JOURNAL OF MEDICINAL CHEM ISTRY Q Copyright 1993 by the American Chemical Society Volume 36, Number 21 October 15,1993 Pe rspe c t iu e Concepts and Progress in the Development of Peptide Mimetics Gary L. Olson,. David R. Bolin, Mary Pat Bonner, Michael BOs, Charles M. Cook, David C. Fry, Bradford J. Graves, Marcos Hatada, David E. Hill, Michael Kahn, Vincent S. Madison, Victoria K. Rusiecki, Ramakanth Sarabu, Jerry Sepinwall, George P. Vincent, and Matthew E. Voss Roche Research Center, Hoffmann-La Roche Inc., Nutley, New Jersey 07110 Received May 19, 1993 Medicinal chemistry research has been dramatically ology is applicable to enzyme inhibition as well. The broad transformed by biotechnology. Previously, synthetic use of the term “peptide mimetics” is unavoidable, but chemistry and natural products screening dominated drug advocates of rational design do not favor its use to describe research, but now molecular biology has become a driving compounds found by screening. Nevertheless, leads found force behind screening and the establishment of macro- by screening contribute to the understanding of phar- molecular targets. Most of the research in biotech macophores that recognize peptide binding sites. Simi- companies has been directed to peptide and protein larly, natural product opiate alkaloids are frequently cited therapeutics in spite of problems associated with their as examples of peptidomimetics2J because they validate low bioavailability, rapid metabolism, and lack of oral many of the concepts invoked in rational design. In fact, activity. Because of these limitations, research groups they also make a case for how structurally different continue to rely upon chemical synthesis of nonpeptide nonpeptides may be from their peptide parents (lacking substances for drug discovery, recognizing that small flexibility, amide bonds, and obvious pharmacophore molecules are likely to remain the most viable avenue for similarity) and how their modification can lead to highly the identification and optimization of potential drugs. The selective ligands for subtypes of receptors in both peptide challenge is to devise strategies that take advantage of the and nonpeptide c~mpounds.~ strengths of biotechnology to define and characterize Another class of peptide mimetic research that lies molecular targets and of medicinal chemistry to develop between the screening approach and de novo mimetics compounds. A promising approach integrating these design is centered on the replacement of individual peptide disciplines is the field of peptide mimetics, a conceptual bonds by a nonpeptidic These peptide surrogates approach which considers peptides and proteins not as are complemented by the synthesis of peptides incorpo- potential therapeutics but rather as leads for the discovery rating unnatural amino acids, conformational constraints, of other classes of compounds. and larger subunits, for example, dipeptide mimetics. The terms “peptide mimetics” and “peptidomimetics” These compounds bridge the gap between simple peptide have been utilized interchangeably to describe compounds analogs and the completely nonpeptide structures. In this discovered through a variety of research strategies.l respect, they represent a step along the path toward the Indeed, even compounds identified by random screening rationally designed nonpeptide. In many cases, peptide and subsequently optimized through structural modifi- surrogates are likely to be an essential stage in the cation have been termed peptidomimetics if the initial development of a pharmacophoric hypothesis for confor- lead was found in an assay in which the natural ligand is mationally flexible peptides.6 In addition, new technol- a peptide or protein.2 The field of enzyme inhibitors uses ogies for the rapid screening of peptide libraries7 will peptide mimetics terminology for replacements of seg- generate many highly flexible lead structures with modest ments of peptide-based substrates and inhibitors. In this binding affinities. Optimization and eventual translation Perspective, the emphasis will be on mimetics of peptide of a peptide lead to a small molecule drug will probably and protein ligands for receptors, although the method- require isosteric replacements, cyclic peptide derivatives, 0022-2623/93/1836-3039$04.00100 1993 American Chemical Society 3040 Journal of Medicinal Chemistry, 1993, Vol. 36, No. 21 Perspective H Bnoy:o@ En0 +-O(CH,),NHR 6 Figure 2. Somatostatin mimetic 6 (R = H)based on a glucose 0 H-f ternplate.l8 analogous to those of the peptide. Even in protein ligand structures where backbone conformations are known from X-ray crystallography, the side chains involved in inter- action with a receptor may move considerably from their orientation on the crystal surface they dock into 3 4 as recognition sites on the receptor. If a lead activity is seen for a flexible mimetic, adding conformational constraints to side chain groups is then a rational approach to enhance potency and selectivity. 