title: Discovery of novel non-carboxylic acid 5-amino-4-cyanopyrazole derivatives as potent and highly selective LPA1R antagonists.
abstract: High throughput screening (HTS) of our chemical library identified 3-alkylamino-2-aryl-5H-imidazo[1,2,b]pyrazol-7-carbonitrile 1 as a potent antagonist of the LPA1 receptor (LPA1R). Further evaluation of this class of compounds indicated that LPA1R antagonist activity originated from the degradation of the parent molecule in DMSO during the assay conditions. Here, we describe the isolation and characterization of the degradation products and their LPA1R antagonist activity. We further profiled these novel non-carboxylic acid LPA1R antagonists and demonstrated their inhibition of LPA-induced proliferation and contraction of normal human lung fibroblasts (NHLF).
authors.affiliation: Discovery Chemistry, Small Molecule Research, Pharmaceutical Research and Early Drug Development, Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ 07110, USA. Electronic address: sidduri@aunovamedchem.com.
authors.forename: Achyutharao
authors.initials: A
authors.lastname: Sidduri
authors.affiliation: Inflammation Discovery and Translational Area, Small Molecule Research, Pharmaceutical Research and Early Drug Development, Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ 07110, USA.
authors.forename: David C
authors.initials: DC
authors.lastname: Budd
authors.affiliation: Inflammation Discovery and Translational Area, Small Molecule Research, Pharmaceutical Research and Early Drug Development, Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ 07110, USA.
authors.forename: Maria E
authors.initials: ME
authors.lastname: Fuentes
authors.affiliation: Discovery Chemistry, Small Molecule Research, Pharmaceutical Research and Early Drug Development, Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ 07110, USA.
authors.forename: Ted
authors.initials: T
authors.lastname: Lambros
authors.affiliation: Inflammation Discovery and Translational Area, Small Molecule Research, Pharmaceutical Research and Early Drug Development, Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ 07110, USA.
authors.forename: Yonglin
authors.initials: Y
authors.lastname: Ren
authors.affiliation: Discovery Chemistry, Small Molecule Research, Pharmaceutical Research and Early Drug Development, Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ 07110, USA.
authors.forename: Vikram
authors.initials: V
authors.lastname: Roongta
authors.affiliation: Discovery Chemistry, Small Molecule Research, Pharmaceutical Research and Early Drug Development, Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ 07110, USA.
authors.forename: Ryan C
authors.initials: RC
authors.lastname: Schoenfeld
authors.affiliation: Discovery Chemistry, Small Molecule Research, Pharmaceutical Research and Early Drug Development, Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ 07110, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Gillespie
authors.affiliation: Inflammation Discovery and Translational Area, Small Molecule Research, Pharmaceutical Research and Early Drug Development, Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ 07110, USA.
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Stevenson
authors.affiliation: Discovery Technology, Small Molecule Research, Pharmaceutical Research and Early Drug Development, Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ 07110, USA.
authors.forename: Theresa
authors.initials: T
authors.lastname: Truitt
authors.affiliation: Discovery Chemistry, Small Molecule Research, Pharmaceutical Research and Early Drug Development, Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ 07110, USA.
authors.forename: Yimin
authors.initials: Y
authors.lastname: Qian
mesh_terms: D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008168:Lung / Q000166:cytology; D008246:Lysophospholipids / Q000037:antagonists & inhibitors / Q000494:pharmacology; D015394:Molecular Structure; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D049368:Receptors, Lysophosphatidic Acid / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D008246:Lysophospholipids; D011720:Pyrazoles; D049368:Receptors, Lysophosphatidic Acid; C000596632:5-amino-4-cyanopyrazole; C032881:lysophosphatidic acid
keywords: Novel LPA1 antagonists