Pyridopyrimidine based cannabinoid-1 receptor inverse agonists: Synthesis and biological evaluation

John S Debenham; Christina B Madsen-Duggan; Junying Wang; Xinchun Tong; Julie Lao; Tung M Fong; Marie-Therese Schaeffer; Jing Chen Xiao; Cathy C R-R Huang; Chun-Pyn Shen; D Sloan Stribling; Lauren P Shearman; Alison M Strack; D Euan Macintyre; Jeffrey J Hale; Thomas F Walsh

doi:10.1016/j.bmcl.2009.03.005

Pyridopyrimidine based cannabinoid-1 receptor inverse agonists: Synthesis and biological evaluation

Bioorg Med Chem Lett. 2009 May 1;19(9):2591-4. doi: 10.1016/j.bmcl.2009.03.005. Epub 2009 Mar 9.

Authors

John S Debenham¹, Christina B Madsen-Duggan, Junying Wang, Xinchun Tong, Julie Lao, Tung M Fong, Marie-Therese Schaeffer, Jing Chen Xiao, Cathy C R-R Huang, Chun-Pyn Shen, D Sloan Stribling, Lauren P Shearman, Alison M Strack, D Euan Macintyre, Jeffrey J Hale, Thomas F Walsh

Affiliation

¹ Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA.

PMID: 19328684
DOI: 10.1016/j.bmcl.2009.03.005

Abstract

The synthesis, SAR and binding affinities are described for cannabinoid-1 receptor (CB1R) specific inverse agonists based on pyridopyrimidine and heterotricyclic scaffolds. Food intake and pharmacokinetic evaluation of several of these compounds indicate that they are effective orally active modulators of CB1R.

MeSH terms

Administration, Oral
Animals
Cannabinoid Receptor Agonists*
Cannabinoids / chemistry
Chemistry, Pharmaceutical / methods
Drug Design
Humans
Inhibitory Concentration 50
Obesity / drug therapy*
Protein Structure, Tertiary
Pyrimidines / chemistry*
Rats
Receptor, Cannabinoid, CB1 / agonists
Receptor, Cannabinoid, CB2 / agonists
Structure-Activity Relationship

Substances

Cannabinoid Receptor Agonists
Cannabinoids
Pyrimidines
Receptor, Cannabinoid, CB1
Receptor, Cannabinoid, CB2
pyrimidine