Synthesis and SAR studies of indole-based MK2 inhibitors.
Chemistry has been developed to specifically functionalize two structurally similar classes of indole-based MK2 inhibitors at positions prompted by a combination of X-ray crystallographic and computer assisted drug design. A gain in molecular potency was obtained by introducing aminomethyl groups to the lactam rings of 6-arylcarbamoyl-tetrahydro-beta-carbolinone and 6-arylcarbamoyl-dihydropyrazino[1,2-a]indolone MK2 inhibitors. In addition, improvements in molecular potency were achieved by expansion of the lactam from a 6- to 7-membered ring leading to 7-arylcarbamoyl-tetrahydro-[1,4]diazepino[1,2-a]indolones.
Xiong
Zhaoming
Z
Research and Development, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, Ridgefield, CT 06877, USA. zhaoming.xiong@boehringer-ingelheim.com
Gao
Donghong Amy
DA
Cogan
Derek A
DA
Goldberg
Daniel R
DR
Hao
Ming-Hong
MH
Moss
Neil
N
Pack
Edward
E
Pargellis
Chris
C
Skow
Donna
D
Trieselmann
Thomas
T
Werneburg
Brian
B
White
Andre
A
D000818:Animals; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D000099190:MAP-Kinase-Activated Kinase 2
D004791:Enzyme Inhibitors; D007211:Indoles; D047908:Intracellular Signaling Peptides and Proteins; D017346:Protein Serine-Threonine Kinases; D000099190:MAP-Kinase-Activated Kinase 2; C030374:indole