title: Imidazopyridazinones as novel PDE7 inhibitors: SAR and in vivo studies in Parkinson's disease model.
abstract: The synthesis and structure-activity relationship studies of a series of compounds from imidazopyridazinone scaffold as PDE7 inhibitors are disclosed. Potent analogs such as compounds 7 (31nM), 8 (27nM), and 9 (12nM) were identified. The PDE selectivity and pharmacokinetic profile of compounds 7, 8 and 9 are also disclosed. The adequate CNS penetration of compound 7 in mice allowed it to be tested in the MPTP induced PD model and haloperidol induced catalepsy model to probe the differential pharmacology of PDE7 in the striatal pathway.
authors.affiliation: Glenmark Pharmaceuticals Limited, Navi Mumbai, Maharashtra 400709, India.
authors.forename: Abhisek
authors.initials: A
authors.lastname: Banerjee
authors.forename: Sandip
authors.initials: S
authors.lastname: Patil
authors.forename: Mahesh Y
authors.initials: MY
authors.lastname: Pawar
authors.forename: Srinivas
authors.initials: S
authors.lastname: Gullapalli
authors.forename: Praveen K
authors.initials: PK
authors.lastname: Gupta
authors.forename: Maulik N
authors.initials: MN
authors.lastname: Gandhi
authors.forename: Deepak K
authors.initials: DK
authors.lastname: Bhateja
authors.forename: Malini
authors.initials: M
authors.lastname: Bajpai
authors.forename: Ramachandra Rao
authors.initials: RR
authors.lastname: Sangana
authors.forename: Girish S
authors.initials: GS
authors.lastname: Gudi
authors.forename: Neelima
authors.initials: N
authors.lastname: Khairatkar-Joshi
authors.forename: Laxmikant A
authors.initials: LA
authors.lastname: Gharat
mesh_terms: D000818:Animals; D054708:Cyclic Nucleotide Phosphodiesterases, Type 7 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004355:Drug Stability; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology*; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008862:Microsomes, Liver / Q000737:chemistry / Q000378:metabolism; D015394:Molecular Structure; D010300:Parkinson Disease / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D011728:Pyridones / Q000737:chemistry / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D007093:Imidazoles; D007527:Isoenzymes; D011728:Pyridones; D011994:Recombinant Proteins; D054708:Cyclic Nucleotide Phosphodiesterases, Type 7; C517458:PDE7A protein, human; C517463:PDE7B protein, human