Blueprint Neurotherapeutics Network (BPN): Small Molecule Drug Discovery and Development (UG3/UH3) is sponsored by National Institutes of Health (NIH). Provides funding and access to industry-standard drug development contract resources (CROs) to advance small molecule drug discovery projects toward Phase I clinical trials.

PAR-25-051: Blueprint Neurotherapeutics Network (BPN): Small Molecule Drug Discovery and Development of Disorders of the Nervous System (UG3/UH3 Clinical Trial Optional) This funding opportunity was updated to align with agency priorities. Carefully reread the full funding opportunity and make any needed adjustments to your application prior to submission. Department of Health and Human Services Part 1.

Overview Information Participating Organization(s) National Institutes of Health ( NIH ) Components of Participating Organizations National Institute of Neurological Disorders and National Eye Institute ( NEI ) National Institute on Alcohol Abuse and Alcoholism ( NIAAA ) National Institute of Dental and Craniofacial Research ( NIDCR ) National Institute on Drug Abuse ( NIDA ) National Institute of Mental Health ( NIMH ) National Center for Complementary and Integrative Health ( NCCIH ) Funding Opportunity Title Blueprint Neurotherapeutics Network (BPN): Small Molecule Drug Discovery and Development of Disorders of the Nervous System (UG3/UH3 Clinical Trial Optional) UG3 / UH3 Exploratory/Developmental Phased Award Cooperative Agreement May 8, 2025 - Notice of Change: Expiration of RFA-NS-24-019: HEAL Initiative: Non-addictive Analgesic Therapeutics Development [Small Molecules and Biologics] to Treat Pain (UG3/UH3 Clinical Trial Optional).

See Notice NOT-NS-25-024 . March 31, 2025 - This funding opportunity was updated to align with agency priorities. Carefully reread the full funding opportunity and make any needed adjustments to your application prior to submission.

April 4, 2024 - Overview of Grant Application and Review Changes for Due Dates on or after January 25, 2025. See Notice NOT-OD-24-084 . August 31, 2022 - Implementation Changes for Genomic Data Sharing Plans Included with Applications Due on or after January 25, 2023.

See Notice NOT-OD-22-198 . August 5, 2022 - Implementation Details for the NIH Data Management and Sharing Policy. See Notice NOT-OD-22-189 .

Funding Opportunity Number (FON) Companion Funding Opportunity See Section III. 3. Additional Information on Eligibility .

Assistance Listing Number(s) 93. 853, 93. 866, 93.

273, 93. 213, 93. 867, 93.

242, 93. 279, 93. 121 Funding Opportunity Purpose The Blueprint Neurotherapeutics Network (BPN) invites applications from neuroscience investigators seeking support to advance their small molecule drug discovery and development projects into the clinic.

Participants in the BPN are responsible for conducting all studies that involve disease- or target-specific assays, models, and other research tools and receive funding for all activities to be conducted in their own laboratories.

In addition, applicants will collaborate with NIH-funded consultants and can augment their project with NIH contract research organizations (CROs) that specialize in medicinal chemistry, pharmacokinetics, toxicology, formulations development, chemical synthesis including under Good Manufacturing Practices (GMP), and Phase I clinical testing. Projects can enter either at the Discovery or the Development stage.

In the Discovery phase the goal is to characterize and optimize promising hit compounds using medicinal chemistry to establish structure activity relationships (SAR) and structure property relationships (SPR) including in vitro and in vivo properties such as metabolism, selectivity, toxicity, etc. As projects enter or advance to the Development stage the goal is to advance a single development candidate through Investigational New Drug (IND)-enabling toxicology studies and phase I clinical testing.

Projects can enter the program at the Development stage and progress in a shorter period to IND enabling toxicology studies and phase I clinical testing. BPN recipient Institutions retain their assignment of intellectual property (IP) rights and gain assignment of IP rights from the BPN contractors and consultants (and thereby control the patent prosecution and licensing negotiations) for drug candidates developed in this program.

Open Date (Earliest Submission Date) Renewal / Resubmission / Revision (as allowed) AIDS - New/Renewal/Resubmission/Revision, as allowed All applications are due by 5:00 PM local time of applicant organization. Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.

