Yi Luo

Publications (3)13.43 Total impact

• Article: Structure- and Property-Based Design of Aminooxazoline Xanthenes as Selective, Orally Efficacious, and CNS Penetrable BACE Inhibitors for the Treatment of Alzheimer's Disease.

  Hongbing Huang, Daniel S La, Alan C Cheng, Douglas A Whittington, Vinod F Patel, Kui Chen, Thomas A Dineen, Oleg Epstein, Russell Graceffa, Dean Hickman, Y-H Kiang, Steven Louie, Yi Luo, Robert C Wahl, Paul H Wen, Stephen Wood, Robert T Fremeau
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  ABSTRACT: A structure- and property-based drug design approach was employed to identify aminooxazoline xanthenes as potent and selective human β-secretase inhibitors. These compounds exhibited good isolated enzyme, cell potency, and selectivity against the structurally related aspartyl protease cathepsin D. Our efforts resulted in the identification of a potent, orally bioavailable CNS penetrant compound that exhibited in vivo efficacy. A single oral dose of compound 11a resulted in a significant reduction of CNS Aβ40 in naive rats.
  Journal of Medicinal Chemistry 08/2012; · 4.80 Impact Factor
• Article: Establishing the Relationship between In Vitro Potency, Pharmacokinetic, and Pharmacodynamic Parameters in a Series of Orally Available, Hydroxyethylamine-Derived β-Secretase Inhibitors.

  Stephen Wood, Paul H Wen, Jianhua Zhang, Li Zhu, Yi Luo, Safura Babu-Khan, Kui Chen, Roger Pham, Joel Esmay, Thomas A Dineen, Matthew R Kaller, Matthew M Weiss, Stephen A Hitchcock, Martin Citron, Wenge Zhong, Dean Hickman, Toni Williamson
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  ABSTRACT: Sequential proteolytic cleavage of the amyloid precursor protein (APP) by β-site APP-cleaving enzyme 1 (BACE1) and the γ-secretase complex produces the amyloid-β peptide (Aβ), which is believed to play a critical role in the pathology of Alzheimer's disease (AD). The aspartyl protease BACE1 catalyzes the rate-limiting step in the production of Aβ, and as such it is considered to be an important target for drug development in AD. The development of a BACE1 inhibitor therapeutic has proven to be difficult. The active site of BACE1 is relatively large. Consequently, to achieve sufficient potency, many BACE1 inhibitors have required unfavorable physicochemical properties such as high molecular weight and polar surface area that are detrimental to efficient passage across the blood-brain barrier. Using a rational drug design approach we have designed and developed a new series of hydroxyethylamine-based inhibitors of BACE1 capable of lowering Aβ levels in the brains of rats after oral administration. Herein we describe the in vitro and in vivo characterization of two of these molecules and the overall relationship of compound properties [e.g., in vitro permeability, P-glycoprotein (P-gp) efflux, metabolic stability, and pharmacological potency] to the in vivo pharmacodynamic effect with more than 100 compounds across the chemical series. We demonstrate that high in vitro potency for BACE1 was not sufficient to provide central efficacy. A combination of potency, high permeability, low P-gp-mediated efflux, and low clearance was required for compounds to produce robust central Aβ reduction after oral dosing.
  Journal of Pharmacology and Experimental Therapeutics 08/2012; 343(2):460-7. · 3.83 Impact Factor
• Article: From fragment screening to in vivo efficacy: optimization of a series of 2-aminoquinolines as potent inhibitors of beta-site amyloid precursor protein cleaving enzyme 1 (BACE1).

  Yuan Cheng, Ted C Judd, Michael D Bartberger, James Brown, Kui Chen, Robert T Fremeau, Dean Hickman, Stephen A Hitchcock, Brad Jordan, Vivian Li, [......], Yi Luo, Klaus Michelsen, Thomas Nixey, Timothy S Powers, Claire Rattan, E Allen Sickmier, David J St Jean, Robert C Wahl, Paul H Wen, Stephen Wood
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  ABSTRACT: Using fragment-based screening of a focused fragment library, 2-aminoquinoline 1 was identified as an initial hit for BACE1. Further SAR development was supported by X-ray structures of BACE1 cocrystallized with various ligands and molecular modeling studies to expedite the discovery of potent compounds. These strategies enabled us to integrate the C-3 side chain on 2-aminoquinoline 1 extending deep into the P2' binding pocket of BACE1 and enhancing the ligand's potency. We were able to improve the BACE1 potency to subnanomolar range, over 10(6)-fold more potent than the initial hit (900 μM). Further elaboration of the physical properties of the lead compounds to those more consistent with good blood-brain barrier permeability led to inhibitors with greatly improved cellular activity and permeability. Compound 59 showed an IC(50) value of 11 nM on BACE1 and cellular activity of 80 nM. This compound was advanced into rat pharmacokinetic and pharmacodynamic studies and demonstrated significant reduction of Aβ levels in cerebrospinal fluid (CSF).
  Journal of Medicinal Chemistry 06/2011; 54(16):5836-57. · 4.80 Impact Factor