Peptides reduced amide

Each of the scaffolds reported in Scheme 24 can be used for the production of a stereo-isomeric sublibrary based on the appropriate peptide sequence. For example, with the sequence A-B-C-D-E and scaffold (1) two types of stereoisomeric sublibraries can be prepared. One type includes the sublibraries A and B of Scheme 26 in which within a given sequence the configuration of each residue is successively inverted thus, retaining the identical connectivity as in the parent linear peptide. In the second type 265 of sublibraries C and D (Scheme 26) the direction of the amide bond is inverted and hence the connectivity is not maintained. In most members of these sublibraries the overall conformation of the scaffold is maintained and therefore these components constitute stereoisomeric sublibraries of the parent library. Conversely, by introducing amide bond surrogates such as reduced amide bonds1465 or thioamide bonds 260,466 the conformation of the scaffolds are changed and their conformational flexibility enhanced. 

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. 

The methyleneamino(hydroxy) or i >[CH2-N(OH)] link 2, which may be also called an N-hydroxy reduced amide bond, was introduced by Grundke et aL in 1987.W Compound 13 can be obtained in good yield by reduction of the homologous (nitrono) peptide 12 (Scheme 2). Alternatively, Urban et aI.15 have prepared the (IV-hydroxy reduced amide) peptide 15, a potent HIV protease inhibitor, by direct oxidation of the amine nitrogen in the homologous reduced peptide 14, obtained by classical reductive amination (Scheme 3). 

Scheme 3 Synthesis of an (A-Hydroxy reduced amide) Peptide by N-Oxidation of a Reduced Peptidel51...

Early studies of the pharmacology of the ORLl system were hindered by the lack of antagonists for this receptor. Therefore there was considerable excitement in the field when the first report of an antagonist appeared in the literature (1024). The reduced amide derivative of OFQ/N [Phe i/f(CH2NH)Gly ]0FQ/ N-(1-13)NH2 (262, Fig. 7.51 referred to as [F/G]NC(1-13)NH2 by Calo and coworkers), which was synthesized to protect the peptide from metabolism by aminopeptidases, was initially reported to be an antagonist of OFQ/N-(1-13)NH2 in smooth muscle preparations... 

Oehlrich et al. [414] described the evolution of amide 3 into conformationally restricted bicyclic triazolo-piperidine 14-S as a Y-secretase modulator with high in vitro and in vivo potency against Ap42 peptide, reduced lipophilicity and enhanced brain free fraction compared to the previous series. 

Modified peptides containing reduced amide bonds, i. e. compounds L-731,735 and L-731,734, were designed by the Merck groups [7] (Fig. 1), and have shown to be potent inhibitors of partially purified FPTase, the homoserine compound being the more active inhibitor in vitro. Subsequent inhibitors include L-739,749 and L-739,750 [8] and even trancated versions of the C-terminal tetrapeptide CAAX motif were prepared which do not have a C-terminal carboxyl... 

Figure 1. Reduced amide containing modified peptides L-731,735, L-731,734, L-739,749, L-739,750 and a truncated CAAX - analog.

In the past 15 years, peptide analogues containing the reduced amide bond i/[Pg.650]

All the US-FDA approved Pis except Tipranavir (7) are substrate-based peptidic inhibitors. These inhibitors were designed using the "transition state peptidomimetic principle, which means that in the inhibitors the hydrolyzable peptide linkage is replaced by a non-hydrolyzable transition-state isostere (Fig. 11a) [158]. A munber of such isosteres were studied including statin, norstatin, hydroxyethylene, reduced amide, hydroxyethylamine, hydroxyethyl urea, monoalcohol, diol and aminodiols (Fig. 11b) [158]. Various classes of inhibitors containing dihydroxyethylene transition state isosteres were extensively developed. As an alternative to the peptide-based approach penicillin-derived C2 symmetric compounds were also pursued. 

Thus, the tendency is that in the absence of any adjacent substituent on either side of an amide bond, the 12-membered turn is favored, the 10-membered being formed when the amide bond is flanked by substituted carbons. The reduced 12/ 10-hehx population or rearrangement to the 3i4-hehx observed upon N-terminal deprotection of mixed /9-peptides can be explained in terms of unfavorable... 

A second strategy is to attach a linker (also referred to as a handle or anchor) to the resin followed by assembly of the molecule. A linker is bifunctional spacer that serves to link the initial synthetic unit to the support in two discrete steps (Fig. 3). To attach a linker to a chloromethyl-PS resin, a phenol functionality such as handle 4 is used to form an ether bond (Fig. 4). To attach the same handle to an amino-functionalized support, acetoxy function 5 or a longer methylene spacer of the corresponding phenol is applied to form an amide bond. Both of these resins perform similarly and only differ in their initial starting resin [4], An alternative approach is to prepare a preformed handle in which the first building block is prederivatized to the linker and this moiety is attached to the resin. For peptide synthesis, this practice is common for the preparation of C-terminal peptide acids in order to reduce the amount of racemization of the a-carbon at the anchoring position [5],... 

With this information in hand, initial attempts to generate BACE inhibitors used the peptidic Swedish variant substrate as a starting point and substituted the scissile amide bond with a statine. For example, Sinha et al. (1999) synthesized a P10-P4 1 Swedish variant peptide with a statine moiety in place of the Pl-Pl scissile bond and showed that this peptidomimetic displayed an IC50 of 40 pM for inhibition of BACE. Optimization of this inhibitor was then performed by systematic replacement of amino acid side chains. Replacement of the PE Asp residue by Val reduced the IC50 for BACE inhibition to 30 nM this inhibitor is referred to here as Stat-Val. 

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