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.
Department of Medicinal Chemistry, Merck Research Laboratories, MRLSDB2, 3535 General Atomics Court, San Diego, CA 92121, USA. brian_stearns@merck.com
Brian A
BA
Stearns
Naomi
N
Anker
Jeannie M
JM
Arruda
Brian T
BT
Campbell
Chixu
C
Chen
Merryl
M
Cramer
Tao
T
Hu
Xiaohui
X
Jiang
Kenneth
K
Park
Kun Kun
KK
Ren
Marciano
M
Sablad
Angelina
A
Santini
Herve
H
Schaffhauser
Mark O
MO
Urban
Benito
B
Munoz
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