title: Structure-activity relationships of a series of pyrrolo[3,2-d]pyrimidine derivatives and related compounds as neuropeptide Y5 receptor antagonists.
abstract: Neuropeptide Y (NPY) has been shown to play an important role in the regulation of food intake and energy balance. Pharmacological data suggests that the Y5 receptor subtype contributes to the effects of NPY on appetite, and therefore a Y5 antagonist might be a useful therapeutic agent for the treatment of obesity. In attempts to identify potential Y5 antagonists, a series of pyrrolo[3, 2-d]pyrimidine derivatives was prepared and evaluated for their ability to bind to Y5 receptors in vitro. We report here the synthesis and initial structure-activity relationship investigations for this class of compounds. The target compounds were prepared by a variety of synthetic routes designed to modify both the substitution and the heterocyclic core of the pyrrolo[3,2-d]pyrimidine lead 1. In addition to identifying several potent Y5 antagonists for evaluation as potential antiobesity agents, a pharmacophore model for the human Y5 receptor is presented.
authors.affiliation: Department of Small Molecule Drug Discovery, Amgen, Inc., One Amgen Center Drive, Thousand Oaks, California 91320-1789, USA. markn@amgen.com
authors.forename: M H
authors.initials: MH
authors.lastname: Norman
authors.forename: N
authors.initials: N
authors.lastname: Chen
authors.forename: Z
authors.initials: Z
authors.lastname: Chen
authors.forename: C
authors.initials: C
authors.lastname: Fotsch
authors.forename: C
authors.initials: C
authors.lastname: Hale
authors.forename: N
authors.initials: N
authors.lastname: Han
authors.forename: R
authors.initials: R
authors.lastname: Hurt
authors.forename: T
authors.initials: T
authors.lastname: Jenkins
authors.forename: J
authors.initials: J
authors.lastname: Kincaid
authors.forename: L
authors.initials: L
authors.lastname: Liu
authors.forename: Y
authors.initials: Y
authors.lastname: Lu
authors.forename: O
authors.initials: O
authors.lastname: Moreno
authors.forename: V J
authors.initials: VJ
authors.lastname: Santora
authors.forename: J D
authors.initials: JD
authors.lastname: Sonnenberg
authors.forename: W
authors.initials: W
authors.lastname: Karbon
mesh_terms: D019440:Anti-Obesity Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D004353:Drug Evaluation, Preclinical; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008566:Membranes / Q000378:metabolism; D008954:Models, Biological; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D017476:Receptors, Neuropeptide Y / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D019440:Anti-Obesity Agents; D011743:Pyrimidines; D017476:Receptors, Neuropeptide Y; C100568:neuropeptide Y5 receptor; C030986:pyrimidine