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
  • 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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