MCSP TORFP NO. NIH-NINDS-21-01: FLORIO (ANAGIN) - BASE EC (STROKE)

The scope of this MCSP task order shall be medicinal chemistry services under Performance Area 2: Medicinal Chemistry Support in support of preclinical drug discovery efforts supported by NIH, NINDS and its Contributors including: Medicinal Chemistry Planning, Synthesis, Isolation, Characterization 1) Project planning 2) Project management 3) Design, procurement, and milligram-scale synthesis of chemical analogs 4) Multi-gram and scale-up synthesis for testing in animal models 5) In vitro ADME and toxicology testing for lead optimization 6) Compound registration and data entry 7) Communication (teleconferences, minutes, written updates) In addition to the specific technical requirements specified below, the Contractor shall fulfill the general technical requirements defined in the Parent Statement of Work, ?Performance Area 2 Medicinal Chemistry Support?, which states the general technical requirements for this solicitation.

The SOW consists of three components: the Base Requirement: Exploratory Chemistry; Option #1 Hit-to-Lead Chemistry; and Option #2 Lead Optimization Chemistry.

Base Award: Exploratory Chemistry The goal of Exploratory Chemistry is to gather sufficient data to determine whether the starting compound(s) and primary bioactivity assay provided by the Contributor are suitable for pursuing Hit-toLead Chemistry.

In order to initiate a Hit-to-Lead effort, compound(s) typically should elicit a reproducible dose response, demonstrate a potency of IC50/EC50 < 10 µM (preferably < 1 µM) with at least 10x selectivity in counterscreens, demonstrate an emerging structure-activity relationship (SAR) across related chemical analogs, and provide a tractable starting point for optimization.

It is expected that this Exploratory Chemistry effort will have a duration of approximately eight (8) months and will require all components including synthesis, Computer Aided Drug Design (CADD) as appropriate, and in vitro ADMET support (as outlined in the Parent SOW).

General Requirements of Exploratory Chemistry Task Orders: The Contractor, the Contributor, and the Contracting Officer?s Representative (COR) shall communicate on a regular basis over the course of an Exploratory Chemistry project to review data and refine the testing strategy as described above. It is recognized that the resource requirements both in terms of staffing and timing may vary from program to program.

The Contractor shall procure and provide each Contributor with samples for testing in their bioactivity assay(s).

The Contractor shall be responsible for maintaining a repository of the compounds synthesized or purchased by the Contractor for each of the Contributor?s projects.

The Contributor shall be responsible for testing the commercial and custom-designed analogs in their bioactivity assay(s) and entering the bioactivity data into an NIH database that will be accessible to the Contractor.

The Exploratory phase of a project will end when the COR determines that sufficient data is available to make a decision as to whether to proceed with Hit-to-Lead Chemistry or terminate the efforts.

Option #1: Hit-to-Lead Chemistry Efforts on a hit series advanced from the Exploratory Chemistry stage will be focused on development of a clear understanding of the SAR as well as the Structure-Property Relationships (SPR) within the hit series, demonstration of favorable outcomes for preliminary ADMET and increased potency in the Contributor?s primary assay, as well as demonstrated potency in a cellular assay.

For each program, a target profile will be established addressing bioactivity, ADMET liabilities and drug-like properties which will serve as decision points and advancement criteria.

For budgeting purposes, it is expected that each Hit-to-Lead project will have a duration of approximately twelve (12) months and will require all components including synthesis, Computer Aided Drug Design (CADD) as appropriate, and in vitro ADMET support (as outlined in the Parent SOW).

General Requirements for Hit-to-Lead Task Order: The Contributor and NIH will be responsible for testing the analogs in bioactivity assays and in in vivo pharmacology, and in vivo toxicology assays.

The Contractor, the Contributor, NIH consultants and COR shall communicate on a regular basis over the course of a Hit-to-Lead project to review data and refine the testing strategy.

It is recognized that the resource requirements both in terms of staffing and timing may vary from program to program during this stage.

The Hit-to-Lead phase will end when the COR determines that the work proposed for that phase has been completed and the project is ready for Lead Optimization or the COR decides to terminate the project due to failure to meet project milestones.

Option #2: Lead Optimization Chemistry The goal of Lead Optimization is to develop a preclinical drug candidate with optimized chemical and ADMET properties and an acceptable therapeutic index as judged by dose ranging toxicology studies performed through other NIH contracts. Projects at the Lead Optimization stage typically focus on a single chemical series.

The exact activity level to be achieved in each assay during Lead Optimization will be determined during the Hit-to-Lead phase.

Projects in Lead Optimization will involve iterative rounds of analog synthesis and testing, typically on a weekly or biweekly schedule.

For each round, the Contractor, the Contributor, COR and NIH-hired consultants will review the most recent data and discuss the next set of analogs to generate.

It is expected that each Lead Optimization project will have a duration of approximately twelve (12) months and will require all components including synthesis, Computer Aided Drug Design (CADD) as appropriate, and in vitro ADMET support (as outlined in the Parent SOW).

General Requirements for a Lead Optimization Task Order: The Contractor, the Contributor, NIH consultants and COR shall communicate on a regular basis over the course of a Lead Optimization project to review data and refine the strategy as outlined above. It is recognized that the resource requirements both in terms of staffing and timing may vary from program to program.

The Lead Optimization phase will end when the COR determines that a preclinical candidate has been advanced that meets the NIH prospective criteria and milestones or the COR decides to terminate the project due to failure to meet project milestones.