4. Select appropriate targets based on availability of a pharmacophore hypothesis, or develop the information as a first step. Attempting to carry out a peptide mimetic H 0 project on a system for which there is no idea of structure- 5 activity relationships and no three-dimensional hypothesis of the bioactive conformation is irrational. Such a program Figure 1. @-Turnmimetics (1,l12,12 3,13 4,14 P). is likely to generate many inactive compounds and little useful guidance for further work. For systems where the bond surrogates, and conformational constraints as logical biological rationale or medical need is sufficient to justify steps in the process. a peptide mimetics approach, efforts to provide a phar- The rational design of nonpeptide compounds thus is macophore hypothesis as a first step are justified and not feasible without the information obtained from the critical to the outcome of the peptide mimetics programs. study of the structure-activity relationships and confor- Nonpeptide leads designed by this strategy might be mational properties of peptide structures. When such expected to behave more like the structures derived from information is available, and the indication is that the screening synthetic compound collections or natural peptide backbone is not a critical element in receptor products in terms of their bioavailability, metabolic binding,* the design of a nonpeptide becomes feasible. stability, and transport. With an appropriate and suc- The transition to a mimetic can then be made rational by cessful design and subsequent modification of an initial adopting some general principles, adapted from the treatise lead structure, the likelihood that these peptide mimetics of Farmer.g will become drug candidates is high. Progress toward this goal is just beginning to emerge. In this Perspective, we Design Criteria for Peptide Mimetics will describe some of our initial efforts to design peptide 1. Replace as much of the peptide backbone as possible mimetics to constrain secondary structural elements of by a nonpeptide framework. If bond surrogates have been peptides and will review the progress in our first cases of shown to retain activity, or peptide bonds are not exposed de novo design following the basic principles outlined in the presumed bioactive conformation, then a structural above. template may be designed to eliminate amide bonds. 2. Maintain peptide side chain pharmacophoric groups Mimicking Architectural Elements of Protein as in the peptide. Rather than completely dispensing with Structure a relationship between peptide and nonpeptide, initially &Turn Mimetics. Major effortslo have been devoted to designed mimetics may retain groups as found on the the development of templates that mimic or stabilize peptide, as these are most likely to be recognized by a several common architectural elements of peptide and receptor. For example, if a lysine residue is known to be protein structure, Le., &turns, helices, and @-sheets. The required for activity in the peptide, then the first- majority of the @-turn mimetics have been dipeptide generation mimetic should have a primary amino group mimetic replacements for the i + 1 and i + 2 residues at at the end of a methylene chain. As the design progresses the corners of the turn. These have been designed to retain through other generations, amine variants, different chain the intramolecular hydrogen bonding network of an lengths, conformational constraints, and substitutions on appended peptide chain (e.g., Figure 1, compounds 1-4). the nitrogen may be fruitful ways to enhance binding However, these examples lackan appendage for the corner affinity. residue side chains. Since these are the residues that are 3. Retain some conformational flexibility in first- most exposed to the surface of a protein, and most likely generation mimetics. The probability that a pharma- to be involved in intermolecular interactions with a cophore hypothesis will be definitive for flexible peptide receptor, their elimination limits the scope of the mimetic side chains is low, making it necessary that the first designs to that of a group that enforces a conformational constraint. leave some of the side chain pharmacophoric groups While these structures are valuable for answering unconstrained so that they may adopt conformations fundamental questions about protein folding, we felt it Perspective Journal of Medicinal Chemistry, 1993, Vol. 36, No. 21 3041 Scheme I FH3 y3 PW13 H?NOH*HCI N-methyllonnanilide odichlorobenzene CHO ? 81% "GO 1. LAH, THF, reflux - Y Br Br 2. (~%uoco)~o, - dioxane, 5% NaOH NKo-'BuCH2CI2, -10 'C 0 CO, PdC12(PPh3)2 7 m Br o-'Bu PPh3,llO0C "2 MeOH, Bu~N K0 88% 62% 7 0 83% 14 Chart I m Ac-Cys-(-N-Me)Arg-Gly-Asp-Pen-", Gly-Pen-Gly-ArgGIy-Asp-Pro-Cys-Ala 7 8 r-- I Ac-Cys-Asn-Dtc-Amf-Gly-Asp-Cys-OH 0 NH O*COOH 11 10 NH NH 12 (Pen= Penicillamine, Dtc= 5,5-dimethylthiazolidine-4-carboxylicacid, and Amf= p- aminometh ylp henylalanine) 3042 Journul of Medicinal Chemistry, 1993, Vol. 36, No. 21 Perspectiue Figure 3. VIP sequence and critical residues (shadowed). Figure 4. VIP structureby NMR in solution (left, 25 9% MeOH in H20;center, 50% MeOH in HnO;right, superposition showing closely aligned central core).