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. 2013 Jul 16;4(9):835-40.
doi: 10.1021/ml4001485. eCollection 2013 Sep 12.

Discovery, Design, and Optimization of Isoxazole Azepine BET Inhibitors

Victor S Gehling  1 , Michael C Hewitt  1 , Rishi G Vaswani  1 , Yves Leblanc  1 , Alexandre Côté  1 , Christopher G Nasveschuk  1 , Alexander M Taylor  1 , Jean-Christophe Harmange  1 , James E Audia  1 , Eneida Pardo  1 , Shivangi Joshi  1 , Peter Sandy  1 , Jennifer A Mertz  1 , Robert J Sims 3rd  1 , Louise Bergeron  1 , Barbara M Bryant  1 , Steve Bellon  1 , Florence Poy  1 , Hariharan Jayaram  1 , Ravichandran Sankaranarayanan  2 , Sreegouri Yellapantula  2 , Nandana Bangalore Srinivasamurthy  2 , Swarnakumari Birudukota  2 , Brian K Albrecht  1
Affiliations

Discovery, Design, and Optimization of Isoxazole Azepine BET Inhibitors

Victor S Gehling et al. ACS Med Chem Lett. .

Abstract

The identification of a novel series of small molecule BET inhibitors is described. Using crystallographic binding modes of an amino-isoxazole fragment and known BET inhibitors, a structure-based drug design effort lead to a novel isoxazole azepine scaffold. This scaffold showed good potency in biochemical and cellular assays and oral activity in an in vivo model of BET inhibition.

Keywords: BET inhibitors; MYC; bromodomain; fragments; isoxazoles.

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Figures

Figure 1
Figure 1
Crystal structures of acetyl-lysine, amino isoxazole 1, JQ1 (2),, and isoxazole azepine 3(101) in BRD4 BD1.
Scheme 1
Scheme 1. Synthesis of Isoxazole Azepine 3
Reagents: (a) (i) Pd2(dba)3, SPhos, K3PO4, n-BuOH, 100 °C; (ii) MeONa (cat.), MeOH (88% over 2 steps); (b) (i) Swern oxidation, (ii) Ti(OEt)4, (S)-t-butyl sulfinylamide (91% over 2 steps); (c) 2-(tert-butoxy)-2-oxoethyl)zinc(II) chloride, NMP, −10 °C (89%, d.r. 7:1 to 5:1); (d) (i) HCl, MeOH, (ii) i-PrMgBr, THF (80% over 2 steps); (e) PCl5, CH2Cl2 (65%); (f) Pd(PPh3)4, K2CO3, 4-chlorophenylboronic acid, toluene/water (10:1), 95 °C (82%); (g) (i) TFA (50 equiv), CHCl3, 36 °C, (ii) HATU, NH4Cl, Et3N, CH2Cl2 (80% over 2 steps).
Figure 2
Figure 2
MYC mRNA expression in Raji tumor in mice with compound 3 dosed 10 to 100 mpk PO (a) and a time course with compound 3 at 100 mpk PO (b).
See this image and copyright information in PMC

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