title: Synthesis and structure-activity relationships of novel arylpiperazines as potent and selective agonists of the melanocortin subtype-4 receptor.
abstract: The melanocortin receptors have been implicated as potential targets for a number of important therapeutic indications, including inflammation, sexual dysfunction, and obesity. We identified compound 1, an arylpiperazine attached to the dipeptide H-d-Tic-d-p-Cl-Phe-OH, as a novel melanocortin subtype-4 receptor (MC4R) agonist through iterative directed screening of nonpeptidyl G-protein-coupled receptor biased libraries. Structure-activity relationship (SAR) studies demonstrated that substitutions at the ortho position of the aryl ring improved binding and functional potency. For example, the o-isopropyl-substituted compound 29 (K(i) = 720 nM) possessed 9-fold better binding affinity compared to the unsubstituted aryl ring (K(i) = 6600 nM). Sulfonamide 39 (K(i) = 220 nM) fills this space with a polar substituent, resulting in a further 2-fold improvement in binding affinity. The most potent compounds such as the diethylamine 44 (K(i) = 60 nM) contain a basic group at this position. Basic heterocycles such as the imidazole 50 (K(i) = 110 nM) were similarly effective. We also demonstrated good oral bioavailability for sulfonamide 39.
authors.affiliation: Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285, USA. timrich@lilly.com
authors.forename: Timothy I
authors.initials: TI
authors.lastname: Richardson
authors.forename: Paul L
authors.initials: PL
authors.lastname: Ornstein
authors.forename: Karin
authors.initials: K
authors.lastname: Briner
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Fisher
authors.forename: Ryan T
authors.initials: RT
authors.lastname: Backer
authors.forename: C Kelly
authors.initials: CK
authors.lastname: Biggers
authors.forename: Michael P
authors.initials: MP
authors.lastname: Clay
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Emmerson
authors.forename: Larry W
authors.initials: LW
authors.lastname: Hertel
authors.forename: Hansen M
authors.initials: HM
authors.lastname: Hsiung
authors.forename: Saba
authors.initials: S
authors.lastname: Husain
authors.forename: Steven D
authors.initials: SD
authors.lastname: Kahl
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Lee
authors.forename: Terry D
authors.initials: TD
authors.lastname: Lindstrom
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Martinelli
authors.forename: John P
authors.initials: JP
authors.lastname: Mayer
authors.forename: Jeffery T
authors.initials: JT
authors.lastname: Mullaney
authors.forename: Thomas P
authors.initials: TP
authors.lastname: O'Brien
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Pawlak
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Revell
authors.forename: Jikesh
authors.initials: J
authors.lastname: Shah
authors.forename: John M
authors.initials: JM
authors.lastname: Zgombick
authors.forename: R Jason
authors.initials: RJ
authors.lastname: Herr
authors.forename: Alex
authors.initials: A
authors.lastname: Melekhov
authors.forename: Peter B
authors.initials: PB
authors.lastname: Sampson
authors.forename: Chi-Hsin R
authors.initials: CH
authors.lastname: King
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D001682:Biological Availability; D002460:Cell Line; D000242:Cyclic AMP / Q000096:biosynthesis; D006801:Humans; D008024:Ligands; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D011916:Rats, Inbred F344; D044105:Receptor, Melanocortin, Type 4 / Q000819:agonists* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; D010879:Piperazines; D044105:Receptor, Melanocortin, Type 4; D000242:Cyclic AMP