Synthesis and biological evaluation of 6-aryl-6H-pyrrolo[3,4-d]pyridazine derivatives: high-affinity ligands to the alpha 2 delta subunit of voltage gated calcium channels.
A novel class of 6-aryl-6H-pyrrolo[3,4-d]pyridazine ligands for the alpha2delta subunit of voltage-gated calcium channels has been described. Substitutions in the aryl ring of the molecule were generally not tolerated, and resulted in diminished binding to the alpha2delta subunit. Modifications to the pyridazine ring revealed numerous permissive substitutions, and detailed SAR studies were carried out in this portion of the molecule. Replacement of the pyridazine ring methyl group with an aminomethyl functionality provided greatly improved potency over the initial lead. The initial lead compound displayed good rat pharmacokinetic properties, and was shown to be efficacious in the Chung model for neuropathic pain in rats.
Stearns
Brian A
BA
Department of Medicinal Chemistry, Merck Research Laboratories, MRLSDB2, 3535 General Atomics Court, San Diego, CA 92121, USA. brian_stearns@merck.com
Anker
Naomi
N
Arruda
Jeannie M
JM
Campbell
Brian T
BT
Chen
Chixu
C
Cramer
Merryl
M
Hu
Tao
T
Jiang
Xiaohui
X
Park
Kenneth
K
Ren
Kun Kun
KK
Sablad
Marciano
M
Santini
Angelina
A
Schaffhauser
Herve
H
Urban
Mark O
MO
Munoz
Benito
B
D000818:Animals; D015220:Calcium Channels / Q000378:metabolism*; D004353:Drug Evaluation, Preclinical / Q000379:methods; D008024:Ligands; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D021122:Protein Subunits / Q000378:metabolism*; D011724:Pyridazines / Q000138:chemical synthesis* / Q000378:metabolism*; D051381:Rats
D015220:Calcium Channels; D008024:Ligands; D021122:Protein Subunits; D011724:Pyridazines