Required Application Instructions It is critical that applicants follow the instructions in the Research (R) Instructions in the How to Apply - Application Guide , except where instructed to do otherwise (in this NOFO or in a Notice from NIH Guide for Grants and Contracts ). Conformance to all requirements (both in the Application Guide and the NOFO) is required and strictly enforced.

Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions. Applications that do not comply with these instructions may be delayed or not accepted for review.

There are several options available to submit your application through Grants. gov to NIH and Department of Health and Human Services partners. You must use one of these submission options to access the application forms for this opportunity.

Use the NIH ASSIST system to prepare, submit and track your application online. Use an institutional system-to-system (S2S) solution to prepare and submit your application to Grants. gov and eRA Commons to track your application.

Check with your institutional officials regarding availability. Workspace to prepare and submit your application and eRA Commons to track your application. Part 1.

Overview Information Part 2. Full Text of Announcement Section I. Notice of Funding Opportunity Description Section II.

Award Information Section III. Eligibility Information Section IV. Application and Submission Information Section V.

Application Review Information Section VI. Award Administration Information Section VII. Agency Contacts Section VIII.

Other Information Part 2. Full Text of Announcement Section I. Notice of Funding Opportunity Description Recent advances in neuroscience offer unprecedented opportunities to discover new treatments for nervous system disorders.

However, before a new chemical entity can be tested in a clinical setting, it must undergo a process of chemical optimization to improve potency, selectivity, and drug-like properties, followed by pre-clinical safety testing to meet the standards set by the Food and Drug Administration (FDA) for clinical testing.

All of the necessary expertise and resources are not commonly available to academic labs and many small companies as these activities are largely the domain of large pharmaceutical and biotechnology companies and contract research organizations (CROs). To facilitate drug discovery and development by the neuroscience community, the NIH Blueprint for Neuroscience Research ( https://neuroscienceblueprint. nih.

gov/ ) established the Blueprint Neurotherapeutics Network (BPN), which offers neuroscience researchers funding for drug discovery and development activities that can be conducted in their own laboratories.

Researchers have the opportunity to collaborate with NIH-funded consultants and CROs that specialize in medicinal chemistry, pharmacokinetics, toxicology, formulations development, chemical synthesis under Good Manufacturing Practices (GMP), and Phase I clinical testing. A current list of BPN contractors and consultants is available at https://neuroscienceblueprint. nih.

gov/bpdrugs/bpn_resources. htm. This Notice of Funding Opportunity (NOFO) invites applications for new BPN projects.

The Principal Investigator (PI) will be responsible for conducting all studies that involve disease- or target-specific assays, models, and other research tools.

A PI with, for example, medicinal chemistry expertise and resources, may additionally request funding to conduct structure-activity relationship (SAR) studies in their own lab but collaborate with BPN contractors on in vitro ADMET, in vivo PK, drug manufacturing and IND-enabling toxicology studies. By contrast, a PI with limited experience in drug discovery and development may opt to collaborate with all available BPN contractors.

Applicants may propose to conduct all drug discovery and development activities themselves or collaborate with BPN contractors on activities of their choice. For each project funded under this NOFO, the NIH will assemble a customized Lead Development Team (LDT). The LDT will be co-chaired by the PI and a BPN consultant and will include members of the PI's team, additional BPN consultants, and NIH staff.

The LDT will establish an overall strategy for the project, including milestones proposals, outline studies to be conducted by BPN contractors, and coordinate activities across different research sites. Potential applicants are strongly encouraged to read the Frequently Asked Questions (FAQs) on the BPN website ( http://neuroscienceblueprint. nih.

gov/bpdrugs/faqs. htm ) and contact NIH Scientific/Research staff and participating NIH Institutes/Centers (IC) prior to preparing an application to discuss how they may best utilize BPN resources and whether their application fits the mission of a particular NIH IC.

