Details

Autor(en) / Beteiligte

• Schiffler, Matthew A
• Antonysamy, Stephen
• Bhattachar, Shobha N
• Campanale, Kristina M
• Chandrasekhar, Srinivasan
• Condon, Bradley
• Desai, Prashant V
• Fisher, Matthew J
• Groshong, Christopher
• Harvey, Anita
• Hickey, Michael J
• Hughes, Norman E
• Jones, Scott A
• Kim, Euibong J
• Kuklish, Steven L
• Luz, John G
• Norman, Bryan H
• Rathmell, Richard E
• Rizzo, John R
• Seng, Thomas W
• Thibodeaux, Stefan J
• Woods, Timothy A
• York, Jeremy S
• Yu, Xiao-Peng

Titel

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

Ist Teil von

• Journal of medicinal chemistry, 2016-01, Vol.59 (1), p.194-205

Ort / Verlag

United States: American Chemical Society

Erscheinungsjahr

2016

Quelle

MEDLINE

Beschreibungen/Notizen

• 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·H 3 PO 4 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.