70547-29-4Relevant articles and documents
Discovery of Novel TRPM8 Blockers Suitable for the Treatment of Somatic and Ocular Painful Conditions: A Journey through p Kaand LogD Modulation
Bianchini, Gianluca,Tomassetti, Mara,Lillini, Samuele,Sirico, Anna,Bovolenta, Silvia,Za, Lorena,Liberati, Chiara,Novelli, Rubina,Aramini, Andrea
, p. 16820 - 16837 (2021/11/24)
Transient receptor potential melastatin 8 (TRPM8) is crucially involved in pain modulation and perception, and TRPM8 antagonists have been proposed as potential therapeutic approaches for pain treatment. Previously, we developed two TRPM8 antagonists and proposed them as drug candidates for topical and systemic pain treatment. Here, we describe the design and synthesis of these two TRPM8 antagonists (27 and 45) and the rational approach of modulation/replacement of bioisosteric chemical groups, which allowed us to identify a combination of narrow ranges of pKa and LogD values that were crucial to ultimately optimize their potency and metabolic stability. Following the same approach, we then pursued the development of new TRPM8 antagonists suitable for the topical treatment of ocular painful conditions and identified two new compounds (51 and 59), N-alkoxy amide derivatives, that can permeate across ocular tissue and reduce the behavioral responses induced by the topical ocular menthol challenge in vivo.
Enabling the (3 + 2) cycloaddition reaction in assembling newer anti-tubercular lead acting through the inhibition of the gyrase ATPase domain: Lead optimization and structure activity profiling
Jeankumar, Variam Ullas,Reshma, Rudraraju Srilakshmi,Janupally, Renuka,Saxena, Shalini,Sridevi, Jonnalagadda Padma,Medapi, Brahmam,Kulkarni, Pushkar,Yogeeswari, Perumal,Sriram, Dharmarajan
supporting information, p. 2423 - 2431 (2015/03/04)
DNA gyrase, the sole type II topoisomerase present in Mycobacterium tuberculosis, is absent in humans and is a well validated target for anti-tubercular drug discovery. In this study, a moderately active inhibitor of Mycobacterium tuberculosis GyrB, the pharmaceutically unexploited domain of DNA gyrase, was reengineered using a combination of molecular docking and medicinal chemistry strategies to obtain a lead series displaying considerable in vitro enzyme efficacy and bacterial kill against the Mycobacterium tuberculosis H37Rv strain. Biophysical investigations using differential scanning fluorimetry experiments re-ascertained the affinity of these molecules towards the GyrB domain. Furthermore, the molecules were completely devoid of hERG toxicity up to 30 μM, as evaluated in a zebra fish model with a good selectivity index, and from a pharmaceutical point of view, turned out as potential candidates against TB. This journal is
TRPM8 ANTAGONISTS
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Page/Page column 14; 15, (2013/07/05)
The invention relates to compounds acting as selective antagonists of Transient Receptor Potential cation channel subfamily M member 8 (TRPM8), and having formula (I). Said compounds are useful in the treatment of diseases associated with activity of TRPM8 such as pain, inflammation, ischaemia, neurodegeneration, stroke, psychiatric disorders, itch, irritable bowel diseases, cold induced and/or exhacerbated respiratory disorders and urological disorders.