The BPN is dedicated to the discovery and development of small molecule compounds, of a size and structure that can be readily synthesized and chemically modified (if optimization is required). This program is not designed to support development of biologics or biotechnology products, including oligonucleotides and proteins, or devices - see BPN-Biologics NOFO PAR-21-163 ( https://grants. nih.

gov/grants/guide/pa-files/PAR-21-163. html ) and Blueprint MedTech NOFO PAR-21-315 ( https://grants. nih.

gov/grants/guide/pa-files/PAR-21-315. html ). Applicants should contact NIH Scientific/Research staff regarding small peptides (typically less than 6 amino acids) and other complex chemical structures, as well as combination therapies, to determine suitability for optimization and development within the BPN.

To be supported by this NOFO, a project must focus on a nervous system condition that falls within the mission of one of the participating Institutes or Centers. Please see Section C below for more information on the interests of the participating Institutes and Centers and alternative programs to consider.

Projects can enter either at the Discovery (Exploratory, Hit to Lead or Lead Optimization Stage ( BPN milestone orientation )) or the Development stage (preclinical candidate chosen no medicinal chemistry optimization required, or the IND enabling Stage).

In the Discovery phase the goal is to characterize and optimize promising hit compounds using medicinal chemistry to establish structure activity relationships (SAR) and structure property relationships (SPR) including in vitro and in vivo properties such as metabolism, selectivity, toxicity, etc. As projects enter or advance to the Development stage the goal is to advance a single development candidate through Investigational New Drug (IND)-enabling toxicology studies and phase I clinical testing.

Projects can enter the program at the Development stage and progress in a shorter period to IND enabling toxicology studies and phase I clinical testing.

Typical Project Research Objectives by Stage (see also the BPN milestone orientation that shows typical project structure and resources available through BPN contractors to supplement your resources): Demonstrating primary and counterscreen assays are robust, reproducible and can support proposed SAR studies Screening funnel is finalized with plans for all in vitro and in vivo assays in place for timely execution to move project to the clinical phase within the grant period Target Product Profile refined and approved Identification of at least one chemical series for future optimization where preliminary SAR and SPR is generated and demonstrates sufficient results to formulate a data driven strategy for multi-parameter optimization, improving physicochemical and ADMET properties in addition to potency SAR should meet perspective criteria for advancement with sufficient results; data should be compelling to formulate data-driven strategy to combine compound attributes into a single stereo- and enantiomerically-pure compound meeting clinical candidate selection in the Lead Optimization stage Pharmacokinetics (PK) should support proposed pharmacodynamic (PD) studies achieving reasonable exposures and duration to achieve efficacy at a dose supportive of advancement to Lead Optimization stage Lead Optimization Stage Goals: Identify a preclinical candidate to advance to the development phase of the program that demonstrates a reasonable therapeutic index (comparing dose range finding data to PK/PD experiments) Complete dose range finding study Patent position established Production of lead compound in sufficient quantity to enable large animal dose range studies Predevelopment Stage Goals: Complete Candidate characterization including dose range finding (DRF) toxicology studies not yet completed in prior stage (large animal DRF typically), compound characterization salt screen/polymorph, tractable and economical synthesis to enable Phase I, in vitro ADMET characterization to support IND (for example FDA's Guidance “ In Vitro Drug Interaction Studies — Cytochrome P450 Enzyme- and Transporter-Mediated Drug Interactions ”) Complete any efficacy studies under rigorous requirements to support clinical dose selections Engage clinician support for TPP and clinical plans IND Enabling Stage Goals: Hold any pre-IND meetings as required Produce materials to enable GLP toxicology studies Complete all required studies for IND and produce reports suitable for IND filings.

This includes GLP repeat dose toxicology studies in two species, safety pharmacology, genotoxicity evaluation, hERG as well as other studies that may be required for a particular target or route of administration Manufacture GMP drug and demonstrate suitable drug product formulation for use in Phase I trial Experience with BPN suggests that many otherwise excellent awarded projects often require additional data or the generation of tools in the first year in order to meet the program's requirements for initiating medicinal chemistry or IND-enabling studies.

For this reason, all BPN projects begin with a preparatory phase of up to a year, funded by the UG3 award mechanism, to allow projects to complete any work needed before launching full scale medicinal chemistry (if entering at the Discovery stage) or IND-enabling studies (if entering at the Development stage).

