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Proceedings of the 31 st European Peptide SymposiumMichal Lebl, Morten Meldal, Knud J. Jensen, Thomas Hoeg-Jensen (Editors)European Peptide Society, 2010Peptides versus Nonpeptides as Therapeutics: AnExciting Challenge for Big PharmaMaurice Manning, Stoytcho Stoev, and Krzysztof BankowskiUniversity of Toledo, College of Medicine, Toledo, Ohio, U.S.A.IntroductionPeptides were abandoned by Big Pharma in favor of small molecule approaches to drugdiscovery, almost two decades ago [1,2]. During this period, the peptide field has beenunder constant siege by the illusionary promise of nonpeptides (see for example [3,4]),despite the striking reemergence of peptides as therapeutic agents [5,6,8]. Using examplesfrom the vasopressin/oxytocin field and from the CRF field, we illustrate that despiteimpressive advances in the discovery of nonpeptide vasopressin and oxytocin antagonists,to date, only one nonpeptide vasopressin V 2 /V 1 antagonist and one nonpeptide vasopressinV 2 antagonist have been approved by the FDA for clinical use [1,2] (Tables 1-4; adaptedfrom 1,2). To date, no nonpeptide CRF antagonists have been approved for clinical use.Results and DiscussionTable 1. Some nonpeptide vasopressin V 1a and V 1b antagonistsNo. Company Code Name Status1 Otsuka OPC-21268 none Phase II2 Sanofi-Synthelabo SR49059 Relcovaptan stopped3 Azevan SRX251 none Phase I4 Sanofi* SSR149415 Nelivaptan stopped5 Organon* ORG52186 none Pre-clinical*V 1b antagonistsSummary: No nonpeptide V 1a or V 1b vasopressin antagonists have been approved by theFDA [1,2].Table 2. Nonpeptide oxytocin agonistNo. Company Code Name Status1 Wyeth-Ayerst WAY-267464 None failedSummary: No nonpeptide oxytocin agonist has been approved for clinical use [1].Table 3. Some nonpeptide vasopressin V 2 and V 2 /V 1a antagonistsReceptor type: V 2No. Company Code Name Status1 Otsuka OPC-31260 Mozavaptan Failed2 Otsuka OPC-41061 Tolvaptan FDA approved 20093 Sanofi SR121463(B) Satavaptan Phase III, marketingSuspended4 Wyeth-Ayrest VPA-985 Lixivaptan Phase III5 Astellas YM-087 Conivaptan + FDA approved 2005,i.v. use only+ V 2 /V 1a antagonistSummary:•One nonpeptide vasopressin antagonist: (Tolvaptan) has received FDA approval [1].•One nonpeptide vasopressin V 2 /V 1a antagonist: (Conivaptan) has received FDAapproval for i.v. use in hospitals [1,2].366