title: Application of structure-based drug design and parallel chemistry to identify selective, brain penetrant, in vivo active phosphodiesterase 9A inhibitors.
abstract: Phosphodiesterase 9A inhibitors have shown activity in preclinical models of cognition with potential application as novel therapies for treating Alzheimer's disease. Our clinical candidate, PF-04447943 (2), demonstrated acceptable CNS permeability in rats with modest asymmetry between central and peripheral compartments (free brain/free plasma = 0.32; CSF/free plasma = 0.19) yet had physicochemical properties outside the range associated with traditional CNS drugs. To address the potential risk of restricted CNS penetration with 2 in human clinical trials, we sought to identify a preclinical candidate with no asymmetry in rat brain penetration and that could advance into development. Merging the medicinal chemistry strategies of structure-based design with parallel chemistry, a novel series of PDE9A inhibitors was identified that showed improved selectivity over PDE1C. Optimization afforded preclinical candidate 19 that demonstrated free brain/free plasma ≥ 1 in rat and reduced microsomal clearance along with the ability to increase cyclic guanosine monophosphosphate levels in rat CSF.
authors.affiliation: Pfizer Worldwide Research and Development, Eastern Point Road, Groton, Connecticut 06340, United States. michelle.m.claffey@pfizer.com
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Claffey
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Helal
authors.forename: Patrick R
authors.initials: PR
authors.lastname: Verhoest
authors.forename: Zhijun
authors.initials: Z
authors.lastname: Kang
authors.forename: Kristina S
authors.initials: KS
authors.lastname: Fors
authors.forename: Stanley
authors.initials: S
authors.lastname: Jung
authors.forename: Jiaying
authors.initials: J
authors.lastname: Zhong
authors.forename: Mark W
authors.initials: MW
authors.lastname: Bundesmann
authors.forename: Xinjun
authors.initials: X
authors.lastname: Hou
authors.forename: Shenping
authors.initials: S
authors.lastname: Lui
authors.forename: Robin J
authors.initials: RJ
authors.lastname: Kleiman
authors.forename: Michelle
authors.initials: M
authors.lastname: Vanase-Frawley
authors.forename: Anne W
authors.initials: AW
authors.lastname: Schmidt
authors.forename: Frank
authors.initials: F
authors.lastname: Menniti
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Schmidt
authors.forename: William E
authors.initials: WE
authors.lastname: Hoffman
authors.forename: Mihaly
authors.initials: M
authors.lastname: Hajos
authors.forename: Laura
authors.initials: L
authors.lastname: McDowell
authors.forename: Rebecca E
authors.initials: RE
authors.lastname: O'Connor
authors.forename: Mary
authors.initials: M
authors.lastname: Macdougall-Murphy
authors.forename: Kari R
authors.initials: KR
authors.lastname: Fonseca
authors.forename: Stacey L
authors.initials: SL
authors.lastname: Becker
authors.forename: Frederick R
authors.initials: FR
authors.lastname: Nelson
authors.forename: Spiros
authors.initials: S
authors.lastname: Liras
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000284:Administration, Oral; D000818:Animals; D001384:Azetidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D001812:Blood-Brain Barrier / Q000378:metabolism*; D018360:Crystallography, X-Ray; D006152:Cyclic GMP / Q000134:cerebrospinal fluid; D003517:Cyclopentanes / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D016208:Databases, Factual; D004285:Dogs; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry* / Q000493:pharmacokinetics; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry* / Q000493:pharmacokinetics; D011744:Pyrimidinones / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C578478:1-cyclopentyl-6-((1R)-1-(3-pyrimidin-2-ylazetidin-1-yl)ethyl)-1,5-dihydro-4H-pyrazolo(3,4-d)pyrimidin-4-one; D001384:Azetidines; D003517:Cyclopentanes; D011720:Pyrazoles; D011743:Pyrimidines; D011744:Pyrimidinones; D015105:3',5'-Cyclic-AMP Phosphodiesterases; C116137:PDE9A protein, human; D006152:Cyclic GMP