- Spirocyclic delta opioid receptor agonists for the treatment of pain: Discovery of N,N-diethyl-3-hydroxy-4-(spiro[chromene-2,4′-piperidine]-4- yl) benzamide (ADL5747)
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Selective, nonpeptidic δ opioid receptor agonists have been the subject of great interest as potential novel analgesic agents. The discoveries of BW373U86 (1) and SNC80 (2) contributed to the rapid expansion of research in this field. However, poor drug-like properties and low therapeutic indices have prevented clinical evaluation of these agents. Doses of 1 and 2 similar to those required for analgesic activity produce convulsions in rodents and nonhuman primates. Recently, we described a novel series of potent, selective, and orally bioavailable delta opioid receptor agonists. The lead derivative, ADL5859 (4), is currently in phase II proof-of-concept studies for the management of pain. Further structure activity relationship exploration has led to the discovery of ADL5747 (36), which is approximately 50-fold more potent than 4 in an animal model of inflammatory pain. On the basis of its favorable efficacy, safety, and pharmacokinetic profile, 36 was selected as a clinical candidate for the treatment of pain.
- Bourdonnec, Bertrand Le,Windh, Rolf T.,Leister, Lara K.,Zhou, Q. Jean,Ajello, Christopher W.,Gu, Minghua,Chu, Guo-Hua,Tuthill, Paul A.,Barker, William M.,Koblish, Michael,Wiant, Daniel D.,Graczyk, Thomas M.,Belanger, Serge,Cassel, Joel A.,Feschenko, Marina S.,Brogdon, Bernice L.,Smith, Steven A.,Derelanko, Michael J.,Kutz, Steve,Little, Patrick J.,Dehaven, Robert N.,DeHaven-Hudkins, Diane L.,Dolle, Roland E.
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experimental part
p. 5685 - 5702
(2010/02/28)
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- 2-PHENYL SUBSTITUTED IMIDAZOL [4 , 5B] PYRIDINE/ PYRAZINE AND PURINE DERIVATIVES AS GLUCOKINASE MODULATORS
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Compounds of Formula (I), wherein R1- R10, A and X1 to X3 are as described in the specification, and their salts and pro-drugs, are activators of glucokinase (GLK) and are thereby useful in the treatment of, for example, type 2 diabetes. Processes for preparing compounds of formula (I) are also described.
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Page/Page column 102-103
(2010/11/25)
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- SUBSTITUTED TRIAZOLE DERIVATIVES AS OXYTOCIN ANTAGONISTS
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The present invention relates to a class of substituted 1,2,4-triazoles of formula (I) with activity as oxytocin antagonists, uses thereof, processes for the preparation thereof and compositions containing, said, inhibitors. These inhibitors have utility in a variety of therapeutic areas including sexual dysfunction, particularly premature ejaculation (P.E.).
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Page/Page column 87-88
(2010/02/11)
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