4H-Thieno[3,2-c]chromene based inhibitors of Notum Pectinacetylesterase

Qiang Han; Praveen K Pabba; Joseph Barbosa; Ross Mabon; Jason P Healy; Michael W Gardyan; Kristen M Terranova; Robert Brommage; Andrea Y Thompson; James M Schmidt; Alan G E Wilson; Xiaolian Xu; James E Tarver Jr; Kenneth G Carson

doi:10.1016/j.bmcl.2016.01.038

4H-Thieno[3,2-c]chromene based inhibitors of Notum Pectinacetylesterase

Bioorg Med Chem Lett. 2016 Feb 15;26(4):1184-7. doi: 10.1016/j.bmcl.2016.01.038. Epub 2016 Jan 18.

Affiliations

¹ Lexicon Pharmaceuticals, 350 Carter Road, Princeton, NJ 08540, United States.
² Lexicon Pharmaceuticals, 8800 Technology Forest Place, The Woodlands, TX 77381, United States.
³ Lexicon Pharmaceuticals, 350 Carter Road, Princeton, NJ 08540, United States. Electronic address: james.tarver2@gmail.com.

PMID: 26821819
DOI: 10.1016/j.bmcl.2016.01.038

Abstract

A group of small molecule thienochromenes inhibitors of Notum Pectinacetylesterase are described. We developed SAR on three series based on carbon, oxygen and sulfur replacement of the 5-position. In each series, highly potent Notum Pectinacetylesterase inhibitors were identified.

Keywords: Femur cortical bone thickness; Notum Pectinacetylesterase; Osteroporosis; SAR; Thienochromene.

MeSH terms

Animals
Benzopyrans / chemistry*
Benzopyrans / pharmacokinetics
Benzopyrans / therapeutic use
Enzyme Inhibitors / chemistry*
Enzyme Inhibitors / pharmacokinetics
Enzyme Inhibitors / therapeutic use
Esterases / antagonists & inhibitors*
Esterases / metabolism
Femur / physiology
Half-Life
Humans
Inhibitory Concentration 50
Male
Mice
Osteoporosis / drug therapy
Osteoporosis / physiopathology
Protein Binding
Structure-Activity Relationship

Substances

Benzopyrans
Enzyme Inhibitors
Esterases
Notum protein, human