2. Academic Validation
  3. 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)

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)

  • J Med Chem. 2015 Feb 26;58(4):1669-90. doi: 10.1021/jm501185j.
Hidenori Takahashi 1,  Doris Riether,  Alessandra Bartolozzi,  Todd Bosanac,  Valentina Berger,  Ralph Binetti,  John Broadwater,  Zhidong Chen,  Rebecca Crux,  Stéphane De Lombaert,  Rajvee Dave,  Jonathon A Dines,  Tazmeen Fadra-Khan,  Adam Flegg,  Michael Garrigou,  Ming-Hong Hao,  John Huber,  J Matthew Hutzler,  Steven Kerr,  Adrian Kotey,  Weimin Liu,  Ho Yin Lo,  Pui Leng Loke,  Paige E Mahaney,  Tina M Morwick,  Spencer Napier,  Alan Olague,  Edward Pack,  Anil K Padyana,  David S Thomson,  Heather Tye,  Lifen Wu,  Renee M Zindell,  Asitha Abeywardane,  Thomas Simpson
Affiliations

Affiliation

  • 1 Department of Medicinal Chemistry, ‡Cardiometabolic Diseases, Boehringer Ingelheim Pharmaceuticals, Inc. , 900 Ridgebury Road, Ridgefield, Connecticut 06877, United States.
PMID: 25671290 DOI: 10.1021/jm501185j
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.

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