title: Solution-Phase parallel synthesis of 5-carboxamido 1-benzyl-3-(3-dimethylaminopropyloxy)-1H-pyrazoles as activators of soluble guanylate cyclase with improved oral bioavailability.
abstract: 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.
authors.affiliation: Biological & Medicinal Chemistry, The Wolfson Institute For Biomedical Research, University College London, UK. d.selwood@ucl.ac.uk
authors.forename: D L
authors.initials: DL
authors.lastname: Selwood
authors.forename: D G
authors.initials: DG
authors.lastname: Brummell
authors.forename: R C
authors.initials: RC
authors.lastname: Glen
authors.forename: M C
authors.initials: MC
authors.lastname: Goggin
authors.forename: K
authors.initials: K
authors.lastname: Reynolds
authors.forename: M A
authors.initials: MA
authors.lastname: Tatlock
authors.forename: G
authors.initials: G
authors.lastname: Wishart
mesh_terms: 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
chemical_list: D020536:Enzyme Activators; D011720:Pyrazoles; D003094:Collagen; D006162:Guanylate Cyclase; D006152:Cyclic GMP