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Document Page 16 The resulting compound, ABT-538 (Table 3), binds to the active site of HIV PR in an extended conformation. The central, asymmetric hydroxyl group is within hydrogen-bonding distance of the catalytic aspartates 25/25', and the P1/P1' phenylalanine side chains are symmetrically distributed in the corresponding subsites. The nitrogens of the symmetric amide bonds on both sides of the central aminoalcohol are barely within the hydrogen-bonding distance of the carbonyl oxygens of Gly27/27' (3.4 Å) and the carbonyl oxygens of these amide bonds participate in the tetrahydral coordination of the flap water molecule Wat301. On the N-terminal side of the compound, the P2 side chain of valine fills the S2 subsite and the terminal 2-isopropyl-4-thiazolyl makes hydrohobic contacts with the residues in the S3 pocket and has a stacking interaction with the P1 phenylalanine. On the C-terminal side, the 5thiazole is positioned to interact within the S2' subsite, and the nitrogen on the 5-membered ring is within hydrogen-bonding distance of the amide of Asp30'. Despite two peptide bonds present in ABT-538, this compound has substantial oral availability in humans and a very high antiviral activity in vivo [30]. Recently, ABT-538, better known as ritonavir, has been approved by the FDA for treatment of AIDS in combination with inhibitors of the reverse transcriptase. Design and Structure of L-735,524 (Indinavir) Indinavir is another example of very potent peptidomimetic compound discovered using the elements the crystal structure-based design [32] and SAR (structure activity relationship). The starting point for the design was a series of compounds containing the hydroxyethylene isostere of a scissile dipeptide [33]. An example of compounds from these series is L-685,434, which consists of a tert-butylcarbamate group forming the P2 moiety, symmetrically distributed phenylalanine side chains in the P1/P1', and the indanol group in the P2' portion of the inhibitor. Although very potent, the optimized molecules from this series lacked aqueous solubility and an acceptable pharmacokinetic profile [32]. The Merck group hypothesized that incorporation of a basic amine-containing functionality, such as the decahydroisoquinoline group of saquinavir, into the backbone of L-685,434 series might improve the solubility and bioavailability of this type of compound. Also the replacement of the P2/P1 functionalities, the tert-butylamide and phenylalanine side chain by the decahydroisoquinoline tertbutylamide, would generate a novel class of hydroxylaminepentanamide isostere with potentially improved metabolic stability in vivo. An additional strong argument for using decahydroisoquinoline as an isostere of P1/P2 moieties was the restricted conformational freedom of the enclosed-into-a-ring basic amine, which should decrease the entropy change upon binding to HIV PR in a similar fashion to that observed in saquinavir. In http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_16.html [4/5/2004 4:44:41 PM]
Document Page 17 the resulting chimeric inhibitor the central hydroxyl group forms hydrogen bonds with the catalytic aspartic acids 25/25' and the hydrophobic side chains of the P1/P1' decahydroisoquinoline and phenylalanine respectively are separated from the central hydroxyl-bearing carbon by the methylene linkers forming a pseudosymmetrical arrangement. In the subsequent optimization of inhibitors from this novel series, a smaller piperazine group was substituted for the decahydroisoquinoline group, which offered a possibility to expand from the N4 position to the partially lipophilic S3 subsite. One of the first compounds from the piperazine series possessed a benzyloxycarbonyl moiety attached to the piperazine ring and the additional hydrophobic interaction in the S3 subsite was reflected by substantial increase in both intrinsic potency and in the ability to inhibit viral spread in infected cells in vitro. Finally, the replacement of the benzyloxycarbonyl group by the 3-pyridylmethyl moiety (Table 3) provided both lipohilicity for binding to the HIV PR active site and a weakly basic nitrogen that increased aqueous solubility and oral bioavailability. The crystal structure of L-735,524 (indinavir) bound to the active site of HIV PR [34] indicates that the 3-pyridylmethyl group attached to the N4 position of the piperazine ring makes hydrophobic contacts with the residues in the S3 and S1 pockets and the tert-butyl moiety fills the S2 subsite in the fashion previously observed in the structure of saquinavir. The positions of the P2 and P1' carbonyls maintain the proper alignment to form hydrogen bonds with the flap water Wat301. The terminal indanol group of indinavir occupies the S2' subsite with the hydroxyl group within hydrogen-bonding distance of the amide nitrogen of Asp29. The high aqueous solubility and largely nonpeptidic character of indinavir may be responsible for the good oral bioavailability, respectable pharmacokinetic profile, and high antiviral activity observed with this compound. Similar to saquinavir and ritonavir, indinavir has been recently approved by the FDA for treatment of AIDS. F. Nonpeptidic Inhibitors of HIV PR The nonpeptidic inhibitors of HIV PR can be divided into two subclasses. Compounds that belong to the first group maintain the general binding mode of the peptidomimetic inhibitors including formation of the key hydrogen bonds with the active site residues. An example of such nonpeptidic inhibitors of HIV PR is AG1343 (nelfinavir). The second group of nonpeptidic HIV PR inhibitors includes compounds with a binding mode significantly different from that described for the peptidomimetic compounds. Most inhibitors in this latter class were initially discovered by screening natural-products libraries or by structurebased de novo design. The most interesting examples of the nonpeptidic inhibitors from this group are the independently discovered but structurally http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_17.html [4/5/2004 4:44:43 PM]
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Document Table 3 HIV-1 RT Amino Aci
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Document Chris Tantillo. The work i
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Document Page 72 16. Goldman ME, Nu
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Document 30. Coffin JM. HIV populat
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Document 45. Majumadar C, Abbotts J
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Document reverse transcriptase inhi
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Document 106. Cirino NM, Cameron CE
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Document dine) and didanosine (dide
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Document 163. Lacey SF, Larder BA.
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Document Figure 1 Retroviral lifecy
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Document Page 92 The role of the N-
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Document cubation of phosphotyrosin
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Document receptor, it has not yet b
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Document Figure 6 Rat and human B2
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Document We determined the structur
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Document Table 1 Inhibition Data fo
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Document 6 Structural Implications
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Document 12 Polypeptide Modulators
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Document C. Specificity Figure 4 Th
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Document Table 1 Known Three-Dimens
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Document All effects of the IL-1 fa
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Document 17 Structure and Functiona
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Document Table 1 Approval Indicatio
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Document factors, 247 Combination t
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Document Cyclotheonamide A (CtA), 2
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Document D ddI, 152 tumour necrosis
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Document antistasin peptides, 281 c
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Document fragment-based programs, 5
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Document [Human immunodeficiency vi
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Document overview, 103-104, 108-109
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Document [Inhibitors] 2-((3,4-dihyd
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Document antagonistic activity, 416
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Document [Interleukin-1] homology w
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Document Kininogen, 119 high molecu
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Document Matrix-metalloproteinase (
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Document RT inhibitor, 41, 56 Nonpe
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Document Phosphoglycerate kinase (P
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Document [Protease targets] serinyl
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