The central working hypothesis of the proposed study is that the direct in vivo high throughput screening (in vivo HTS) will yield enhanced leads, thereby accelerating the discovery of analgesics with improved safety profiles. This work continues the work of the completed R21 (NIDA DA019620) entitled, """"""""In Vivo Screening of Mixture-Based Combinatorial Libraries"""""""". The overall approach described herein will accelerate drug discovery and the subsequent identification of more advanced therapeutic candidates poised for preclinical studies. The traditional approach to small molecule drug discovery is to identify individual compounds through in vitro HTS assays, before selected compounds are tested in vivo. However, such a late transition to animal testing fosters a high rate of attrition that is costly in both time and research dollars. To circumvent this problem, this proposal utilizes a novel translational approach capable of eliminating non-efficacious compounds at the earliest stage. The long-term goal of these studies is to apply in vivo HTS to accelerate drug discovery in multiple therapeutic areas. As the first step towards that goal, the specific objective in the present application applies this technique to address the need for potent, but inherently safer, analgesic compounds. Marketed opioid analgesics are both potent and effective, but are strongly addictive with potentially life- threatening side effects. This proposal will identify new chemical entities (NCEs) with the potential to advance to human clinical trials and, if successful, improve patients'quality of life while reducing the societal problems posed by nonmedical use of opioid analgesics. The potential of this proposal is clearly supportive of the mission of NIDA, """"""""to lead the Nation in bringing the power of science to bear on drug abuse and addiction."""""""" The research design uses a method of screening large, mixture-based libraries in vivo to identify compounds that are active in an in vivo mouse model of nociception. A total of 37 available, in-house, small molecule library mixtures (representing over 7 million small molecules) will be screened in vivo with animal models of antinociception to identify additional scaffolds for development, complementing a previously identified scaffold. Individual compounds selected from these three scaffolds will be synthesized and purified for additional development which will include in vitro analysis, pharmaceutical profiling, and additional in vivo models. Ultimately, we will examine multiple scaffolds and select 2-3 new chemical entities to initiate preclinical studies. By the end of the proposed study, we will have clearly demonstrated the utility of combining large mixture- based libraries of small molecules with in vivo screening (in vivo HTS) to identify therapeutic hits and leads with demonstrated efficacy and minimized side effects. By utilizing in vivo HTS, compounds may be identified with in vivo efficacies that function through previously unidentified biological pathways, providing potential advances in both the clinical and scientific realms.
This proposal utilizes a new methodology which has the potential to accelerate drug discovery in multiple therapeutic areas. Highly innovative approaches now permit literally millions of compounds to be tested in animal models at a very early stage of the discovery process. Initial studies will be targeted toward the identification of small molecules useful for the treatment of pain and that lack the negative effects of existing pain medications (addiction potential, respiratory depression, tolerance and psychological effects).
|Houghten, Richard A; Ganno, Michelle L; McLaughlin, Jay P et al. (2016) Direct Phenotypic Screening in Mice: Identification of Individual, Novel Antinociceptive Compounds from a Library of 734,821 Pyrrolidine Bis-piperazines. ACS Comb Sci 18:51-64|
|Li, Yangmei; Cazares, Margret; Wu, Jinhua et al. (2016) Potent Î¼-Opioid Receptor Agonists from Cyclic Peptides Tyr-c[D-Lys-Xxx-Tyr-Gly]: Synthesis, Biological, and Structural Evaluation. J Med Chem 59:1239-45|
|Eans, Shainnel O; Ganno, Michelle L; Mizrachi, Elisa et al. (2015) Parallel Synthesis of Hexahydrodiimidazodiazepines Heterocyclic Peptidomimetics and Their in Vitro and in Vivo Activities at Î¼ (MOR), Î´ (DOR), and Îº (KOR) Opioid Receptors. J Med Chem 58:4905-17|
|Knapinska, Anna M; Dreymuller, Daniela; Ludwig, Andreas et al. (2015) SAR Studies of Exosite-Binding Substrate-Selective Inhibitors of A Disintegrin And Metalloprotease 17 (ADAM17) and Application as Selective in Vitro Probes. J Med Chem 58:5808-24|
|Hu, Miao; Giulianotti, Marc A; McLaughlin, Jay P et al. (2015) Synthesis and biological evaluations of novel endomorphin analogues containing Î±-hydroxy-Î²-phenylalanine (AHPBA) displaying mixed Î¼/Î´ opioid receptor agonist and Î´ opioid receptor antagonist activities. Eur J Med Chem 92:270-81|
|Onwuha-Ekpete, Lillian; Tack, Lisa; Knapinska, Anna et al. (2014) Novel pyrrolidine diketopiperazines selectively inhibit melanoma cells via induction of late-onset apoptosis. J Med Chem 57:1599-608|
|Chang, Yi-Pin; Banerjee, Jayati; Dowell, Cheryl et al. (2014) Discovery of a potent and selective Î±3Î²4 nicotinic acetylcholine receptor antagonist from an Î±-conotoxin synthetic combinatorial library. J Med Chem 57:3511-21|
|Chavaroche, Anais; Cudic, Mare; Giulianotti, Marc et al. (2014) Glycosylation of a disintegrin and metalloprotease 17 affects its activity and inhibition. Anal Biochem 449:68-75|
|Haslach, Erica M; Huang, Huisuo; Dirain, Marvin et al. (2014) Identification of tetrapeptides from a mixture based positional scanning library that can restore nM full agonist function of the L106P, I69T, I102S, A219V, C271Y, and C271R human melanocortin-4 polymorphic receptors (hMC4Rs). J Med Chem 57:4615-28|
|Pinilla, Clemencia; Edwards, Bruce S; Appel, Jon R et al. (2013) Selective agonists and antagonists of formylpeptide receptors: duplex flow cytometry and mixture-based positional scanning libraries. Mol Pharmacol 84:314-24|
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