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

• Published in: European journal of medicinal chemistry 2022-11, Vol.242, p.114642-114642, Article 114642
• Main Authors: Singh, Kailash, Nawabjan, Shaik Abdullah, Zhang, Li, El-Nezami, Hani, Annapureddy, Rajasekar reddy, Chow, Billy KC
• Format: Article
• Language: English
• Subjects: Hypertension; Positive allosteric modulator; Purmorphamine; Secretin receptor; Small-molecule drugs; Structure activity relationship
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2022.114642

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. [Display omitted] •Discovered a small molecule compound Purmorphamine as a modulator for Secretin receptor (SCTR).•SAR studies revealed the presence of morpholine core to be important for positive allosteric modulation of SCT function.•For the first time, we provide critical evidence for Purmorphamine to be used as novel anti-hypertensive drug candidate.•Preclinical studies revealed extended bioavailability and low toxicity of Purmorphamine.