schmidlin
Marc
M
Lecomte
Melanie
M
Schultz
Didier
D
Roche
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007211:Indoles / Q000737:chemistry*; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D011759:Pyrrolidines / Q000737:chemistry*; D013329:Structure-Activity Relationship
C023422:7-azaindole dimer; D000577:Amides; D004791:Enzyme Inhibitors; D007211:Indoles; D011759:Pyrrolidines; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; C032519:pyrrolidine