Synthesis and structure-activity relationships of novel arylpiperazines as potent and selective agonists of the melanocortin subtype-4 receptor.
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.
Richardson
Timothy I
TI
Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285, USA. timrich@lilly.com
Ornstein
Paul L
PL
Briner
Karin
K
Fisher
Matthew J
MJ
Backer
Ryan T
RT
Biggers
C Kelly
CK
Clay
Michael P
MP
Emmerson
Paul J
PJ
Hertel
Larry W
LW
Hsiung
Hansen M
HM
Husain
Saba
S
Kahl
Steven D
SD
Lee
Jonathan A
JA
Lindstrom
Terry D
TD
Martinelli
Michael J
MJ
Mayer
John P
JP
Mullaney
Jeffery T
JT
O'Brien
Thomas P
TP
Pawlak
Joseph M
JM
Revell
Kevin D
KD
Shah
Jikesh
J
Zgombick
John M
JM
Herr
R Jason
RJ
Melekhov
Alex
A
Sampson
Peter B
PB
King
Chi-Hsin R
CH
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
D008024:Ligands; D010879:Piperazines; D044105:Receptor, Melanocortin, Type 4; D000242:Cyclic AMP