title: Improved P1/P1' substituents for cyclic urea based HIV-1 protease inhibitors: synthesis, structure-activity relationship, and X-ray crystal structure analysis.
abstract: We present several novel P1/P1' substituents that can replace the characteristic benzyl P1/P1' moiety of the cyclic urea based HIV protease inhibitor series. These substituents typically provide 5-10-fold improvements in binding affinity compared to the unsubstituted benzyl analogs. The best substituent was the 3,4-(ethylenedioxy)benzyl group. Proper balancing of the molecule's lipophilicity facilitated the transfer of this improved binding affinity into a superior cellular antiviral activity profile. Several analogs were evaluated further for protein binding and resistance liabilities. Compound 18 (IC90 = 8.7 nM) was chosen for oral bioavailability studies based on its log P and solubility profile. A 10 mg/kg dose in dogs provided modest bioavailability with Cmax = 0.22 microg/mL. X-ray crystallographic analysis of two analogs revealed several interesting features responsible for the 3,4-(ethylenedioxy)benzyl-substituted analog's potency: (1) Comparing the two complexes revealed two distinct binding modes for each P1/P1' substituent; (2) The ethylenedioxy moieties are within 3.6 A of Pro 81 providing additional van der Waals contacts missing from the parent structure; (3) The enzyme's Arg 8 side chain moves away from the P1 substituent to accommodate the increased steric volume while maintaining a favorable hydrogen bond distance between the para oxygen substituent and the guanidine NH.
authors.affiliation: The DuPont Merck Pharmaceutical Company, Wilmington, Delaware 19880-0500, USA.
authors.forename: D A
authors.initials: DA
authors.lastname: Nugiel
authors.forename: K
authors.initials: K
authors.lastname: Jacobs
authors.forename: L
authors.initials: L
authors.lastname: Cornelius
authors.forename: C H
authors.initials: CH
authors.lastname: Chang
authors.forename: P K
authors.initials: PK
authors.lastname: Jadhav
authors.forename: E R
authors.initials: ER
authors.lastname: Holler
authors.forename: R M
authors.initials: RM
authors.lastname: Klabe
authors.forename: L T
authors.initials: LT
authors.lastname: Bacheler
authors.forename: B
authors.initials: B
authors.lastname: Cordova
authors.forename: S
authors.initials: S
authors.lastname: Garber
authors.forename: C
authors.initials: C
authors.lastname: Reid
authors.forename: K A
authors.initials: KA
authors.lastname: Logue
authors.forename: L J
authors.initials: LJ
authors.lastname: Gorey-Feret
authors.forename: G N
authors.initials: GN
authors.lastname: Lam
authors.forename: S
authors.initials: S
authors.lastname: Erickson-Viitanen
authors.forename: S P
authors.initials: SP
authors.lastname: Seitz
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D002460:Cell Line; D018360:Crystallography, X-Ray; D004285:Dogs; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D013329:Structure-Activity Relationship; D014508:Urea / Q000031:analogs & derivatives*
chemical_list: D019380:Anti-HIV Agents; D017320:HIV Protease Inhibitors; D014508:Urea