RAD140 is a potent, orally bioavailable, nonsteroidal selective androgen receptor modulator (SARM). It was developed to overcome increased risks of prostate cancer, dysfunction and disease in androgen-responsive tissues, including brain, caused by testosterone therapy in men experiencing decline in testosterone levels during normal aging. It was characterized in several rat and monkey models of anabolic androgen action and demonstrated neuroprotective actions relevant to cachexia, Alzheimer's disease and related neurodegenerative diseases. In experiments with gonadectomized, adult male rats, RAD140 was shown to exhibit peripheral tissue-specific androgen action that largely spared prostate, neural efficacy as demonstrated by activation of androgenic gene regulation effects, and neuroprotection of hippocampal neurons against cell death caused by systemic administration of the excitotoxin kainate. In cultured hippocampal neurons, RAD140 was as effective as testosterone in reducing cell death induced by apoptotic insults. RAD140 neuroprotection was dependent upon MAPK signaling, as evidenced by elevation of ERK phosphorylation and inhibition of protection by the MAPK kinase inhibitor U0126.

PL-3994 is a novel natriuretic cyclic peptide. It is a receptor-A (NPR-A) and receptor-C (NPR-C) agonist. PL-3994 has high affinity for recombinant human, dog, or rat NPR-As. PL-3994 produced concentration-dependent relaxation of pre-contracted guinea-pig trachea. PL-3994 elicited a potent, concentration-dependent but small relaxation of pre-contracted human precision-cut lung slices. Intratracheal PL-3994 produced a dose-dependent inhibition of the bronchoconstrictor response evoked by aerosolized methacholine, but was without significant effect on cardiovascular parameters. PL-3994 was resistant to degradation by human neutral endopeptidase. PL-3994 was well tolerated in subjects with controlled hypertension. A phase I and phase II trial have been successfully completed with PL-3994 with no safety concerns identified. In phase II study in subjects with hypertension who were receiving >1 antihypertensive medications, a significant reduction in blood pressure compared with placebo was observed. It appears that PL-3994 works synergistically with ACE inhibitors.