Discovery of a Series of Pyrimidine Carboxamides as Inhibitors of Vanin-1

被引：7

作者：

Casimiro-Garcia, Agustin ^{[3
]}

Allais, Christophe ^{[1
]}

Brennan, Agnes ^{[2
]}

Choi, Chulho ^{[1
]}

Dower, Gabriela ^{[2
]}

Farley, Kathleen A. ^{[1
]}

Fleming, Margaret ^{[2
]}

Flick, Andrew ^{[1
]}

Frisbie, Richard K. ^{[1
]}

Hall, Justin ^{[1
]}

Hepworth, David ^{[3
]}

Jones, Hannah ^{[3
]}

Knafels, John D. ^{[1
]}

Kortum, Steve ^{[1
]}

Lovering, Frank E. ^{[3
]}

Mathias, John P. ^{[3
]}

Mohan, Sashi ^{[2
]}

Morgan, Paul M. ^{[2
]}

Parng, Chuenlei ^{[3
]}

Parris, Kevin ^{[1
]}

Pullen, Nick ^{[2
]}

Schlerman, Franklin ^{[2
]}

Stansfield, John ^{[4
]}

Strohbach, Joseph W. ^{[3
]}

Vajdos, Felix F. ^{[1
]}

Vincent, Fabien ^{[1
]}

Wang, Hong ^{[1
]}

Wang, Xiaolun ^{[3
]}

Webster, Robert ^{[3
]}

Wright, Stephen W. ^{[1
]}

机构：

[1] Pfizer Inc, Med Design, Groton, CT 06340 USA

[2] Pfizer Inc, Inflammat & Immunol Res Unit, Cambridge, MA 02139 USA

[3] Pfizer Inc, Med Design, Cambridge, MA 02139 USA

[4] Pfizer Inc, Early Clin Dev Nonclin Stat, Cambridge, MA 02139 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2022年 / 65卷 / 01期

关键词：

INFLAMMATORY BOWEL DISEASES; ASYMMETRIC-SYNTHESIS; COLITIS; BENZOPHENONE; GENE; PHOTOSENSITIZATION; PERMEABILITY; CHALLENGES; KETOPROFEN; INSIGHTS;

D O I：

10.1021/acs.jmedchem.1c01849

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A diaryl ketone series was identified as vanin-1 inhibitors from a high-throughput screening campaign. While this novel scaffold provided valuable probe 2 that was used to build target confidence, concerns over the ketone moiety led to the replacement of this group. The successful replacement of this moiety was achieved with pyrimidine carboxamides derived from cyclic secondary amines that were extensively characterized using biophysical and crystallographic methods as competitive inhibitors of vanin-1. Through optimization of potency and physicochemical and ADME properties, and guided by co-crystal structures with vanin-1, 3 was identified with a suitable profile for advancement into preclinical development.

引用

页码：757 / 784

页数：28

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