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Development of 4-(aroylamino)piperidine-based entry inhibitors as anti-influenza therapeutics

Award Number: R42AI155039
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Development of 4-(aroylamino)piperidine-based entry inhibitors as anti-influenza therapeutics - Influenza A viruses belong to the orthomyxoviridae family, and have a negative-sense, segmented RNA genome, which can cause seasonal or pandemic flu with high morbidity and significant mortality. Vaccination is the most prevalent prophylactic means for controlling influenza infections. However, an effective vaccine usually takes at least six months to develop. Furthermore, vaccination has limited effectiveness in the treatment of immunocompromised patients, and its effectiveness is also limited during a pandemic. The current therapeutic options for flu infections are all based on the neuraminidase inhibitors (NAIs; oseltamivir, zanamivir and peramivir), while the influenza M2 ion channel blockers (amantadine and rimantadine) are not now recommended since all of the circulating influenza strains have acquired resistance. (Xofluza, a polymerase acidic endonuclease inhibitor, has just been approved in 2018 and is yet untried during a flu season.) The rapid emergence of the NAI-resistant strains of influenza A viruses strongly suggests that NAIs alone may not be sufficient as effective therapies, and thus new treatment options targeting the other viral/host factors are urgently needed. This application defines a plan to develop potent, small molecule inhibitors, which block entry of influenza A viruses. We have identified compounds that inhibit entry of infectious influenza A viruses, with IC50 values in the nanomolar range. We have synthesized structurally diverse analogs of the anti-influenza hit series using structure-activity relationships (SARs) to improve potency and selectivity; validated the lead inhibitor candidates in the infectious assay and investigated the mechanism of action (MOA) of the these inhibitors; and selected anti-influenza inhibitors with excellent in vitro potency and selectivity values and druglike in vivo pharmacokinetic properties. In this Fast Track STTR Phase I &II application, we propose four specific aims: (1) optimize the lead scaffold and select development candidates; (2) investigate the mechanism of action (MOA) of the advanced lead compounds with HA proteins; (3) evaluate the pharmacokinetics/toxicokinetics of the advanced lead compounds; and (4) preclinical development.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = $999,234 )
2024	2024	CHICAGO BIOSOLUTIONS INC	2242 W HARRISON ST	CHICAGO	IL	60612	COOK	USA	Allergy and Infectious Diseases Research	000	4	4/23/2024	NON-COMPETING CONTINUATION	$999,234
														Subtotal = $999,234

Issue Date FY: 2023 ( Subtotal = $999,369 )
2023	2023	CHICAGO BIOSOLUTIONS INC	2242 W HARRISON ST	CHICAGO	IL	60612	COOK	USA	Allergy and Infectious Diseases Research	000	3	4/27/2023	NON-COMPETING CONTINUATION	$999,369
2023	2021	CHICAGO BIOSOLUTIONS INC	2242 W HARRISON ST	CHICAGO	IL	60612	COOK	USA	Allergy and Infectious Diseases Research	001	1	6/20/2023	NEW	$0
														Subtotal = $999,369

Issue Date FY: 2022 ( Subtotal = $999,369 )
2022	2022	CHICAGO BIOSOLUTIONS, INC.	2242 WEST HARRISON SUITE 201	CHICAGO	IL	60612	COOK	USA	Allergy and Infectious Diseases Research	000	2	5/5/2022	EXTENSION WITH OR WITHOUT FUNDS	$999,369
														Subtotal = $999,369

Issue Date FY: 2021 ( Subtotal = $300,000 )
2021	2021	CHICAGO BIOSOLUTIONS, INC.	2242 WEST HARRISON SUITE 201	CHICAGO	IL	60612	COOK	USA	Allergy and Infectious Diseases Research	000	1	4/1/2021	NEW	$300,000
														Subtotal = $300,000

Grand Total All Awards = $3,297,972

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Development of 4-(aroylamino)piperidine-based entry inhibitors as anti-influenza therapeutics

Award Number: R42AI155039

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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