Isosteres, hydroxy-ethylene

Further modification on 2 at P1( P/, and IV led to several hydroxy ethylene isosteres (e.g., 6 and 7),12-14 which displayed poorer enzyme inhibitory and antiviral potencies than 2 (Table 24.1). Incorporation of the constrained 3-S-tetrahydrofuranyl urethane in place of the (V-term in us acyclic tert-butyl urethane in 2 resulted in a remarkable 10-fold increase in enzyme inhibitory potency (IC50 <0.03 nM) and more than 100-fold increase in antiviral potency (CIC95 = 3 nM).15 Although very potent, the optimized inhibitors of the hydroxy ethylene isostere series still lacked adequate aqueous solubility and acceptable pharmacokinetic profile (Figure 24.2). 

A third dataset was built in order to demonstrate that the descriptor is relevant for estimating binding affinity in a QSAR analysis. This last dataset contains 49 HIV-1 protease inhibitors, the 3D coordinates of which were those used by Pastor et al. (30). It has the four transition-state isosteres—hydroxy ethylene, hydroxyethylamine, statine, and a symmetrical diol. The X-ray structures of molecules numbered 1 and 3-34 have been reported (31), whereas molecules numbered 35-50 were modeled on the crystallographic structure of the complex of HIV-1 protease with L-689,502 solved at 2.25 A resolution (32). The binding affinity is expressed as pIC50 values. 

A lactone-based synthesis converted keto-alkyne 6.245 to carboxylic acid 6.246 in four steps. Formation of lactone 6.247 was followed by conversion to azide 6.248. Reaction with butylamine and hydrogenation gave N-butyl 5-amino-6-cycIohexyI-2-isopropylhexanamide, 6.249. This amino acid product is considered to an hydroxy-ethylene dipeptide isostere. 115,143 jn the case of 6.249, the term isostere essentially refers to replacing one group in a molecule with another that will give similar chemical or physiological properties. 

Epoxide 6.254 was condensed with the enolate anion of 6.255. In this case, high diastereoselectivity was achieved when alcohol 6.347 was produced in >90% yield. The high diastereoselectivity is due to using enantiopurc 6.254 as a chiral template and "equipping" 6.255 with the auxiliary shown. Amino-amide 6.256 (a derivative 5-amino-2-benzyl-4-hydroxy-6-phenylhexanoic acid) is an intermediate in a synthetic route to hydroxy ethylene dipeptide isostere inhibitors of HIV-1 protease. 

The 2-hydroxyethylene isostere is different from the 1-hydroxyethylene isostere only in the position of the hydroxy goup. In the 2-hydroxyethylene isostere the hydroxy group is attached to the C2 of ethylene, while it is on Cl in the 1-hydroxyethylene isostere. The 2-hydroxyethylene isostere has been applied to the design HIV-1 protease inhibitors.[51] However, the activity of the resulting compounds is lower than that of inhibitors in which the isostere is replaced with the 1-hydroxyethylene group. 

In this section we consider peptide analogues containing the amide surrogates 1 to 11 (Scheme 1). These can be isosteric with the amide group in the sense that consecutive a-carbons are separated by three bonds, as in link 1, the (nitrono) peptides, and link 2, the [methyleneamino(hydroxy)] or (TV-hydroxy reduced amide) peptides. They also can be an N-modified amide, as in link 3, the (TV-hydroxy amide) peptides, and link 4, the (V-aminoamide) peptides. Elongation of the peptide unit by one covalent bond has been realized by the introduction of a heteroatom or a methylene into the backbone, as in link 5, the (hydrazide) peptides, link 6, the (amidoxy) peptides, link 7, the (oxomethyleneamino) peptides, link 8, the [(hydroxy)ethyleneamino] peptides, link 9, the (ethyleneamino) peptides, and link 10 the (oxime) peptides. Finally, insertion of an ethylenic bond (two covalent bonds) between the a-carbon and the carbonyl gives rise to link 11, the (but-2-enamide) or (vinylogous amide) peptides. 

Thereafter, the groups of Spero and Ojima have independently demonstrated the utility of this approach to the efficient preparation of aminopolyols and hydroxy (keto)ethylene dipeptide isosteres, respectively. Thus, as shown in Scheme 35, the... 

Scheme 36 (3-lactam ring opening with Li-enolates of esters. An access to the hydroxy (keto) ethylene dipeptide isostere... 

In its turn, the hydroxy(keto)ethylene dipeptide isostere 110 has also been prepared in a straightforward manner from [3-lactam 109, Scheme 36 [103]. 

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