PDE9 inhibitor
BI 409306
BI 409306 (osoresnontrine) is an oral, highly selective phosphodiesterase-9 (PDE9) inhibitor1,2,3. Inhibition of PDE9 is expected to restore physiological cGMP levels in neurons to improve NMDA receptor signaling and thus strengthening synaptic plasticity. Additionally, PDE9 inhibition may also impact cGMP-dependent processes in other cell types expressing PDE9, e.g. to improve cardiovascular function. BI-8777 is a structural close analog of BI 409306 and can be used as negative control.
More information
Phosphodiesterase-9 (PDE9) is an enzyme that specifically hydrolyzes cyclic guanosine monophosphate (cGMP), a critical second messenger involved in various physiological processes, including neuronal signaling, vascular function, and cell survival. By breaking down cGMP, PDE9 regulates its intracellular levels and, consequently, the signaling pathways dependent on this molecule. Highly selective PDE9 inhibitors work by blocking the activity of PDE9, leading to an increase in cGMP levels1,2.
Selective PDE9 inhibitors were/are being investigated for their potential in treating a variety of diseases, particularly those involving the central nervous system (CNS)3. In neurological and psychiatry disorders, they aimed to address cognitive deficits in schizophrenia5 and Alzheimer’s disease6 by enhancing synaptic plasticity and neuronal communication. Beyond CNS applications, PDE9 inhibitors were/are being explored for cardiovascular diseases7,8, where they could improve vascular function and reduce cardiac stress, as well as for other indications beyond neurological disorders and cardiovascular diseases9.
While highly selective PDE9 inhibitors represent a promising class of drugs with potential applications in neurological, psychiatric, and cardiovascular diseases, further research is needed to fully understand their therapeutic potential and address the challenges associated10.
Model of the complex of PDE9 with BI409306, based on the crystal structure with a highly related inhibitor
BI 409306 (osoresnontrine) is a potent and selective PDE9 inhibitor2.
| Probe name / Negative control | BI409306 (osoresnontrine) | BI-8777 |
| MW [Da]a | 311.3 | 339.4 |
| PDE9A (IC50) [nM] | 65 | 2,541 |
| PDE1A (IC50) [nM] | 1,278 | n.a. |
| PDE1C (IC50) [nM] | 1,300 | 3,552 |
| PDE2A (IC50) [nM] | >10,000 | n.a. |
| PDE3A (IC50) [nM] | >10,000 | n.a. |
| PDE4B (DC50) [nM] | >10,000 | n.a. |
| PDE5A (IC50) [nM] | >10,000 | n.a. |
| PDE6AB (IC50) [nM] | >10,000 | n.a. |
| PDE7A (IC50) [nM] | >10,000 | n.a. |
| PDE10A (IC50) [nM] | >10,000 | n.a. |
a For the salt form you will get, please refer to the label on the vial and for the molecular weight of the salt, please refer to the FAQs
BI 409306 exhibits good solubility, excellent fraction unbound and low in-vitro efflux ratio, which makes it especially suited for brain penetrance and CNS indications & research.
| Probe name / Negative control | BI 409306 (osoresnontrine) | BI-8777 |
| logD @ pH 2, 7, 11 | - / 1.7/ - | -0.34 / n.a. / 0.05 |
| Solubility @ pH 7 [µg/ml] | 500 | tbd |
| Caco-2 permeability AB @ pH 7.4 [*10-6 cm/s] | 58.5 | 53 |
| Caco-2 efflux ratio | 1.2 | 0.8 |
| MDCK permeability PappAB @ 1µM [10-6 cm/s] | 24 | 42 |
| MDCK efflux ratio | 1.5 | 1.4 |
| Microsomal stability (human/mouse/rat) [% QH] | <23 / <30 / <9 | <23 / <23 / <23 |
| Hepatocyte stability (human/mouse/rat) [% QH] | 9 / 46 / 9 | 14 / 81 / 51 |
| Plasma Protein Binding (human/mouse/rat) [%] | 24 / 33.8 / 42 | 46.7 / 46.9 / 28.6 |
| hERG (IC50) [nM] | >100 | tbd |
| CYP 3A4 (IC50) [µM] | >50 | tbd |
| CYP 1A2 (IC50) [µM] | >50 | >50 |
| CYP 2C9 (IC50) [µM] | >50 | >50 |
| CYP 2C19 (IC50) [µM] | >50 | >50 |
| CYP 2D6 (IC50) [µM] | >50 | >50 |
BI 409306 (osoresnontrine) shows excellent brain penetrance, free brain exposure and high oral availability in rodents.