During this preparatory period, the NIH will form the LDT, which will identify and oversee the studies necessary to meet the BPN requirements for initiating medicinal chemistry or IND-enabling studies. The LDT will also design plans and go/no-go milestones for all subsequent Discovery and/or Development work, which will be funded by the UH3 award.

Progression from the UG3 award to the UH3 award will be based on administrative review (see Section D. , Milestones). After successful completion of the UG3 phase, a project may proceed either to the UH3 phase in either hit-to-lead/lead optimization SAR (the discovery stage) or to IND-enabling studies (the development stage).

A schematic of this project structure is available on the BPN website at https://neuroscienceblueprint. nih. gov/bpdrugs/bpn_resources.

htm . The following sections describe the Discovery and Development stages in more detail, including the program entry criteria, the program requirements for initiating medicinal chemistry and IND-enabling studies, and examples of activities that can be conducted during the UG3 preparatory phase.

Potential applicants are strongly encouraged to contact NIH Scientific/Research staff prior to preparing an application to clarify which entry stage is most appropriate for their project and what to include in their plans for the UG3 preparatory phase. Projects that require medicinal chemistry to improve the potency and/or drug-like properties of promising bioactive compounds will enter the BPN at the Discovery stage.

The process of understanding the structure-activity relationship (SAR) for desired drug properties typically requires dozens of rounds of compound synthesis and testing. Initially, medicinal chemistry will focus heavily on optimizing activity and potency of compounds in primary and secondary in vitro assays.

Therefore, it is required to demonstrate robust SAR driving assays and tractable synthetic routes during the UG3 phase including blinded test-retest reliability and sufficient throughput with the primary and secondary screening assays (other standard reliability metrics are listed in the first year BPN milestones ).

Subsequently, SAR will increase emphasis on ADMET (absorption, distribution, metabolism, excretion, toxicity) properties of the compounds, with continued monitoring and optimization of bioactivity.

The ultimate goal of the SAR effort is the selection of a single development candidate with sufficient bioactivity, therapeutic index, and drug-like properties to proceed to IND-directed pre-clinical safety assessment with reasonable projected human doses.

Entry Criteria for Discovery Stage Projects must meet the following requirements prior to entering at the Discovery stage: Rigorous data supporting the hypothesis that modulating the putative drug target/affected pathway will produce a desirable outcome for the intended disease indication (it is not necessary to know the precise drug target or mechanism of action).

These data may be supporting literature; evidence of the translational relevance from human studies is also encouraged. It is not required, nor it is expected that a project entering at the exploratory stage of discovery ( BPN milestones ) will have in vivo data with the proposed hit compounds.

The preparatory phase (UG3) should be used to characterize the hits in order to develop appropriate tool compounds for in vivo testing in the Hit to Lead stage where in vivo efficacy may be a milestone if in vivo testing is proposed.

A bioactive compound, in hand, that will serve as a starting point for optimization with: Proof of identity and purity (typically >95%, as determined by, e.g., NMR, melting point, or LC/MS, with no single impurity > 0.

5%) in vitro biological activity (typically < 1µM in biochemical assays and <10µM in cell-based assays relevant to the drug target), confirmed by repeat dose-response testing, with more than one batch of compound Information on selectivity for the intended target over closely related targets, if desired (and when the target is known) Primary and secondary in vitro bioactivity assays that can be used for driving SAR studies (may require further optimization for throughput during Preparatory stage) Selectivity and counter-screening assays to address potential activity at related targets and other undesirable activities or artifacts (may require further optimization for throughput during Preparatory stage) In vivo efficacy is not required at the entry to Exploratory discovery stage.

Availability of preclinical animal model(s) that can be used to assess in vivo efficacy and/or target engagement (measurement of target binding or proximal downstream effects) in the hit to lead or lead optimization stages should be available for the Hit to Lead stage where in vivo efficacy testing is included as a required milestone if animal model testing is proposed.

