title: Aminopyridinecarboxamide-based inhaled IKK-2 inhibitors for asthma and COPD: Structure-activity relationship.
abstract: Installation of sites for metabolism in the lead compound PHA-767408 was the key focus of the IKK-2 inhaled program. This paper reports our efforts to identify a novel series of aminopyridinecarboxamide-based IKK-2 inhibitors, which display low nanomolar potency against IKK-2 with long duration of action (DOA), and metabolically labile to phase I and/or phase II metabolizing enzymes with potential capability for multiple routes of clearance. Several compounds have demonstrated their potential usefulness in the treatment of asthma and chronic obstructive pulmonary disease (COPD).
authors.affiliation: Department of Medicinal Chemistry, Pfizer Inc., 700 Chesterfield Parkway West, St. Louis, MO 63017, USA. jin.xie@pfizer.com
authors.forename: Jin
authors.initials: J
authors.lastname: Xie
authors.forename: Gennadiy I
authors.initials: GI
authors.lastname: Poda
authors.forename: Yiding
authors.initials: Y
authors.lastname: Hu
authors.forename: Natalie X
authors.initials: NX
authors.lastname: Chen
authors.forename: Richard F
authors.initials: RF
authors.lastname: Heier
authors.forename: Serge G
authors.initials: SG
authors.lastname: Wolfson
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Reding
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Lennon
authors.forename: Ravi G
authors.initials: RG
authors.lastname: Kurumbail
authors.forename: Shaun R
authors.initials: SR
authors.lastname: Selness
authors.forename: Xiong
authors.initials: X
authors.lastname: Li
authors.forename: Nandini N
authors.initials: NN
authors.lastname: Kishore
authors.forename: Cynthia D
authors.initials: CD
authors.lastname: Sommers
authors.forename: Lori
authors.initials: L
authors.lastname: Christine
authors.forename: Sheri L
authors.initials: SL
authors.lastname: Bonar
authors.forename: Neetu
authors.initials: N
authors.lastname: Venkatraman
authors.forename: Sumathy
authors.initials: S
authors.lastname: Mathialagan
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Brustkern
authors.forename: Horng-Chih
authors.initials: HC
authors.lastname: Huang
mesh_terms: D000280:Administration, Inhalation; D000631:Aminopyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001249:Asthma / Q000188:drug therapy*; D001667:Binding, Competitive; D015195:Drug Design; D057809:HEK293 Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors*; D007191:Indazoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D007539:Isonicotinic Acids / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D008862:Microsomes, Liver / Q000187:drug effects; D008958:Models, Molecular; D015394:Molecular Structure; D058990:Molecular Targeted Therapy; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D010627:Phenethylamines / Q000378:metabolism; D026902:Potassium Channel Blockers / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy*; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000378:metabolism
chemical_list: D000631:Aminopyridines; D007191:Indazoles; D007539:Isonicotinic Acids; C548309:PHA 408; D010627:Phenethylamines; D026902:Potassium Channel Blockers; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D013449:Sulfonamides; D009536:Niacinamide; D051550:I-kappa B Kinase; C063533:dofetilide