SAR of a series of 5,6-dihydro-(9H)-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-α]pyridines as potent inhibitors of human eosinophil phosphodiesterase

被引：29

作者：

Duplantier, Allen J. ^{[1
]}

Bachert, Elizabeth L. ^{[1
]}

Cheng, John B. ^{[1
]}

Cohan, Victoria L. ^{[1
]}

Jenkinson, Teresa H. ^{[1
]}

Kraus, Kenneth G. ^{[1
]}

McKechney, Michael W. ^{[1
]}

Pillar, Joann D. ^{[1
]}

Watson, John W. ^{[1
]}

机构：

[1] Pfizer Global Res & Dev, Groton, CT 06340 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2007年 / 50卷 / 02期

关键词：

D O I：

10.1021/jm060904g

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The potency and physical properties of a previously reported 7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine series of human eosinophil phosphodiesterase inhibitors were improved by tying the lactam moiety into a triazolo ring. The resulting 5,6-dihydro-(9H)-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-alpha]pyridine series provided nonionizable analogs with melting point properties suitable for micronization. Substitution at the 3-position of the 5,6-dihydro-(9H)-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-alpha]pyridine tricycle led to a 2-thienyl analog, 19 (tofimilast), a potent PDE4 inhibitor with low oral bioavailability and no emesis-associated behaviors in ferrets at plasma concentrations up to 152 ng/mL.

引用

页码：344 / 349

页数：6

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[1] COPD: current therapeutic interventions and future approaches [J].