No obvious legal (e.g., intellectual property) constraints to pursuing the proposed chemical scaffold(s) and using the proposed assays and models for research purposes and/or commercial development Preparatory Activities for Discovery Stage Projects All Discovery projects will begin with a UG3 preparatory phase of up to one year to prepare for SAR studies, which will be supported during the UH3 phase.

The PI will be responsible for conducting all studies that involve disease- or target-specific assays, models, and other research tools.

The following are general expectations for a BPN project to initiate SAR studies: Completion of an in vitro ADME and physicochemical profile for the starting compound that includes measures of aqueous solubility, microsome stability, CYP inhibition, and permeability (e.g., MDCK or Caco-2) Demonstration that the primary assay meets the following validation criteria to reliably rank compounds with similar activities: A statistical demonstration of reliability, e.g., a Z-factor (Z') ?

0. 5 and a coefficient of variation (CV) ? 20% Concentration response testing over at least 10 concentrations generates reproducible EC 50 values within a 3-fold range for at least 4 compounds Blinded test-retest reliability with R 2 of at least 0.

75 on at least 8 compounds exhibiting EC 50 values across a 100-fold range of potency Throughput of at least 10 compounds per week, run with sufficient replicates to produce robust and reproducible 10-point dose-response curves Demonstration that the proposed secondary bioactivity assays and counter-screening and selectivity assays have sufficient reliability and throughput for their proposed use in the project Demonstration of a clear correlation between activity in the primary assay and activity in confirmatory assays and models, sufficient to justify advancement criteria in a testing funnel Examples of activities that can be supported during the Discovery (UG3) preparatory phase include: Establishment of a project milestone plan, including milestones that must be met to initiate SAR studies and desired compound profiles (including prospective criteria) at completion of lead optimization Refinement of a compound testing funnel, including studies to correlate activity across different bioactivity assays to justify advancement criteria In vivo pharmacology and if applicable studies using established biomarkers to demonstrate target engagement Studies to develop or validate target engagement markers that will be used in critical-path experiments Optimization and validation of bioactivity, selectivity, and counter-screening assays Critical-path pharmacology studies to clarify the compound mechanism of action (e.g., agonist vs. positive allosteric modulator) ADMET profiling of starting compound(s) to identify liabilities to address through medicinal chemistry Limited exploratory medicinal chemistry (approximately 1-2 chemists for 8-10 months) to enable demonstration/confirmation of synthetic route, establishment of initial structure property relationships (SPR) for metabolism, selectivity and toxicity and bioactivity of proposed hit compounds Procurement of commercially available analogs ("SAR by catalog") The PI(s) will be responsible for conducting all studies that involve disease- or target-specific assays, models, and other research tools.

Applicants may propose to use BPN contractors for chemical synthesis and ADMET profiling or request funds to conduct this work themselves. UH3 Phase Activities for Discovery Phase Projects The BPN typically supports up to an additional two years of medicinal chemistry in the UG3 phase if project entered the UG3 phase at the exploratory stage.

By the end of the first year of the UH3 phase, the PI is expected to demonstrate in vivo activity for a representative compound from the lead series, delivered by any route of administration if in vivo testing is proposed. By the end of the second year of full scale chemistry (lead optimization stage), the PI should identify a development candidate that meets the entry criteria for Development (below).

The Discovery UH3 phase typically includes the following activities: Design and synthesis of analogs for SAR studies Compound scale up for in vivo testing, dose ranging finding toxicity (DRF) evaluation Testing of analogs in bioactivity assays and animal models Testing of analogs in selectivity and counter-screening assays Testing of analogs in ADMET assays (e.g., microsome stability, CYP induction and inhibition, solubility, permeability in MDCK or Caco-2 cells, plasma protein binding, brain/plasma ratio, pharmacokinetics [PK] in multiple species) The PI will be responsible for conducting primary in vitro biological assessment of compounds on a one- to two-week schedule to inform the design of subsequent iterations of compound synthesis.

In addition to a regular testing schedule in the primary assay, the PI will provide confirmation of the activity of select compounds in secondary and counter-screening assays and animal models relevant to the drug target and therapeutic indication.

