title: Metabolic investigation on ZL006 for the discovery of a potent prodrug for the treatment of cerebral ischemia.
abstract: 4-((3,5-Dichloro-2-hydroxybenzyl)amino)-2-hydroxybenzoic acid (ZL006, 1) is a small-molecular inhibitor of the nNOS/PSD-95 interaction, that is under preclinical evaluation stage for cerebral ischemia. However, the fast metabolism and low permeability across the blood brain barrier (BBB) have restricted its further use. In this manuscript, the mass spectroscopy analysis showed that ZL006 mainly combined with glucuronic acid in mice plasma, which accelerated its metabolism and elimination. Hence, six ZL006 analogs were designed according to the probable metabolism sites of ZL006, and featured the alkylation at phenolic hydroxyl, secondary amine and carboxyl groups. These compounds were synthesized in moderate to good yields, and fully characterized with (1)H NMR and MS. Further metabolism investigation of ZL006 analogs showed that phenolic hydroxyl group of aromatic ring A was the major conjugation site with glucuronic acid, and ZL006 cyclohexyl ester (6) had a better permeability across BBB, which was a potent prodrug for cerebral ischemia.
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Nanjing Medical University, Nanjing 211166, PR China.
authors.forename: Dongyin
authors.initials: D
authors.lastname: Chen
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Nanjing Medical University, Nanjing 211166, PR China.
authors.forename: Ting
authors.initials: T
authors.lastname: Zhao
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Nanjing Medical University, Nanjing 211166, PR China.
authors.forename: Kaidong
authors.initials: K
authors.lastname: Ni
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Nanjing Medical University, Nanjing 211166, PR China.
authors.forename: Peng
authors.initials: P
authors.lastname: Dai
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Nanjing Medical University, Nanjing 211166, PR China.
authors.forename: Lei
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Nanjing Medical University, Nanjing 211166, PR China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Nanjing Medical University, Nanjing 211166, PR China. Electronic address: kldlf@njmu.edu.cn.
authors.forename: Fei
authors.initials: F
authors.lastname: Li
mesh_terms: D000636:Aminosalicylic Acids / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D001596:Benzylamines / Q000737:chemistry / Q000378:metabolism*; D001812:Blood-Brain Barrier / Q000378:metabolism; D002545:Brain Ischemia / Q000188:drug therapy*; D004951:Esterification; D020719:Glucuronides / Q000378:metabolism; D051379:Mice; D018696:Neuroprotective Agents / Q000138:chemical synthesis / Q000378:metabolism / Q000627:therapeutic use*; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use*
chemical_list: D000636:Aminosalicylic Acids; D001596:Benzylamines; D020719:Glucuronides; D018696:Neuroprotective Agents; D011355:Prodrugs; C000607694:ZL006 compound
keywords: Cerebral ischemia; Metabolic investigation; Neuronal nitric oxide synthase; Postsynaptic density protein-95; Prodrug; ZL006