(M1430-04-19) Discovery of BB99: A Potent T2R54 (TAS2R39) Antagonist that Blocks the Bitterness of Select Active Pharmaceutical Ingredients (APIs)

Purpose: Bitter taste is mediated by members of the GPCR family called TAS2Rs (T2Rs).[1] It is often believed that TAS2Rs sense bitterness to help safeguard against ingestion of toxic nutrients.[2] Yet, no coherent correlation between bitterness and toxicity has been established. The bitterness of active pharmaceutical ingredients (APIs) and essential nutrients is a significant barrier to compliance.[3] However, improving their palatability by traditional coating or sweetening is often unsatisfactory or incompatible.[3] The discovery of TAS2Rs modulators is, thus, important not only to generate tools for studying the physiological function of TAS2Rs but also to develop alternative solutions for improving the palatability of bitter tasting products.

Methods: Acetaminophen, guaifenesin, and vitamin B1 are sought-after health ingredients. Unfortunately, they also taste bitter, due entirely or in part to TAS2R39 activation.[4] Therefore, a TAS2R39 antagonist may provide a viable alterative to improve their palatability and thus the adherence to health products containing them. To identify such antagonists, we screened a library of 150K compounds in HTS assays against TAS2R39 leading to S6869 as the top hit.[5] TAS2R39 inhibition by S6869 was further validated using acetaminophen and guaifenesin as agonists. However, S6869 also exhibits undesired agonist activity on TAS2R30 (EC50 = 3.6µM).

Results: Optimization of S6869 antagonist activity led to more potent analogs such as 1-3. While these potently block TAS2R39, they also activate other TAS2Rs. Hence, 1 and 2 tasted bitter on their own. SAR refinement with concurrent optimization of TAS2R39 inhibition, TAS2Rs agonist/antagonist selectivity, stability and solubility among others yielded BB99. Further profiling revealed that BB99 also has decent TAS2R07 and TAS2R46 antagonist activity.

Conclusion: Receptor guided SAR optimization led to the identification of BB99 as a potent TAS2R39 antagonist with decent TAS2R07 and TAS2R46 inhibition. In taste tests, BB99 significantly blocks the bitterness of targeted TAS2R agonists including acetaminophen, guaifenesin, and vitamin B1. Thus, BB99 may be used to reduce the bitterness of products imparting their bitter effect through TAS2R07, TAS2R39, and TAS2R46. Considering these results, BB99 was selected for development. This work further validates TAS2R blocking as an effective approach to mitigate bitterness. We intend to further study and expand our knowledge of TAS2Rs function and related applications.

References: References
[1] M.C. Lagerstrom and H.B. Schioth, Structural diversity of G protein-coupled receptors and significance for drug discovery. Nature reviews. Drug discovery, 2008. 7(4): p. 339-57.
[2] J.R. Fotsing, V. Darmohusodo, A.P. Patron, B.W. Ching, T. Brady, M. Arellano, Q. Chen, T.J. Davis, H. Liu, G. Servant, L. Zhang, M. Williams, M. Saganich, T. Ditschun, C. Tachdjian, and D.S. Karanewsky, Discovery and Development of S6821 and S7958 as Potent TAS2R8 Antagonists. J Med Chem 63(9) (2020) 4957-4977
[3] a) J.A. Mennella, A.C. Spector, D.R. Reed, and S.E. Coldwell, The bad taste of medicines: overview of basic research on bitter taste. Clin Ther 35(8) (2013) 1225-46. b) J. Boateng, Drug Delivery Innovations to Address Global Health Challenges for Pediatric and Geriatric Populations (Through Improvements in Patient Compliance), J Pharm Sci 106(11) (2017) 3188-3198.
[4] a) A.A. Clark, S.B. Liggett, and S.D. Munger, Extraoral bitter taste receptors as mediators of off-target drug effects. FASEB J. 2012 Dec; 26(12): 4827–4831. b) W. Meyerhof, C. Batram, C. Kuhn, A. Brockhoff, E. Chudoba, B. Bufe, G. Appendino, and M. Behrens, The molecular receptive ranges of human TAS2R bitter taste receptors, Chemical senses 35(2) (2010) 157-70.
[5] Chloroquine was used as agonist in the assay.

Acknowledgements: This study was supported by dsm-firmenich.