BPN contractors can produce compound analogs for SAR testing, scale up compounds as needed for in vivo testing, and provide standard screening services to assess in vitro and in vivo ADMET characteristics of the compounds.

Typically, in the UH3 phase the BPN contractors will assign approximately 4 medicinal chemist FTEs to a project, generating approximately 4-8 compounds per week, plus additional staff to support computational chemistry modeling and in vitro ADMET studies as appropriate. Compounds that meet the BPN's criteria for a development candidate can continue seamlessly on into Development stage activities in the UH3 phase (see below).

The Development stage includes IND-directed preclinical safety studies, GMP synthesis of clinical trial material, formulation development, and phase I clinical testing. Projects that have completed medicinal chemistry optimization and identified a development candidate may initiate Development activities within BPN. The BPN does not support SAR studies during Development.

Entry Criteria for Development Stage Applications for entry into the Development stage must have identified the candidate compound and cannot request additional medicinal chemistry resources. It may be acceptable to have 2 candidates that will be narrowed to a single candidate as part of the UG3 phase activities (time and budget permitting).

Applications must meet the following requirements prior to entering the Development Stage: A strong package of data linking the putative drug target/affected pathway to the proposed disease indication and supporting the hypothesis that altering the target activity as proposed will produce desirable outcomes for the disease.

Proposed compound must have in vitro and in vivo biological activity and ADMET properties appropriate for the intended clinical use (i.e., the disease indication, patient population, delivery mode, treatment duration, and treatment regimen) and outcomes.

Applicants should show that their proposed compounds are efficacious when delivered by the clinically intended route of administration, at exposure levels that can likely be achieved clinically with the proposed human dosing regimen. Proposed compounds should give defensible results in tests for Ames mutagenicity, hERG activity, microsome stability, CYP inhibition, plasma protein binding, and aqueous solubility.

In cases where the molecular target of compound action is known, the applicant should demonstrate the degree of selectivity for the intended target over closely related targets. Counter-screening to determine selectivity across a broad panel of unrelated pharmacological targets (e.g., G protein-coupled receptors, kinases, etc.) is also required.

Demonstration that the ability of the PI's institution to develop and commercialize the proposed compound(s) is unlikely to be blocked or impeded by legal (e.g., intellectual property) constraints and that there is support from the institution to file and maintain the patents estate and necessary regulatory documents along with associated cost (see Other Attachments below).

Preparatory Activities for Development Stage Projects All applications proposing to enter at the Development stage will begin with a UG3-funded preparatory phase of up to one year, to prepare for IND-enabling studies, which will be supported during the UH3 phase. Projects that entered at the Discovery stage will conduct this preparatory work during their UH3 phase.

The following are general expectations for a project to initiate IND-enabling studies within BPN: Dose-range finding (DRF) toxicology studies (rodent and non-rodent) show an acceptable safety margin (e.g., 5x if toxicity can be monitored, reversible, and has premonitory signs; 10x if toxicity is more severe but controllable/reversible; 30x if toxicity is unlikely to be easily monitored, controllable, reversible, or have premonitory signs).

Formulation to enable exposure margins suitable for these toxicology studies may need to be explored.

Viable synthetic route for manufacturing (acceptable cost, number of steps and purification techniques needed) to enable GLP toxicology and Phase I testing Viable API (active pharmaceutical ingredient; salt and polymorph selection complete, acceptable stability to support initial clinical trial) Examples of activities that can be supported during the Development preparatory phase include: Establishment of a preclinical development plan, including milestones for advancement into IND-enabling studies and the desired profile for a development candidate Design and planning for the Phase I clinical trials (if applicable) Replication/confirmation of key in vivo pharmacology data Scale-up synthesis for toxicology studies and formulation (including required material amounts for DRF studies if not available at time of award) Salt and polymorph screening Compound stability studies Pre-formulation/formulation work to enable toxicology studies Multiple-dose rodent PK testing, with pharmacodynamic (PD) correlations if applicable Dose-range finding toxicology studies Metabolite identification The PI is responsible for conducting all studies that involve disease- or target-specific assays, models, and other research tools.

BPN contractors can perform all other work.

