Cyclic protease inhibitors

Previous reviews on peptidomimetics have addressed pseudopeptides (11), macrocyclic mimetics (13), natural product mimetics (14), cyclic protease inhibitors (15), mimetics for receptor ligands (16-22), and earlier general overviews (23-29). This review will focus on the design process itself. Novel peptidomimetics in which the structural relationship between parent peptide and the peptidomimetic has been established by biophysical methods are used to clarify the principles. Successful approaches are highlighted to illustrate how these concepts are currently used. 

Flow chart showing the design of novel orally active HIV-1 protease inhibitor. (Figure adapted from Lam P K ]adhav, C E Eyermann, C N Hodge, Y Ru, L T Bacheler, ] L Meek, M ] Otto, M M Rayner, Y N V /ong, ang, P C Weber, D A Jackson, T R Sharpe and S Erickson-Viitanen 1994. Rational Design of Potent, able. Nonpeptide Cyclic Ureas as HIV Protease Inhibitors. Science 263 380-384.)... 

Other types of HIV-1 protease inhibitors have also been prepared using microwave-promoted Suzuki reaction [37]. The symmetric cyclic sulfamide (3K,4S,5S,6it)-3,6-bis(phenoxymethyl)-2,7-bis[4-(2-thienyl)benzyl]-l,2,7-thi-adiazepane-4,5-diol 1,1-dioxide, for instance, was synthesized via cross-couphng of (3aS,4R,8it,8aS) - 5,7 - bis(4 - bromobenzyl) - 2,2 - dimethyl - 4,8 - bis-(phenoxymethyl) hexahydro [1,3] dioxolo [4,5 - d] [ 1,2,7 ] - thiadiazepine 6,6 - dioxide with 2-thienylboronic acid for 3 min at 45 W (Scheme 19). 

Further, Wasserman and coworkers developed a direct acylation of stabilized phosphonium ylides by carboxylic acids in presence of the EDCI/DMAP (way c). This last method allows the introduction of a-aminoacid structures into the resulting P-oxo phosphorus ylides [19-25],opening the way to the total synthesis of depsipeptide elastase inhibitors [22,24] or cyclic peptidic protease inhibitor EurystatinA [20]. 

Lam PYS, Jadhav PK, Eyermann CJ, Hodge CN, Ru Y, Bacheler LT, Meek JL, Otto MJ, Rayner MM, Wong YN, Chang CH, Weber PC, Jackson DA, Sharpe TR, Erickson-Viitanen S. Rational design of potent, bioavailable, nonpeptide cyclic ureas as HIV protease inhibitors. Science 1994 263 380-4. 

De Lucca GV, Erickson-Viitanen S, Lam PYS. Cyclic HIV protease inhibitors capable of displacing the active site strnctnral water molecule. Drug Discov Today 1997 2 6-18. 

Incorporation of the position of water molecules that are firmly bound to the protein can impart affinity and novelty to the designed ligand. A prime example is the design of a class of HIV protease cyclic urea inhibitors by DuPont scientists that incorporated a water molecule bound to both flaps of the enzyme into their ligand [32]. The crystal structure of the HIV protease-cyclic urea complex [32] shows the urea carbonyl oxygen substituting for the position of the water molecule. 

An expeditious route to the cyclic sulfamide HIV-1 protease inhibitors of type 145 and 146 (tetrahydro-l,2,7-thiadiazepine 1,1-dioxide derivatives) from 141 and 142 hinges on palladium-catalysed amidation reactions. These reactions of 144 and 143 were microwave promoted and provided, after removal of the cyclic ketal protecting group, moderate to good yields of (145, 57%) and (146, 66%) for example with R = NHCOCH2-2-naphthyl <06T4671>. 

Equation (11.21) is an example of a single-mode microwave-promoted Suzuki coupling, delivering a cyclic H IV-protease inhibitor after a subsequent hydrolysis of the ketal group [35], Half a dozen compounds were synthesized with the help of micro-waves and some of the compounds had K, values in the nanomolar range. 

