Discovery of small-molecule modulators of the secretin receptor: Purmorphamine as novel anti-hypertensive agent.

Autor: Singh K; School of Biological Science, The University of Hong Kong, HK, China., Nawabjan SA; School of Biological Science, The University of Hong Kong, HK, China., Zhang L; GHM Institute of CNS Regeneration Jinan University, China., El-Nezami H; School of Biological Science, The University of Hong Kong, HK, China., Annapureddy RR; Department Chemie, Ludwig-Maximilians-Universität München, Germany. Electronic address: raja.annapureddy@cup.uni-muenchen.de., Chow BK; School of Biological Science, The University of Hong Kong, HK, China. Electronic address: bkcc@hku.hk.
Jazyk: angličtina
Zdroj: European journal of medicinal chemistry [Eur J Med Chem] 2022 Nov 15; Vol. 242, pp. 114642. Date of Electronic Publication: 2022 Aug 05.
DOI: 10.1016/j.ejmech.2022.114642
Abstrakt: The Secretin/Secretin receptor (SCTR) axis is well-known for its important role in water/salt homeostasis and blood pressure control. Recent studies revealed that absence of Secretin could lead to hypertension in animals and the administration of external Secretin leads to a sharp drop in blood pressure. Therefore, Secretin receptor has emerged as a crucial drug target of interest. In this report, using structure based drug design strategy, we have identified a small compound-based Secretin receptor modulator (i.e. purmorphamine or KSD179019). The virtual docking of KSD179019 with SCTR crystal structure and homology models revealed similar binding interactions. Based on active pharmacophores of KSD179019, several derivatives were designed and sythesized. SAR studies revealed that KSD179019 is the most effective SCTR modulator and chosen for further biological evaluation, including drug like properties and anti-hypertensive effect. KSD179019 not only has a similar blood pressure lowering effect as SCT peptide, but more importantly, it has a much longer half-life (∼8 h) and can be taken orally. Preliminary preclinical studies revealed extended bioavailability and low toxicity of this compound.
Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. K.S., and B. KC Chow have patent licensed to WO/2020/211772, International application no. PCT/CN2020/084879. no.
(Copyright © 2022 Elsevier Masson SAS. All rights reserved.)
Databáze: MEDLINE
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