Computational design, synthesis and biological evaluation of PDE5 inhibitors based on N2, N4-diaminoquinazoline and N2, N6-diaminopurine scaffolds. (15th December 2022)

• Record Type: Journal Article
• Authors: Somnarin, Thanachon; Pobsuk, Nattakarn; Chantakul, Ruttanaporn; Panklai, Teerapap; Temkitthawon, Prapapan; Hannongbua, Supa; Chootip, Krongkarn; Ingkaninan, Kornkanok; Boonyarattanakalin, Kanokthip; Gleeson, Duangkamol; Paul Gleeson, M.
• Is Part Of: Bioorganic & medicinal chemistry. Volume 76(2022)
• Publication Date: 2022-12-15
• Subjects: Pulmonary arterial hypertension -- N2, N4-diaminoquinazoline -- N2, N6-diaminopurine -- PDE5 inhibitors -- SAR study -- Structure-based design; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2022.117092
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Highlights: Molecular docking and molecular dynamics used to determine the most probable binding mode of our previously reported 2, 4 diamino-pyrimidine lead. Twenty-nine new compounds have been prepared and tested against phosphodiesterase type 5 (PDE5). Compounds displayed PDE5 activities ranging from 43 μM to 0.1 μM. Analysis of the SAR data validates the proposed binding mode from computational analysis. 25 was found to have a PDE5 IC50 of 0.15 µM and ∼ 1000-fold better solubility compared to our original lead and improved selectivity over PDE1. Abstract: We report the synthesis, and characterization of twenty-nine new inhibitors of PDE5. Structure-based design was employed to modify to our previously reported 2, 4-diaminoquinazoline series. Modification include scaffold hopping to 2, 6-diaminopurine core as well as incorporation of ionizable groups to improve both activity and solubility. The prospective binding mode of the compounds was determined using 3D ligand-based similarity methods to inhibitors of known binding mode, combined with a PDE5 docking and molecular dynamics based-protocol, each of which pointed to the same binding mode. Chemical modifications were then designed to both increase potency and solubility as well as validate the binding mode prediction. Compounds containing a quinazoline core displayed IC50 s ranging from 0.10 to 9.39 µM while those consisting of a purine scaffold ranging from 0.29 to 43.16 µM. We identified 25 with a PDE5 IC50 of 0.15 µM, and much improved solubility (1.77 mg/mL) over the starting lead. Furthermore, it was found that the predicted binding mode was consistent with the observed SAR validating our computationally driven approach.