Pharmacokinetics, Safety, and Intraocular Pressure-Lowering Profile of Omidenepag Isopropyl, a Selective, Nonprostaglandin, Prostanoid EP2 Receptor Agonist, in Healthy Japanese and Caucasian Volunteers (Phase I Study).

Purpose: Omidenepag isopropyl (OMDI) is a prodrug of OMD, a selective, nonprostaglandin, prostanoid EP2 receptor agonist. This phase I study aimed to investigate the pharmacokinetic properties, safety, and intraocular pressure (IOP)-lowering efficacy of OMDI. Methods: Fourteen healthy male volunteers (7 Japanese and 7 Caucasian) 20-35 years of age received 1 drop of OMDI 0.0025% at 9:00 h in both eyes for 7 days. Blood samples were taken predose and up to 8 h postdose on days 1, 3, and 7. The plasma concentration of OMD was determined using high-performance liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters measured included the maximum plasma concentration (Cmax) and the half-life (t½) of OMD. IOP, adverse events (AEs), ophthalmic examinations, vital signs, and laboratory values were assessed. Results:Cmax for all subjects was reached after 10-15 min and decreased with a t½ of ∼30 min. Ad hoc statistical analyses found significant differences in some pharmacokinetic parameters between Japanese and Caucasian subjects, likely due to differences in body weight. These differences reduced over 7 days of dosing and were not thought to be clinically meaningful. There was no OMD accumulation after 7 days of repeated dosing. Mean IOP was reduced by ∼4-5 mmHg between baseline and 2 h postdose, remaining stable from day 3 onward. All AEs were mild and considered treatment related. Conclusions: Pharmacokinetic parameters of OMD were similar between Japanese and Caucasian subjects. There was no accumulation of OMD after 7 days of dosing. OMDI was well tolerated and demonstrated clinically significant IOP reductions.

Pharmacologic Characterization of Omidenepag Isopropyl, a Novel Selective EP2 Receptor Agonist, as an Ocular Hypotensive Agent.

Purpose: The objective of this study was to investigate the pharmacologic characteristics of omidenepag isopropyl (OMDI), a compound developed as a novel intraocular pressure (IOP)-lowering agent, with better IOP control and fewer side effects than other prostanoid receptor agonists such as prostaglandin F receptor (FP) agonists. Methods: Binding activities of OMDI and its hydrolyzed form, omidenepag (OMD), to human recombinant prostanoid receptors (DP1-2, EP1-4, FP, and IP) were evaluated. Based on these binding assays, the agonistic activities of OMDI and OMD were further evaluated using cultured cells expressing selected prostanoid receptors. The pharmacokinetics of OMDI after topical administration was assessed in rabbits by measurement of the concentrations of both OMDI and OMD in aqueous humor. The ocular hypotensive effect of OMDI was evaluated in ocular normotensive rabbits, dogs, and both ocular normotensive and hypertensive monkeys. Results: OMD was determined to be a selective EP2 receptor agonist. OMDI weakly bound to EP1; however, the agonistic activity of OMDI to this receptor was not demonstrated in the functional assay. After topical administration of OMDI, OMD was detected in aqueous humor whereas OMDI was not detectable. OMDI significantly lowered IOP in both ocular normotensive and hypertensive animals. The significant ocular hypotensive effects of OMDI were demonstrated by both single and repeated dosing, and its effective duration suggests sufficient efficacy by once-daily dosing. Conclusions: These studies demonstrated that OMDI is hydrolyzed in the eye to OMD, an EP2 receptor agonist, with a significant ocular hypotensive effect in both ocular normotensive and hypertensive animal models.

Discovery of {1-[4-(2-{hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl}-1H-benzimidazol-1-yl)piperidin-1-yl]cyclooctyl}methanol, systemically potent novel non-peptide agonist of nociceptin/orphanin FQ receptor as analgesic for the treatment of neuropathic pain: design, synthesis, and structure-activity relationships.

Neuropathic pain is a serious chronic disorder caused by lesion or dysfunction in the nervous systems. Endogenous nociceptin/orphanin FQ (N/OFQ) peptide and N/OFQ peptide (NOP) receptor [or opioid-receptor-like-1 (ORL1) receptor] are located in the central and peripheral nervous systems, the immune systems, and peripheral organs, and have a crucial role in the pain sensory system. Indeed, peripheral or intrathecal N/OFQ has displayed antinociceptive activities in neuropathic pain models, and inhibitory effects on pain-related neurotransmitter releases and on synaptic transmissions of C- and Aδ-fibers. In this study, design, synthesis, and structure-activity relationships of peripheral/spinal cord-targeting non-peptide NOP receptor agonist were investigated for the treatment of neuropathic pain, which resulted in the discovery of highly selective and potent novel NOP receptor full agonist {1-[4-(2-{hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl}-1H-benzimidazol-1-yl)piperidin-1-yl]cyclooctyl}methanol 1 (HPCOM) as systemically (subcutaneously) potent new-class analgesic. Thus, 1 demonstrates dose-dependent inhibitory effect against mechanical allodynia in chronic constriction injury-induced neuropathic pain model rats, robust metabolic stability and little hERG potassium ion channel binding affinity, with its unique and potentially safe profiles and mechanisms, which were distinctive from those of N/OFQ in terms of site-differential effects.

Discovery of 1-[1-(1-methylcyclooctyl)-4-piperidinyl]-2-[(3R)-3-piperidinyl]-1H-benzimidazole: integrated drug-design and structure-activity relationships for orally potent, metabolically stable and potential-risk reduced novel non-peptide nociceptin/orphanin FQ receptor agonist as antianxiety drug.

Anxiety disorders, caused by continuous or acute stress or fear, have been highly prevailing psychiatric disorders. For the acute treatment of the disorders, benzodiazepines have been widely used despite having liabilities that limit their utility. Alternatively, endogenous nociceptin/orphanin FQ and nociceptin/orphanin FQ peptide receptor (or opioid-receptor-like-1 receptor) have important roles in the integration of emotional components, e.g. anxiolytic activity is the key behavioral action of nociceptin/orphanin FQ in brain. In our preceding study, various structurally novel 1,2-disubstituted benzimidazole derivatives were designed and synthesized as highly potent nociceptin/orphanin FQ peptide receptor selective full agonists in vitro with high or moderate nociceptin/orphanin FQ peptide receptor occupancy in the mice brain per os based on appropriate physicochemical properties for the oral brain activity [Hayashi et al. (2009) J Med Chem;52:610-625]. In the present study, drug design and structure-activity relationships for Vogel anticonflict activities in mice per os, metabolic stabilities in human liver microsome, CYP2D6 inhibitions, serum protein bindings, and human ether-a-go-go related gene binding affinities of novel nociceptin/orphanin FQ peptide receptor agonists were investigated. Through the series of coherent drug discovery studies, the strongest nociceptin/orphanin FQ peptide receptor agonist, 1-[1-(1-methylcyclooctyl)-4-piperidinyl]-2-[(3R)-3-piperidinyl]-1H-benzimidazole was designed and identified as a new-class orally potent anxiolytic with little side-effects, as significant findings.