UH3 Phase Activities for Development Stage Projects The Development UH3 phase may include the following: Manufacturing of material for toxicology studies (DRF & GLP) and/or GMP manufacturing of material for phase I clinical testing IND-enabling toxicology studies Phase I clinical trial (a single and/or multiple ascending dose study to characterize safety, PK, and PD) The PI's Institution will be responsible for assembly and submission of the IND application and scheduling meetings with the FDA and therefore should include support for this activity in their plan.

NIH staff and consultants on the LDT must be included in all meetings with the FDA. The development of the protocol and management of the phase I trial will be performed by a Clinical Development Team (CDT), which will evolve from the LDT and include the PI, clinical consultants identified by the PI and NIH, and NIH staff.

The protocol, selected supporting trial documents, and regulatory documents will be submitted to NIH for administrative review (including internal and external experts) prior to commencement of the clinical trial (defined as signing of first informed consent). BPN contractors can conduct the preclinical safety studies, GMP synthesis, formulation and other activities required to prepare for human testing.

BPN contractors will provide data and reports in a format suitable for inclusion in an IND application and will assist in the development of the application. The phase I clinical trial can also be conducted through BPN contractors. Applications Not Responsive to this NOFO: Nonresponsive applications will not be reviewed.

The following activities are considered non-responsive to this NOFO: Screening to identify hit compounds Basic research and studies of disease mechanism Development of risk, detection, diagnostic, prognostic, predictive, and prevention biomarkers as well as PET ligands Development of diagnostics and diagnostic devices Development of biologics and biotechnology products Studies directed beyond Phase I clinical testing C.

NIH Institute and Center Interests and Guidance National Institute on Aging (NIA) NIA is interested in studies that will provide drug development expertise and infrastructure support to researchers interested in developing novel small molecules aimed at modifying the behavioral symptoms in Alzheimer's disease (AD), delaying the onset or slowing the progression of AD, mild cognitive impairment (MCI), other dementias of aging and age-related cognitive decline.

Ideally, this initiative is aimed at researchers who have promising small molecule compounds but lack the necessary outside expertise and infrastructure to advance these compounds to the clinic.

Researchers who may have the necessary drug development expertise and access to infrastructure to advance small molecules to the clinic should consider submitting an application to the Alzheimer's Drug Development Program ( PAR 22-047 ) or its reissue. This program is also available to researchers who are interested in the preclinical development of small molecules and biologics.

National Institute on Alcohol Abuse and Alcoholism (NIAAA) Alcohol interacts directly and indirectly with a wide spectrum of molecular targets in the brain, and alcohol-seeking behaviors and alcohol use disorders (AUD) involve multiple neurotransmitter systems, neuromodulators, hormones, signal transduction pathways, etc. These include signaling systems and signal transduction pathways of opioids, serotonin, dopamine, glutamate, γ-aminobutyric acid (GABA), endocannabinoids, neuropeptides (e.g. corticotropin releasing factor (CRF), neuropeptide Y, substance P), and protein kinases A and C.

Numerous therapeutic agents targeting these and other molecular systems have been studied preclinically and in clinical trials. NIAAA is interested in research aimed to develop new pharmaceuticals to provide effective therapy for AUD. Studies involving novel targets previously un-recognized or understudied for the treatment of AUD are particularly encouraged.

Specific genetic variants that may contribute to the risk for alcoholism and/or render alcohol dependent individuals responsive to specific therapeutic agent have been discovered. NIAAA is interested in supporting research to develop pharmaceuticals targeting individuals with identified genotypic and phenotypic characteristics to improve efficacy and safety.

National Eye Institute (NEI) The National Eye Institute (NEI) interest in BP neuro-therapeutics is to develop novel therapies to treat diseases and disorders of the visual system, especially blinding eye diseases such as cataracts, glaucoma, age-related macular degeneration, retinitis pigmentosa, ocular pain and other conditions.

The NEI is also interested in other visual system disorders such as strabismus and amblyopia that could be treated with pharmacological interventions. Each project should have a well-defined endpoint, achievable within a five-year time frame, for developing a treatment for a specific disease or disorder of the visual system. The steps towards