| BI 409306 (osoresnontrine) | Mousea | Ratb |
| Clearance [% QH] | 30 | 30 |
| Brain / Plasma ratio | 0.2 | 0.2 |
| CSF / Plasma ratio | 0.3 | 0.2 |
| Mean residence time after i.v. dose [h]a | 0.4 | 0.5 |
| tmax [h] | 0.5 | 0.5 |
| Cmax [nM] | 2681 | 465 |
| F [%] | >100% | 57 |
| Vss [L/kg] | 0.5 | 0.7 |
a i.v. dose: 3.1 mg/kg, p.o. dose: 1.6 mg/kg
b i.v. dose: 3.1 mg/kg, p.o. dose: 1.6 mg/kg
As also published previously1,2,3, BI 409306 (osoresnontrine) has been tested in various animal test demonstrating:
- proof-of-mechanism regarding synaptic plasticity by enhancement of hippocampal LTP
- indirect target engagement by increase of cGMP in brain, microdialysis and CSF
- pro-cognitive efficacy in two mouse tasks addressing spatial working memory and episodic/ recognition memory
- efficacy in a neurodevelopmental model mouse related to schizophrenia
The effect of PDE9 inhibition on synaptic plasticity has been investigated by determination of long-term potentiation (LTP) in rat hippocampal brain slices. During the procedure, the compound was applied specifically during the stimulation period and subsequently washed out. PDE9 inhibition was found to induce a long-lasting enhancement of LTP (Fig. 4), highlighting its potential to strengthen synaptic plasticity, which serves as the molecular and cellular basis to improve memory-related processes.
Inhibition of PDE9 by BI 409306 led to a significant enhancement LTP in rat hippocampal brain slice
To demonstrate the increase of cGMP after PDE9 inhibition in vivo, extracellular cGMP was measured via microdialysis after systemic administration (i.p.) of BI 409306. Here, BI 409306 showed a dose-dependent increase of cGMP in the prefrontal cortex (Fig. 5a). Furthermore, in order to evaluate cGMP increase in CSF as indirect target engagement, BI 409306 was administered orally to rats and the cGMP increase in CSF was determined. In this study, BI 409306 showed a dose-dependent increase of cGMP in rat CSF from 0.3 - 10 mg/kg p.o. up to 2.5-fold (Fig. 5b).
The effect of BI 409306 on increase of cGMP levels in (A) rat prefrontal cortex by microdialysis and (B) by collection of CSF samples after systemic administration of compound
BI 409306 was profiled in two different cognition tests in mice, i.e. T-maze spontaneous alternation test (T-maze) and novel object recognition test (NOR). In both tasks, BI 409306 showed significant improvement of cognitive performance and memory function (Fig. 6a and 6b, respectively).
Efficacy of BI 409306 on (A) working memory in the T-maze spontaneous alternation task (reversal of MK-801 induced impairment) determined by spontaneous alternation behaviour and (B) on episodic memory in the object recognition task in mice determined
Furthermore, BI 409306 was tested in a neurodevelopmental mouse model, which is based on a maternal immune activation (MIA) of pregnant mice by a single injection of polyI:C (double stranded RNA), leading to a phenotype in the offspring related to schizophrenia. In this mouse model, BI 409306 significantly mitigated MIA induced social interaction deficits and amphetamine-induced hyperlocomotion, but not prepulse inhibition impairments, in a dose- dependent manner. In addition, in a second study BI 409306 treatment restricted to adolescence prevented adult deficits of the offspring in social interaction (Fig. 7).
