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Joseph Pontillo,
Dongpei Wu,
Brett Ching,
Sarah Hudson,
Marc J Genicot,
Yinghong Gao,
Todd Ewing,
Beth A Fleck,
Kathleen Gogas,
Anna Aparicio, Hua Wang,
Jenny Wen,
Warren S Wade
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ABSTRACT: The design synthesis and SAR of a series of chiral ring-constrained norepinephrine reuptake inhibitors with improved physicochemical properties is described. Typical compounds are potent (IC(50)s<10 nM), selective against the other monoamine transporters, weak CYP2D6 inhibitors (IC(50)s>1 microM) and stable to oxidation by human liver microsomes. In addition, the compounds exhibit a favorable polarity profile.
Bioorganic & medicinal chemistry letters 12/2008; 18(23):6151-5. · 2.65 Impact Factor
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Sarah Hudson,
Mehrak Kiankarimi,
Wendy Eccles,
Wesley Dwight,
Yalda S Mostofi,
Marc J Genicot,
Beth A Fleck,
Kathleen Gogas,
Anna Aparicio, Hua Wang,
Jenny Wen,
Warren S Wade
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ABSTRACT: The synthesis and SAR of a series of chiral heterocyclic ring-constrained norepinephrine reuptake inhibitors are described. The best compounds compare favorably with atomoxetine in potency (IC(50)s<10 nM), selectivity against the other monoamine transporters, and inhibition of CYP2D6 (IC(50)s>1 microM). In addition, the compounds are generally more stable than atomoxetine to oxidative metabolism and thus are likely to have lower clearance in humans.
Bioorganic & medicinal chemistry letters 08/2008; 18(16):4491-4. · 2.65 Impact Factor
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Martin W Rowbottom,
Troy D Vickers,
Junko Tamiya,
Mingzhu Zhang,
Brian Dyck,
Jonathan Grey,
David Schwarz,
Christopher E Heise,
Michael Hedrick,
Jenny Wen,
Hui Tang, Hua Wang,
Andrew Fisher,
Anna Aparicio,
John Saunders,
Val S Goodfellow
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ABSTRACT: The design, synthesis, and SAR of a series of substituted spirohydantoins are described. Optimization of an in-house screening hit gave compounds that exhibited potent binding affinity and functional activity at MCH-R1.
Bioorganic & Medicinal Chemistry Letters 05/2007; 17(8):2171-8. · 2.55 Impact Factor
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Sarah Hudson,
Mehrak Kiankarimi,
Martin W Rowbottom,
Troy D Vickers,
Dongpei Wu,
Joseph Pontillo,
Brett Ching,
Wesley Dwight,
Val S Goodfellow,
David Schwarz,
Christopher E Heise,
Ajay Madan,
Jenny Wen,
William Ban, Hua Wang,
Warren S Wade
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ABSTRACT: The design, synthesis, and SAR of a series of retro bis-aminopyrrolidine ureas are described. Compounds from this series exhibited considerable binding affinity (Ki = 1 nM) and functional activity at MCH-R1, acceptable CYP2D6 inhibition, and good rat brain exposure.
Bioorganic & Medicinal Chemistry Letters 10/2006; 16(18):4922-30. · 2.55 Impact Factor