Discovery of an Orally Active PDE1 Inhibitor for Disease-Modifying Treatment of Postmenopausal Osteoporosis via Dual Anabolic-Antiresorptive Mechanisms.

Abstract

Postmenopausal osteoporosis (PMO) is characterized by an imbalance in bone remodeling with increased osteoclast and decreased osteoblast activity, leading to bone loss and higher fracture risk. Current treatments, such as teriparatide, boost bone formation but also elevate resorption, limiting their long-term effectiveness. We discovered 3-butyl-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4(3H)-one (5cc), an orally active phosphodiesterase-1 (PDE1) inhibitor aimed at restoring this balance. 5cc enhances osteoblast differentiation assessed by increased alkaline phosphatase activity, Runx2 expression, and mineralized nodule formation. Additionally, it inhibited osteoclastogenesis by suppressing the RANKL/OPG ratio, modulating Eph-Ephrin signaling, and attenuating IL-1β-induced ROS and NF-κB activation in vitro. In ovariectomized mice, 5cc administration (5 mg/kg) improved the trabecular microarchitecture, bone mineral density, and strength, at levels comparable to teriparatide, while significantly reducing bone resorption markers. With 13.57% oral bioavailability and selectivity for PDE1A1 (32% inhibition at 500 nM), 5cc offers an innovative therapeutic candidate for PMO with a dual anabolic-antiresorptive profile and oral efficacy, warranting further clinical development.