Discovery and Characterization of 2-Acylaminoimidazole Microsomal Prostaglandin E Synthase-1 Inhibitors

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• 作者：Matthew A. Schiffler ; Stephen Antonysamy ; Shobha N. Bhattachar ; Kristina M. Campanale ; Srinivasan Chandrasekhar ; Bradley Condon ; Prashant V. Desai ; Matthew J. Fisher ; Christopher Groshong ; Anita Harvey ; Michael J. Hickey ; Norman E. Hughes ; Scott A. Jones ; Euibong J. Kim ; Steven L. Kuklish ; John G. Luz ; Bryan H. Norman ; Richard E. Rathmell ; John R. Rizzo ; Thomas W. Seng ; Stefan J. Thibodeaux ; Timothy A. Woods ; Jeremy S. York ; Xiao-Peng Yu
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：January 14, 2016
• 年：2016
• 卷：59
• 期：1
• 页码：194-205
• 全文大小：511K
• ISSN：1520-4804

文摘

As part of a program aimed at the discovery of antinociceptive therapy for inflammatory conditions, a screening hit was found to inhibit microsomal prostaglandin E synthase-1 (mPGES-1) with an IC₅₀ of 17.4 μM. Structural information was used to improve enzyme potency by over 1000-fold. Addition of an appropriate substituent alleviated time-dependent cytochrome P450 3A4 (CYP3A4) inhibition. Further structure–activity relationship (SAR) studies led to 8, which had desirable potency (IC₅₀ = 12 nM in an ex vivo human whole blood (HWB) assay) and absorption, distribution, metabolism, and excretion (ADME) properties. Studies on the formulation of 8 identified 8·H₃PO₄ as suitable for clinical development. Omission of a lipophilic portion of the compound led to 26, a readily orally bioavailable inhibitor with potency in HWB comparable to celecoxib. Furthermore, 26 was selective for mPGES-1 inhibition versus other mechanisms in the prostanoid pathway. These factors led to the selection of 26 as a second clinical candidate.