Potent, Metabolically Stable Benzopyrimido-pyrrolo-oxazine-dione (BPO) CFTR Inhibitors for Polycystic Kidney Disease

• Published in: Journal of medicinal chemistry Vol. 54; no. 15; pp. 5468 - 5477
• Main Authors: Snyder, David S, Tradtrantip, Lukmanee, Yao, Chenjuan, Kurth, Mark J, Verkman, A. S
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 11-08-2011
• Subjects: Animals; Cystic Fibrosis Transmembrane Conductance Regulator - antagonists & inhibitors; Kidney - embryology; Mice; Microsomes, Liver - metabolism; Organ Culture Techniques; Oxazines - chemical synthesis; Oxazines - metabolism; Oxazines - pharmacology; Polycystic Kidney Diseases - drug therapy; Pyrimidines - chemical synthesis; Pyrimidines - metabolism; Pyrimidines - pharmacology; Pyrroles - chemical synthesis; Pyrroles - metabolism; Pyrroles - pharmacology; Rats
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm200505e

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, IC50 ∼ 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 IC50 ∼ 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 IC50 ∼ 100 nM. Benzopyrimido-pyrrolo-oxazinediones such as 42 are potential development candidates for antisecretory therapy of PKD.