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(+)-2-Aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (1), also known as LY354740, is a highly potent and selective agonist for group II metabotropic glutamate receptors (mGlu receptors 2 and 3) tested in clinical trials. It has been shown to block anxiety in the fear-potentiated startle model. Its relatively low bioavailability in different animal species drove the need for an effective prodrug form that would produce a therapeutic response at lower doses for the treatment of anxiety disorders. We have investigated the increase of intestinal absorption of this compound by targeting the human peptide transporter hPepT1 for active transport of di- and tripeptides derived from 1. We have found that oral administration of an N dipeptide derivative of 1 (12a) in rats shows up to an 8-fold increase in drug absorption and a 300-fold increase in potency in the fear-potentiated startle model in rats when compared with the parent drug 1.

The azetidinone LY307174 (1) was identified as a screening lead for the vasopressin V1a receptor (IC 50 45 nM at the human V1a receptor) based on molecular similarity to ketoconazole (2), a known antagonist of the luteinizing hormone releasing hormone receptor. Structure-activity relationships for the series were explored to optimize receptor affinity and pharmacokinetic properties, resulting in compounds with K i values < 1 nM and brain levels after oral dosing ~100-fold higher than receptor affinities.The neurohypophysial hormones vasopressin 1 and oxytocin exert a wide range of physiological effects through binding to specific membrane receptors belonging to the G protein-coupled receptor (GPCR) superfamily. To date, three vasopressin receptor subtypes and one oxytocin receptor have been pharmacologically and functionally described 1 . V1a, V1b, and oxytocin receptors activate phospholipase C, resulting in the production of inositol 1,4,5-trisphosphate and diacylglycerol, mobilization of intracellular calcium, and activation of protein kinase C. V2 receptors stimulate adenylyl cyclase, resulting in the accumulation of cyclic AMP and activation of protein kinase A. All four receptor subtypes from several mammalian species have been recently cloned 2-5 , as well as closely related receptors from bony fishes and invertebrates 6, 7 . Although vasopressin is perhaps best-known for its role in the cardiovascular system, it also has actions in the central nervous system (CNS), and several CNS applications of vasopressin receptor antagonists have been suggested (reviewed in references 8 and 9 ). A number of research groups have prepared antagonists directed at the vasopressin V1 receptor 10-15 . While V1a antagonists have been made, none of these have been reported to penetrate the CNS efficiently. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptBioorg Med Chem. Author manuscript; available in PMC 2007 November 8. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptOur vasopressin antagonist program was initiated to identify a CNS-active V1a antagonist: one with potent affinity for the human V1a receptor (IC 50 < 10 nM), good oral availability, and ability to penetrate the blood brain barrier -in short, a candidate for human clinical development targeting CNS disorders. The program began at Lilly in 1990 with the selection of a 1,500-compound "Neuropeptide Cassette" -a library intended to identify nonpeptide ligands for neuropeptide receptors. The library applied the concept of receptor crosstalk -previously well...

The melanocortin receptors have been implicated as potential targets for a number of important therapeutic indications, including inflammation, sexual dysfunction, and obesity. We identified compound 1, an arylpiperazine attached to the dipeptide H-d-Tic-d-p-Cl-Phe-OH, as a novel melanocortin subtype-4 receptor (MC4R) agonist through iterative directed screening of nonpeptidyl G-protein-coupled receptor biased libraries. Structure-activity relationship (SAR) studies demonstrated that substitutions at the ortho position of the aryl ring improved binding and functional potency. For example, the o-isopropyl-substituted compound 29 (K(i) = 720 nM) possessed 9-fold better binding affinity compared to the unsubstituted aryl ring (K(i) = 6600 nM). Sulfonamide 39 (K(i) = 220 nM) fills this space with a polar substituent, resulting in a further 2-fold improvement in binding affinity. The most potent compounds such as the diethylamine 44 (K(i) = 60 nM) contain a basic group at this position. Basic heterocycles such as the imidazole 50 (K(i) = 110 nM) were similarly effective. We also demonstrated good oral bioavailability for sulfonamide 39.