J. Hulten, et al., Cyclic HIV-1 protease inhibitors derived from mannitol Synthesis,... 

Janetka and Rich (78) have utilized the considerable stability of ruthenium-77-arene systems in the synthesis of cyclic tripeptides as analogs of the protease inhibitor K-13 (cf. 34, Scheme 28). Their approach involves the construction of linear tripeptide complexes (35) using diimide/HOBt coupling of [Ru(Cp)(Boc-p-Cl-PheOH)]PF6 (Cp = 775-C5H5) with the appropriate dipeptide ester. Cyclization of 35 affords the biphenyl ether 36, which on photolysis (350 nm) gives 34. 

Another significant work in this area entails the modeling of the activity of cyclic urea HIV-1 protease inhibitors using artificial neural networks <2006BMC280>. 

This strategy was employed by Semple and co-workers [29] in the synthesis of the N(10)-C(17) fragment of cyclotheonamides, a family of 19-membered cyclic penta-peptides isolated from the sponge Theonella swinhoei, which are serine protease inhibitors. 

A class of HIV-l protease inhibitors extensively examined in our department are the cyclic sulfamides [73,74]. These compounds are related to our linear 1,2-dihydroxyethylene inhibitors described above in that they are also derived from L-mannitol and employ a 1,2-dihydroxyethylene transition-state isostere. These cyclic inhibitors are comprised of seven-membered rings where the sulfonyl oxygens are designed to displace a structural water in the enzyme when the inhibitors bind to the active site [73]. The synthesis of the... 

Scheme 15 Synthesis and inhibitory activities of symmetric cyclic HIV-1 protease inhibitors...

Scheme 20 Generation of cyclic HIV-1 protease inhibitors by microwave-heated amidation reactions...

Various non-legume, non-Poaceae Bowman-Birk protease inhibitors have been isolated that have sequence homology to the other BBPIPs [137-140, 285-288] (Table 10). The Ananas BBPIPs are disulphide-linked heterodimers [137-140]. The Helianthus BBPIP SFTI-1 is a small cyclic peptide (cyclotide) [285, 286] whereas the Solanum tuberosum BBPIP is similar to the single-headed Poaceae BBPIPs [287, 288]. 

Vietnamese squash) which are cyclic peptides (cyclotides) [541]. The small size, exceptional stability and protease inhibitor potency of these cyclic squash family PIPs make them potentially very useful lead compounds and structural scaffolds for pharmaceutical development [541], The structures of various squash family PIPs have been determined, namely those of Cucurbita maxima CMTI-I [544, 545], Cucurbita pepo CPTI-n [545], Momordica charantia MCTI-A [556, 557] and the cyclotide Momordica cochinchinensis McoTI-U [541]. The linear squash PIP structures involve anti-parallel P-strand elements beneath a loop which contains the protease binding site [544, 545, 556, 557]. 

Burello E., Frecer V, Miertus S, Combinatorial design and focusing of library of cyclic urea inhibitors of aspartic protease of HIV-1, chem. Biochem. submitted. 

HIV-protease/inhibitor complexes have a molecular weight of approximately 22 kDa. Although NMR spectroscopy is well suited to determination of the structure of molecules in this size range, efforts to determine the solution structure of the complex were hampered by the fact that the protease undergoes rapid autocatalysis in solution. It required the development of potent inhibitors before NMR studies of the complex became feasible. The first solution structure of HIV-protease bound to the cyclic urea inhibitor DMP-323 (Fig. 25) was reported by Yamazaki in 1996.133 The protease exists as a homodimer. Each 99-residue monomer contains ten /3-strands and the dimer is stabilized by a four-stranded antiparallel /3-sheet formed by the N- and C-terminal strands of each monomer. The active site of the enzyme is formed at the interface, where each monomer contributes a catalytic triad (Asp25-Thr26-Gly27) that is... 

Additionally, a number of biologically significant molecules have in their structure a chiral nonracemic sulfinyl group. Among these molecules (Fig. 1), it is worth noting the new immunosuppressive thiaspirane sulfoxide Nuphar alkaloid type la and lb,13 the gastric antisecretory omeprazole 2,14 the new potassium channel activators of Rhone Poulenc aprikalim 3,15 the cyclic hexapeptide waiakeamide 4,16 the ACAT inhibitor 5,17 and the potent human immunodeficiency virus type 1 protease inhibitor 6.18... 

Lam, P.Y.S., et al. Rational design ofpotent, bioavailable, nonpeptide cyclic ureas as HIV protease inhibitors, Science, 1994, 263, 380-384. 

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