title: Synthesis, SAR, and series evolution of novel oxadiazole-containing 5-lipoxygenase activating protein inhibitors: discovery of 2-[4-(3-{(r)-1-[4-(2-amino-pyrimidin-5-yl)-phenyl]-1-cyclopropyl-ethyl}-[1,2,4]oxadiazol-5-yl)-pyrazol-1-yl]-N,N-dimethyl-acetamide (BI 665915).
abstract: The synthesis, structure-activity relationship (SAR), and evolution of a novel series of oxadiazole-containing 5-lipoxygenase-activating protein (FLAP) inhibitors are described. The use of structure-guided drug design techniques provided compounds that demonstrated excellent FLAP binding potency (IC50 < 10 nM) and potent inhibition of LTB4 synthesis in human whole blood (IC50 < 100 nM). Optimization of binding and functional potencies, as well as physicochemical properties resulted in the identification of compound 69 (BI 665915) that demonstrated an excellent cross-species drug metabolism and pharmacokinetics (DMPK) profile and was predicted to have low human clearance. In addition, 69 was predicted to have a low risk for potential drug-drug interactions due to its cytochrome P450 3A4 profile. In a murine ex vivo whole blood study, 69 demonstrated a linear dose-exposure relationship and a dose-dependent inhibition of LTB4 production.
authors: Department of Medicinal Chemistry, ‡Cardiometabolic Diseases, Boehringer Ingelheim Pharmaceuticals, Inc. , 900 Ridgebury Road, Ridgefield, Connecticut 06877, United States.
authors: Hidenori
authors: H
authors: Takahashi
authors: Doris
authors: D
authors: Riether
authors: Alessandra
authors: A
authors: Bartolozzi
authors: Todd
authors: T
authors: Bosanac
authors: Valentina
authors: V
authors: Berger
authors: Ralph
authors: R
authors: Binetti
authors: John
authors: J
authors: Broadwater
authors: Zhidong
authors: Z
authors: Chen
authors: Rebecca
authors: R
authors: Crux
authors: Stéphane
authors: S
authors: De Lombaert
authors: Rajvee
authors: R
authors: Dave
authors: Jonathon A
authors: JA
authors: Dines
authors: Tazmeen
authors: T
authors: Fadra-Khan
authors: Adam
authors: A
authors: Flegg
authors: Michael
authors: M
authors: Garrigou
authors: Ming-Hong
authors: MH
authors: Hao
authors: John
authors: J
authors: Huber
authors: J Matthew
authors: JM
authors: Hutzler
authors: Steven
authors: S
authors: Kerr
authors: Adrian
authors: A
authors: Kotey
authors: Weimin
authors: W
authors: Liu
authors: Ho Yin
authors: HY
authors: Lo
authors: Pui Leng
authors: PL
authors: Loke
authors: Paige E
authors: PE
authors: Mahaney
authors: Tina M
authors: TM
authors: Morwick
authors: Spencer
authors: S
authors: Napier
authors: Alan
authors: A
authors: Olague
authors: Edward
authors: E
authors: Pack
authors: Anil K
authors: AK
authors: Padyana
authors: David S
authors: DS
authors: Thomson
authors: Heather
authors: H
authors: Tye
authors: Lifen
authors: L
authors: Wu
authors: Renee M
authors: RM
authors: Zindell
authors: Asitha
authors: A
authors: Abeywardane
authors: Thomas
authors: T
authors: Simpson
mesh_terms: D000081:Acetamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism*; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006801:Humans; D016859:Lipoxygenase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D008968:Molecular Conformation; D010069:Oxadiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: C000597466:2-(4-(3-(1-(4-(2-aminopyrimidin-5-yl)phenyl)-1-cyclopropylethyl)-(1,2,4)oxadiazol-5-yl)pyrazol-1-yl)-N,N-dimethylacetamide; D000081:Acetamides; D016859:Lipoxygenase Inhibitors; D010069:Oxadiazoles; D001094:Arachidonate 5-Lipoxygenase