Dihydro-pyrano[2,3-b]pyridines and tetrahydro-1,8-naphthyridines as CB1 receptor inverse agonists: synthesis, SAR and biological evaluation

Christina B Madsen-Duggan; John S Debenham; Thomas F Walsh; Lin Yan; Pei Huo; Junying Wang; Xinchun Tong; Julie Lao; Tung M Fong; Jing Chen Xiao; Cathy R-R C Huang; Chun-Pyn Shen; D Sloan Stribling; Lauren P Shearman; Alison M Strack; Mark T Goulet; Jeffrey J Hale

doi:10.1016/j.bmcl.2010.04.071

Dihydro-pyrano[2,3-b]pyridines and tetrahydro-1,8-naphthyridines as CB1 receptor inverse agonists: synthesis, SAR and biological evaluation

Bioorg Med Chem Lett. 2010 Jun 15;20(12):3750-4. doi: 10.1016/j.bmcl.2010.04.071. Epub 2010 Apr 21.

Authors

Christina B Madsen-Duggan¹, John S Debenham, Thomas F Walsh, Lin Yan, Pei Huo, Junying Wang, Xinchun Tong, Julie Lao, Tung M Fong, Jing Chen Xiao, Cathy R-R C Huang, Chun-Pyn Shen, D Sloan Stribling, Lauren P Shearman, Alison M Strack, Mark T Goulet, Jeffrey J Hale

Affiliation

¹ Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA.

PMID: 20483606
DOI: 10.1016/j.bmcl.2010.04.071

Abstract

Synthesis and structure-activity relationships of cannabinoid-1 receptor (CB1R) inverse agonists based on dihydro-pyrano[2,3-b] pyridine and tetrahydro-1,8-naphtyridine scaffolds are presented. Rat food intake and pharmacokinetic evaluation of 13g, 13i, 13k and 17a revealed these compounds to be highly efficacious orally active modulators of CB1R.

MeSH terms

Administration, Oral
Animals
Eating
Humans
Naphthyridines / chemical synthesis
Naphthyridines / chemistry*
Naphthyridines / pharmacology
Pharmacokinetics
Pyridines / chemical synthesis
Pyridines / chemistry*
Pyridines / pharmacology
Rats
Receptor, Cannabinoid, CB1 / agonists*
Receptor, Cannabinoid, CB1 / drug effects
Receptor, Cannabinoid, CB2 / agonists
Receptor, Cannabinoid, CB2 / drug effects
Structure-Activity Relationship
Weight Loss / drug effects*

Substances

Naphthyridines
Pyridines
Receptor, Cannabinoid, CB1
Receptor, Cannabinoid, CB2