Combinatorial diversification of indinavir: In vivo mixture dosing of an HIV protease inhibitor library

Bioorganic and Medicinal Chemistry Letters

Volumn 10, Issue 14, 2000, Pages 1527-1530

  Rano, Thomas A ^a   Cheng, Yuan ^a   Huening, Tracy T ^a   Zhang, Fengqi ^a   Schleif, William A ^a   Gabryelski, Lori ^a   Olsen, David B ^a   Kuo, Lawrence C ^a   Lin, Jiunn H ^a   Xu, Xin ^a   Olah, Timothy V ^a   McLoughlin, Debra A ^a   King, Richard ^a   Chapman, Kevin T ^a   Tata, James R ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANTI HUMAN IMMUNODEFICIENCY VIRUS AGENT; INDINAVIR; INDINAVIR DERIVATIVE; PROTEINASE INHIBITOR; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ARTICLE; CHEMICAL MODIFICATION; DOG; DRUG BIOAVAILABILITY; ENZYME INHIBITION; HUMAN; HUMAN CELL; HUMAN IMMUNODEFICIENCY VIRUS; IN VITRO STUDY; IN VIVO STUDY; LYMPHOID CELL LINE; NONHUMAN; ORGANIC CHEMISTRY; PROTEINASE INHIBITION; STRUCTURE ACTIVITY RELATION; VIRUS INHIBITION;

ANIMALS; CELL LINE; COMBINATORIAL CHEMISTRY TECHNIQUES; DOGS; HIV PROTEASE; HIV PROTEASE INHIBITORS; HUMANS; INDINAVIR; MODELS, MOLECULAR; MOLECULAR CONFORMATION; MOLECULAR STRUCTURE; T-LYMPHOCYTES;

EID: 0034679649     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0960-894X(00)00276-6     Document Type: Article

References (21)

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6. The solid-phase synthesis of HIV protease inhibitors has been previously reported: (a) Baker, C. T.; Salituro, F. G.; Court, J. J.; Deininger, D. D.; Kim, E. E.; Li, B.; Novak, P. M.; Rao, B. G.; Pazhanisamy, S.; Schairer, W. C.; Tung, R. D. Bioorg. Med. Chem. Lett. 1998, 8, 3631.
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11. Washing the resin with glacial acetic acid efficiently removed palladium based residues. Standard washing protocols throughout the synthesis typically involved various combinations of DMF, DCM, THF, and IPA. Final resin washing included either DCM or DMF, depending on the next reaction sequence.
12. The initial amide coupling conditions employed were amine (10 equiv), EDC (15 equiv), and HOBT (15 equiv) for 24 h. The conditions were later improved by employing HBTU (2.5 equiv), HOBT (3.75 equiv), DIEA (5 equiv), and amine (2.5 equiv) for 1 h.
13. 2O containing 0.1% TFA, 1.0 mL/min for 15 min) by area integration at 210 nm and 254 nm. The structure assigned to each new compound is in accord with its 400 MHz NMR spectrum as well as appropriate ion identification by mass spectrometry.
14. The synthesis of these amino indanol analogues will be reported elsewhere.
15. The resin was neutralized by washing with 30% TEA/THF, then THF or DCM prior to initiating the sulfonylation reaction.
16. Spatially addressing the Y dimension is the subject of a subsequent library and will be reported in due course.
17. Overall, this strategy afforded 3 distinct pools diversified at X, Y, and spatially addressed at Z.
18. Vacca J.P., Dorsey B.D., Schleif W.A., Levin R.B., McDaniel S.L., Darke P.L., Zugay J., Quintero J.C., Blahy O.M., Roth E., Sardana V.V., Schlabach A.J., Graham P.I., Condra J.H., Gotlib L., Holloway M.K., Lin J., Chen I.-W., Vastag K., Ostovic D., Anderson P.S., Emini E.A., Huff J.R. Proc. Nat. Acad. Sci. USA. 91:1994;4096.
19. The use of quantitative LC/MS/MS to detect minute quantities of closely related mixtures of drug substances in the extracts of biological fluids has been reported: Olah, T. V.; McLoughlin, D. A.; Gilbert, J. D. Rapid Commun. Mass Spectrom. 1997, 11, 17 and references sited therein.
20. For other publications involving mixture dosing, see: Allen, M. C.; Shah, T. S.; Day, W. W. Pharm. Res. 1998, 15, 93.
21. max of this substrate would indicate the presence of a CYP3A4 inhibitor in that particular pool.