title: Preparation and optimization of pyrazolo[1,5-a]pyrimidines as new potent PDE4 inhibitors.
abstract: A new series of pyrazolo[1,5-a]pyrimidines exemplified by compound 1, has been identified with moderate activity (IC50=165nM), following GSK256066 rescaffolding. Compound 1 optimization at positions 2, 3, 6 and 7 gave compound 10 with high in vitro activity (IC50=0.7nM). Modeling studies based on the PDB structure 3GWT with compound 5 showed the expected overlay with the carboxamide, the aryl moiety and the sulfone. Cyclisation of the primary amide to the 5 position of the pyrazolo[1,5-a]pyrimidines scaffold afforded compounds 15 and 16 with 200-fold enhancement in activity and cellular potency.
authors.affiliation: Sanofi Research Center, 13 Quai Jules Guesde, 94400 Vitry-sur-Seine, France.
authors.forename: Jacques
authors.initials: J
authors.lastname: Le Roux
authors.affiliation: Sanofi Ophthalmology, 17 Rue Moreau, 75012 Paris, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Leriche
authors.affiliation: Sanofi Ophthalmology, 17 Rue Moreau, 75012 Paris, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Chamiot-Clerc
authors.affiliation: SYN|thesis Med Chem, 399 Royal Parade, Parkville, VIC 3052, Australia.
authors.forename: John
authors.initials: J
authors.lastname: Feutrill
authors.affiliation: Sanofi Research Center, 13 Quai Jules Guesde, 94400 Vitry-sur-Seine, France. Electronic address: frank.halley@sanofi.com.
authors.forename: Frank
authors.initials: F
authors.lastname: Halley
authors.affiliation: Sanofi Research Center, 13 Quai Jules Guesde, 94400 Vitry-sur-Seine, France.
authors.forename: David
authors.initials: D
authors.lastname: Papin
authors.affiliation: Sanofi Open innovation Access Plateform, 16 Rue d'Ankara, 67000 Strasbourg, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Derimay
authors.affiliation: Sanofi Open innovation Access Plateform, 16 Rue d'Ankara, 67000 Strasbourg, France.
authors.forename: Christelle
authors.initials: C
authors.lastname: Mugler
authors.affiliation: Sanofi Ophthalmology, 17 Rue Moreau, 75012 Paris, France.
authors.forename: Claudine
authors.initials: C
authors.lastname: Grépin
authors.affiliation: Sanofi Research Center, 13 Quai Jules Guesde, 94400 Vitry-sur-Seine, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Schio
mesh_terms: D000634:Aminoquinolines / Q000737:chemistry; D045744:Cell Line, Tumor; D000242:Cyclic AMP / Q000096:biosynthesis; D006801:Humans; D008958:Models, Molecular; D058988:Phosphodiesterase 4 Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D011720:Pyrazoles / Q000138:chemical synthesis / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: C549469:6-((3-((dimethylamino)carbonyl)phenyl)sulfonyl)-8-methyl-4-((3-methyloxyphenyl)amino)-3-quinolinecarboxamide; D000634:Aminoquinolines; D058988:Phosphodiesterase 4 Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D013450:Sulfones; D000242:Cyclic AMP
keywords: Carboxamide; PDE4 inhibitor; cAMP