title: Improved cyclic urea inhibitors of the HIV-1 protease: synthesis, potency, resistance profile, human pharmacokinetics and X-ray crystal structure of DMP 450.
abstract: BACKGROUND
  Effective HIV protease inhibitors must combine potency towards wild-type and mutant variants of HIV with oral bioavailability such that drug levels in relevant tissues continuously exceed that required for inhibition of virus replication. Computer-aided design led to the discovery of cyclic urea inhibitors of the HIV protease. We set out to improve the physical properties and oral bioavailability of these compounds.
  
  
  RESULTS
  We have synthesized DMP 450 (bis-methanesulfonic acid salt), a water-soluble cyclic urea compound and a potent inhibitor of HIV replication in cell culture that also inhibits variants of HIV with single amino acid substitutions in the protease. DMP 450 is highly selective for HIV protease, consistent with displacement of the retrovirus-specific structural water molecule. Single doses of 10 mg kg-1 DMP 450 result in plasma levels in man in excess of that required to inhibit wild-type and several mutant HIVs. A plasmid-based, in vivo assay model suggests that maintenance of plasma levels of DMP 450 near the antiviral IC90 suppresses HIV protease activity in the animal. We did identify mutants that are resistant to DMP 450, however; multiple mutations within the protease gene caused a significant reduction in the antiviral response.
  
  
  CONCLUSIONS
  DMP 450 is a significant advance within the cyclic urea class of HIV protease inhibitors due to its exceptional oral bioavailability. The data presented here suggest that an optimal cyclic urea will provide clinical benefit in treating AIDS if it combines favorable pharmacokinetics with potent activity against not only single mutants of HIV, but also multiply-mutant variants.
authors.affiliation: Department of Chemical Sciences, DuPont Merck Pharmaceutical Co., Wilmington, DE 19880, USA. hodgecn@carbon.dmpc.com
authors.forename: C N
authors.initials: CN
authors.lastname: Hodge
authors.forename: P E
authors.initials: PE
authors.lastname: Aldrich
authors.forename: L T
authors.initials: LT
authors.lastname: Bacheler
authors.forename: C H
authors.initials: CH
authors.lastname: Chang
authors.forename: C J
authors.initials: CJ
authors.lastname: Eyermann
authors.forename: S
authors.initials: S
authors.lastname: Garber
authors.forename: M
authors.initials: M
authors.lastname: Grubb
authors.forename: D A
authors.initials: DA
authors.lastname: Jackson
authors.forename: P K
authors.initials: PK
authors.lastname: Jadhav
authors.forename: B
authors.initials: B
authors.lastname: Korant
authors.forename: P Y
authors.initials: PY
authors.lastname: Lam
authors.forename: M B
authors.initials: MB
authors.lastname: Maurin
authors.forename: J L
authors.initials: JL
authors.lastname: Meek
authors.forename: M J
authors.initials: MJ
authors.lastname: Otto
authors.forename: M M
authors.initials: MM
authors.lastname: Rayner
authors.forename: C
authors.initials: C
authors.lastname: Reid
authors.forename: T R
authors.initials: TR
authors.lastname: Sharpe
authors.forename: L
authors.initials: L
authors.lastname: Shum
authors.forename: D L
authors.initials: DL
authors.lastname: Winslow
authors.forename: S
authors.initials: S
authors.lastname: Erickson-Viitanen
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001381:Azepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D004352:Drug Resistance, Microbial / Q000235:genetics; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D015497:HIV-1 / Q000201:enzymology* / Q000502:physiology; D006801:Humans; D007262:Infusions, Intravenous; D051379:Mice; D008854:Microscopy, Electron; D012995:Solubility; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D014779:Virus Replication / Q000187:drug effects
chemical_list: D001381:Azepines; D017320:HIV Protease Inhibitors; D014508:Urea; C099851:DMP 450