# Preclinical Development of a Novel Disease Modifying Therapy for Pulmonary Arterial Hypertension > **NIH NIH R33** · VASCULONICS, LLC · 2021 · $400,526 ## Abstract PROJECT SUMMARY Vasculonics, an Indiana-based small business is developing a novel therapy to reduce progression of pulmonary arterial hypertension (PAH), a debilitating disease with high mortality. Vasculonics technology is a novel modulator of dimethylarginine dimethylaminohydrolase (DDAH) which metabolizes asymmetric dimethyl arginine (ADMA) and an important molecular mechanism contributing to the pulmonary as well as cardiac pathology in PAH. High levels of ADMA and reduced DDAH occur in patients and preclinical models of PAH. In addition to reducing nitric oxide synthesis, high levels of ADMA induce mitochondrial dysfunction, cell death, inflammation and fibrosis. Persistent high ADMA levels can contribute to the progressive vascular remodeling and cardiac hypertrophy observed in PAH. The proof of concept that deficiency of DDAH promoted PAH and cardiovascular disease, and that restauration of DDAH in transgenic animals improved endothelial function, and modified the pathology in the lung and the heart, have been demonstrated. Currently, drugs modulating the DDAH pathway are not available. Vasculonics is developing a novel small molecule modulator of DDAH to reduce pathological levels of ADMA and the progressive vasculopathy in PAH. Vasculonics has identified VN-317 as a novel lead series which enhanced transcription of DDAH-1 in a DDAH promoter based screen. In a preclinical model of PAH, VN-317 has shown robust efficacy by reducing occlusion of lung arteries, and improving lung and cardiac functions. Vasculonics has investigated the structure-activity relationship (SAR) of this chemical scaffold and demonstrated clear SAR for DDAH modulation. In order to advance the VN-317 structural class for the selection of a clinical candidate, Vasculonics is proposing to optimize the drug-like properties of the series and additional chemical scaffold designed as stilbene-mimetics. Structurally distinct compounds will be sequentially evaluated for ideal in vitro and in vivo drug-ability characteristics in tier1 and tier2 assays. The in vivo efficacy of two structurally distinct leads will be confirmed for reducing PAH progression in a rat Sugen- hypoxia model. These studies are expected to enable selection of candidate molecules with desired drug-ability and efficacy to propel two lead molecules to late stage non-clinical CMC and safety studies. Vasculonics has assembled a highly experienced scientific and drug development team to pursue IND enabling studies and advance this potentially new therapy to PAH patients. The proposed studies will help secure future grants and investor funding for further development. A significant market exists for PAH therapy with an estimated value in excess of $4 billion. Therefore, a new disease modifying therapy is expected to have a major medical as well as commercial impact. ## Key facts - **NIH application ID:** 10260552 - **Project number:** 5R33HL154135-02 - **Recipient organization:** VASCULONICS, LLC - **Principal Investigator:** Jaipal Singh - **Activity code:** R33 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2021 - **Award amount:** $400,526 - **Award type:** 5 - **Project period:** 2020-09-15 → 2023-07-31 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10260552 ## Citation > US National Institutes of Health, RePORTER application 10260552, Preclinical Development of a Novel Disease Modifying Therapy for Pulmonary Arterial Hypertension (5R33HL154135-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10260552. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*