Effects of early chronic or preventive treatment with BI 409306 in adolescent CON or MIA offspring. Effects of vehicle or drug exposure on social interaction, as indexed by the social preference index, shows efficacy of BI 409306 on preventing social interaction deficits in adult offsprings
BI-8777 is a structurally close analog and can be used as negative control.
BI-8777 which serves as a negative control
BI 409306 (osoresnontrine) inhibited none out of 97 tested targets in an extended SafetyScreen44™ by greater than 50% @ 10µM.
| SELECTIVITY DATA AVILABLE | BI 409306 (osoresnontrine) | BI‑8777 |
SafetyScreen44™ with kind support of  | Yes | No |
Download selectivity data:
BI-409306_selectivityData.xlsx
Possible PDE9 tool compounds are Bay73-669111 and PF-444794312.
Inhibition of PDE9 is expected to restore physiological cGMP levels in neurons, thereby enhancing NMDA receptor signaling and synaptic plasticity. BI 409306 (osoresnontrine) is a highly selective oral PDE9 inhibitor and BI-8777 an inactive analog which serves as a negative control.
The Novel Phosphodiesterase 9A Inhibitor BI 409306 Increases Cyclic Guanosine Monophosphate Levels in the Brain, Promotes Synaptic Plasticity, and Enhances Memory Function in Rodents
Rosenbrock H., Giovannini R., Schänzle G., Koros E., Runge F., Fuchs H., Marti A., Reymann K. G., Schröder U. H., Fedele E., Dorner-Ciossek C.
J Pharmacol Exp Ther 2019, 371(3), 633–641.
A randomized Phase II trial evaluating efficacy, safety, and tolerability of oral BI 409306 in attenuated psychosis syndrome: Design and rationale Early
Keefe R. S. E., Woods S. W., Cannon T. D., Ruhrmann S., Mathalon D. H., McGuire P., Rosenbrock H., Daniels K., Cotton D., Roy D., Pollentier S., Sand M.
Early Interv Psychiatry 2021, 15(5), 1315–1325.
Symptomatic and preventive effects of the novel phosphodiesterase-9 inhibitor BI 409306 in an immune-mediated model of neurodevelopmental disorders
Scarborough J., Mattei D., Dorner-Ciossek C., Sand M., Arban R., Rosenbrock H., Richetto J., Meyer U.
Neuropsychopharmacology 2021, 46(8), 1526–1534.
The novel selective PDE9 inhibitor BAY 73-6691 improves learning and memory in rodents
van der Staay F. J., Rutten K., Bärfacker L., Devry J., Erb C., Heckroth H., Karthaus D., Tersteegen A., van Kampen M., Blokland A., Prickaerts J., Reymann K. G., Schröder U. H., Hendrix M.
Neuropharmacology 2008, 55(5), 908–918.
The selective phosphodiesterase 9 (PDE9) inhibitor PF-04447943 (6-(3S,4S)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo3,4-dpyrimidin-4-one) enhances synaptic plasticity and cognitive function in rod
Hutson P. H., Finger E. N., Magliaro B. C., Smith S. M., Converso A., Sanderson P. E., Mullins D., Hyde L. A., Eschle B. K., Turnbull Z., Sloan H., Guzzi M., Zhang X., Wang A., Rindgen D., Mazzola R., Vivian J. A., Eddins D., Uslaner J. M., Bednar R., Gambone C., Le-Mair W., Marino M. J., Sachs N., Xu G., Parmentier-Batteur S.
Neuropharmacology 2011, 61(4), 665–676.
When you plan a publication, please use the following acknowledgement:
BI409306 was kindly provided by Boehringer Ingelheim via its open innovation platform opnMe, available at https://www.opnme.com.