title: Synthesis and SAR studies of indole-based MK2 inhibitors.
abstract: 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.
authors.affiliation: Research and Development, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, Ridgefield, CT 06877, USA. zhaoming.xiong@boehringer-ingelheim.com
authors.forename: Zhaoming
authors.initials: Z
authors.lastname: Xiong
authors.forename: Donghong Amy
authors.initials: DA
authors.lastname: Gao
authors.forename: Derek A
authors.initials: DA
authors.lastname: Cogan
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Goldberg
authors.forename: Ming-Hong
authors.initials: MH
authors.lastname: Hao
authors.forename: Neil
authors.initials: N
authors.lastname: Moss
authors.forename: Edward
authors.initials: E
authors.lastname: Pack
authors.forename: Chris
authors.initials: C
authors.lastname: Pargellis
authors.forename: Donna
authors.initials: D
authors.lastname: Skow
authors.forename: Thomas
authors.initials: T
authors.lastname: Trieselmann
authors.forename: Brian
authors.initials: B
authors.lastname: Werneburg
authors.forename: Andre
authors.initials: A
authors.lastname: White
mesh_terms: 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
chemical_list: D004791:Enzyme Inhibitors; D007211:Indoles; D047908:Intracellular Signaling Peptides and Proteins; D017346:Protein Serine-Threonine Kinases; D000099190:MAP-Kinase-Activated Kinase 2; C030374:indole