ADVERTISEMENT RETURN TO ISSUEReviewNEXTComprehensive Survey of Chemical Libraries for Drug Discovery and Chemical Biology: 2009Roland E. Dolle*†, Bertrand Le Bourdonnec†, Karin Worm†, Guillermo A. Morales‡, Craig J. Thomas§, and Wei Zhang∥View Author Information Adolor Corporation, 700 Pennsylvania Drive, Exton, Pennsylvania 19341, Morales Consulting, LLC, 11474 Perkins Street, Carmel, Indiana 46032, NIH Chemical Genomics Center, National Human Genome Research Institute, National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland 20850, and Department of Chemistry, University of Massachusetts, 100 Morrissey Boulevard, Boston, Massachusetts 02125* To whom correspondence should be addressed. E-mail: [email protected]. Phone: 484-595-1024. Fax: 484-595-1551.†Adolor Corporation.‡Morales Consulting.§NIH Chemical Genomics Center.∥University of Massachusetts.Cite this: J. Comb. Chem. 2010, 12, 6, 765–806Publication Date (Web):October 5, 2010Publication History Received9 July 2010Published online5 October 2010Published inissue 8 November 2010https://pubs.acs.org/doi/10.1021/cc100128whttps://doi.org/10.1021/cc100128wreview-articleACS PublicationsCopyright © 2010 American Chemical SocietyRequest reuse permissionsArticle Views4955Altmetric-Citations85LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access options SUBJECTS:Antagonists,Chemical synthesis,Inhibitors,Organic compounds,Receptors Get e-Alerts

Chiral recognition and resolution of methanobenzazocines was investigated by HPLC using polysaccharide, Pirkle-type, native and derivatized β-cyclodextrin chiral stationary phases. Enantioseparation of phenyl substituted 2,6-methanobenzazocines was achieved with multiple chiral stationary phases throughout the classes described. Chiral resolution of the enantiomers of 1,5-methano-3-methyl-6-oxo-1,2,3,4,5,6-hexahydro-3-benzazocine was produced on both polysaccharide and Pirkle-type phases. In the case of 1,5-methano-3-methyl-6-phenyl-1,2,3,4,5,6-hexahydro-3-benzazocine only a dinitrophenyl substituted β-cyclodextrin produced a separation of enantiomers.

Replacement of the phenyl ring in our previous (morpholinomethyl)aniline carboxamide cannabinoid receptor ligands with a pyridine ring led to the discovery of a novel chemical series of CB2 ligands. Compound 3, that is, 2,2-dimethyl-N-(5-methyl-4-(morpholinomethyl)pyridin-2-yl)butanamide was identified as a potent and selective CB2 agonist exhibiting in vivo efficacy after oral administration in a rat model of neuropathic pain.

Recently sulfamoyl benzamides were identified as a novel series of cannabinoid receptor ligands. Replacing the sulfonamide functionality and reversing the original carboxamide bond led to the discovery of N-(3-(morpholinomethyl)-phenyl)-amides as potent and selective CB2 agonists. Selective CB2 agonist 31 (Ki = 2.7; CB1/CB2 = 190) displayed robust activity in a rodent model of postoperative pain.

Non-selective cannabinoid ligands display a wide range of physiological effects including analgesic, antiinflammatory, anti-convulsive and immuno-suppressive activities. A separation between therapeutic effects and undesirable CNS side effects may be accomplished by increasing the selectivity for the CB2 receptor over the CB1 receptor. There is considerable interest in developing new cannabimimetic compounds possessing preferentially high affinity for the CB2 receptor as potential novel therapeutics for the treatment of inflammation and chronic pain. This review will summarize the literature on selective cannabinoid CB2 receptor agonists from 2007 to the present, with special emphasis on SAR and medicinal chemistry strategies to improve physicochemical properties, metabolic stability and oral bioavailabilty of these inherently lipophilic ligands. Incorporating physicochemical property filters early in hit identification, concurrent screening of liver microsomal stability and addressing metabolic hot-spots through structural modifications or bio-isosteric replacements during lead optimization led to a number of structurally diverse CB2 agonists with good oral bioavailability and in vivo efficacy in rodent models of pain.

A lead optimization campaign in our previously reported sulfamoyl benzamide class of CB(2) agonists was conducted to improve the in vitro metabolic stability profile in this series while retaining high potency and selectivity for the CB(2) receptor. From this study, compound 14, N-(3,4-dimethyl-5-(morpholinosulfonyl)phenyl)-2,2-dimethylbutanamide, was identified as a potent and selective CB(2) agonist exhibiting moderate in vitro metabolic stability and oral bioavailability. Compound 14 demonstrated in vivo efficacy in a rat model of post-surgical pain.

Previous research within our laboratories identified sulfamoyl benzamides as novel cannabinoid receptor ligands. Optimization of the amide linkage led to the reverse amide 40. The compound exhibited robust antiallodynic activity in a rodent pain model when administered intraperitoneally. Efficacy after oral administration was observed only when ABT, a cytochrome P450 suicide inhibitor, was coadministered.

Sulfamoyl benzamides were identified as a novel series of cannabinoid receptor ligands. Starting from a screening hit 8 that had modest affinity for the cannabinoid CB(2) receptor, a parallel synthesis approach and initial SAR are described, leading to compound 27 with 120-fold functional selectivity for the CB(2) receptor. This compound produced robust antiallodynic activity in rodent models of postoperative pain and neuropathic pain without traditional cannabinergic side effects.

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