title: Benzylmorpholine analogs as selective inhibitors of lung cytochrome P450 2A13 for the chemoprevention of lung cancer in tobacco users.
abstract: OBJECTIVE
  4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), one of the most prevalent and procarcinogenic compounds in tobacco, is bioactivated by respiratory cytochrome P450 (CYP) 2A13, forming DNA adducts and initiating lung cancer. CYP2A13 inhibition offers a novel strategy for chemoprevention of tobacco-associated lung cancer.
  
  
  METHODS
  Twenty-four analogs of a 4-benzylmorpholine scaffold identified by high throughput screening were evaluated for binding and inhibition of both functional human CYP2A enzymes, CYP2A13 and the 94%-identical hepatic CYP2A6, whose inhibition is undesirable. Thus, selectivity is a major challenge in compound design.
  
  
  RESULTS
  A key feature resulting in CYP2A13-selective binding and inhibition was substitution at the benzyl ortho position, with three analogs being >25-fold selective for CYP2A13 over CYP2A6.
  
  
  CONCLUSIONS
  Two such analogs were negative for genetic and hERG toxicities and metabolically stable in human lung microsomes, but displayed rapid metabolism in human liver and in mouse and rat lung and liver microsomes, likely due to CYP2B-mediated degradation. A specialized knockout mouse mimicking the human lung demonstrates compound persistence in lung and provides an appropriate test model. Compound delivered by inhalation may be effective in the lung but rapidly cleared otherwise, limiting systemic exposure.
authors.affiliation: Department of Medicinal Chemistry, University of Kansas, 1251 Wescoe Hall Dr., Lawrence, Kansas 66045, USA.
authors.forename: Linda C
authors.initials: LC
authors.lastname: Blake
authors.forename: Anuradha
authors.initials: A
authors.lastname: Roy
authors.forename: David
authors.initials: D
authors.lastname: Neul
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Schoenen
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Aubé
authors.forename: Emily E
authors.initials: EE
authors.lastname: Scott
mesh_terms: D000818:Animals; D016588:Anticarcinogenic Agents / Q000737:chemistry / Q000494:pharmacology*; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002273:Carcinogens / Q000378:metabolism; D018890:Chemoprevention; D065637:Cytochrome P-450 CYP2A6; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008168:Lung / Q000187:drug effects / Q000201:enzymology*; D008175:Lung Neoplasms / Q000209:etiology* / Q000378:metabolism / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D009025:Morpholines / Q000737:chemistry / Q000494:pharmacology*; D009602:Nitrosamines / Q000009:adverse effects / Q000378:metabolism; D051381:Rats; D012907:Smoking / Q000009:adverse effects* / Q000378:metabolism
chemical_list: D016588:Anticarcinogenic Agents; D002273:Carcinogens; D009025:Morpholines; D009602:Nitrosamines; C068455:2-benzylmorpholine; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; D001189:Aryl Hydrocarbon Hydroxylases; C414206:CYP2A13 protein, human; C585710:CYP2A6 protein, human; D065637:Cytochrome P-450 CYP2A6