Orally bioavailable prodrugs of a BCS class 2 molecule, an inhibitor of HIV-1 reverse transcriptase

Bioorganic and Medicinal Chemistry Letters

Volumn 18, Issue 24, 2008, Pages 6344-6347

  Elworthy, Todd R ^a   Dunn, James P ^a   Hogg, J Heather ^a   Lam, Grace ^a   Saito, Y David ^a   Silva, Tania M P C ^a   Stefanidis, Dimitrios ^a   Woroniecki, Witold ^a   Zhornisky, Eugenia ^a   Zhou, Amy S ^a   Klumpp, Klaus ^a  

^a ROCHE BIOSCIENCE   (United States)

Author keywords

Class 2 molecule; Dissolution limiting pharmacokinetics; HIV 1 reverse transcriptase inhibitor; Hydroxymethyl derivatives; NNRTI; Oral bioavailability; Prodrug; Pyridazinone

Indexed keywords

FOSPHENYTOIN SODIUM; PRODRUG; PYRIDAZINONE DERIVATIVE; RNA DIRECTED DNA POLYMERASE INHIBITOR;

ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; DRUG BIOAVAILABILITY; DRUG BLOOD LEVEL; DRUG DELIVERY SYSTEM; DRUG HALF LIFE; DRUG SOLUBILITY; DRUG STRUCTURE; MALE; NONHUMAN; RAT; STRUCTURE ACTIVITY RELATION;

ADMINISTRATION, ORAL; ANIMALS; BIOLOGICAL AVAILABILITY; CARBONATES; CHEMISTRY, PHARMACEUTICAL; DRUG DESIGN; ESTERS; HIV REVERSE TRANSCRIPTASE; HIV-1; HYDROGEN-ION CONCENTRATION; MODELS, CHEMICAL; PRODRUGS; RATS; REVERSE TRANSCRIPTASE INHIBITORS; SOLUBILITY;

HUMAN IMMUNODEFICIENCY VIRUS 1; RATTUS;

EID: 56349166604     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2008.10.090     Document Type: Article

References (7)

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7. 2: C, 43.10; H, 2.93; N, 9.58. Found: C, 43.12; H, 2.67; N, 9.23.Method C. A DMF (25 mL) solution of 2 (4.5 g, 10.6 mmol) was generated at rt and without delay treated with triethylamine (0.3 mL, 2.1 mmol) and a toluene (15 mL) solution of N-tert-butoxycarbonyl (S)-valine N-carboxyanhydride (3.1 g, 12.7 mmol). The resulting solution was stirred for 2 h and poured into water (120 mL) and extracted with 2:1 hexane/EtOAc (4 × 100 mL). The combined organic extracts was washed brine, stored over anhydrous sodium sulfate, and loaded onto a pad of silica gel (eluant gradient: 1:1 to 3:1 EtOAc/hexane). The desired N-Boc amino ester was obtained (5.6 g, 8.9 mmol, 84%) as a foam and was dissolved in EtOAc at