title: Potent, metabolically stable benzopyrimido-pyrrolo-oxazine-dione (BPO) CFTR inhibitors for polycystic kidney disease.
abstract: We previously reported the discovery of pyrimido-pyrrolo-quinoxalinedione (PPQ) inhibitors of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel and showed their efficacy in an organ culture model of polycystic kidney disease (PKD) (J. Med. Chem. 2009, 52, 6447-6455). Here, we report related benzopyrimido-pyrrolo-oxazinedione (BPO) CFTR inhibitors. To establish structure-activity relationships and select lead compound(s) with improved potency, metabolic stability, and aqueous solubility compared to the most potent prior compound 8 (PPQ-102, IC(50) ∼ 90 nM), we synthesized 16 PPQ analogues and 11 BPO analogues. The analogues were efficiently synthesized in 5-6 steps and 11-61% overall yield. Modification of 8 by bromine substitution at the 5-position of the furan ring, replacement of the secondary amine with an ether bridge, and carboxylation, gave 6-(5-bromofuran-2-yl)-7,9-dimethyl-8,10-dioxo-11-phenyl-7,8,9,10-tetrahydro-6H-benzo[b]pyrimido [4',5':3,4]pyrrolo [1,2-d][1,4]oxazine-2-carboxylic acid 42 (BPO-27), which fully inhibited CFTR with IC(50) ∼ 8 nM and, compared to 8, had >10-fold greater metabolic stability and much greater polarity/aqueous solubility. In an embryonic kidney culture model of PKD, 42 prevented cyst growth with IC(50) ∼ 100 nM. Benzopyrimido-pyrrolo-oxazinediones such as 42 are potential development candidates for antisecretory therapy of PKD.
authors.affiliation: Department of Medicine, University of California, San Francisco, California 94143-0521, United States.
authors.forename: David S
authors.initials: DS
authors.lastname: Snyder
authors.forename: Lukmanee
authors.initials: L
authors.lastname: Tradtrantip
authors.forename: Chenjuan
authors.initials: C
authors.lastname: Yao
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Kurth
authors.forename: A S
authors.initials: AS
authors.lastname: Verkman
mesh_terms: D000818:Animals; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000037:antagonists & inhibitors*; D007668:Kidney / Q000196:embryology; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D009924:Organ Culture Techniques; D010078:Oxazines / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D007690:Polycystic Kidney Diseases / Q000188:drug therapy; D011743:Pyrimidines / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D011758:Pyrroles / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats
chemical_list: D010078:Oxazines; D011743:Pyrimidines; D011758:Pyrroles; D019005:Cystic Fibrosis Transmembrane Conductance Regulator