Solution-Phase parallel synthesis of 5-carboxamido 1-benzyl-3-(3-dimethylaminopropyloxy)-1H-pyrazoles as activators of soluble guanylate cyclase with improved oral bioavailability.
A lipophilicity constrained library of 5-carboxamido 1-benzyl-3-(3-dimethylaminopropyloxy)-1H-pyrazoles was prepared by solution-phase parallel synthesis with removal of acidic by-products using the strongly basic MP-carbonate resin. Compounds show both activation of soluble guanylate cyclase and inhibition of platelet aggregation. Compound 12 also shows 22% oral bioavailability in rats.
Selwood
D L
DL
Biological & Medicinal Chemistry, The Wolfson Institute For Biomedical Research, University College London, UK. d.selwood@ucl.ac.uk
Brummell
D G
DG
Glen
R C
RC
Goggin
M C
MC
Reynolds
K
K
Tatlock
M A
MA
Wishart
G
G
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D003094:Collagen / Q000494:pharmacology; D006152:Cyclic GMP / Q000032:analysis; D020536:Enzyme Activators / Q000138:chemical synthesis* / Q000494:pharmacology*; D006162:Guanylate Cyclase / Q000187:drug effects*; D020128:Inhibitory Concentration 50; D010974:Platelet Aggregation / Q000187:drug effects*; D011720:Pyrazoles / Q000138:chemical synthesis / Q000494:pharmacology; D051381:Rats
D020536:Enzyme Activators; D011720:Pyrazoles; D003094:Collagen; D006162:Guanylate Cyclase; D006152:Cyclic GMP