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High throughput in vivo screening: translational generation of novel analgesics

Award Number: R01DA031370
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2011
PERIOD OF PERFORMANCE END DATE: 05/31/2017

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High throughput in vivo screening: translational generation of novel analgesics - DESCRIPTION (provided by applicant): The central working hypothesis of the proposed study is that the direct in vivo high throughput screening (in vivo HTS) will yield enhanced leads, thereby accelerating the discovery of analgesics with improved safety profiles. This work continues the work of the completed R21 (NIDA DA019620) entitled, "In Vivo Screening of Mixture-Based Combinatorial Libraries". The overall approach described herein will accelerate drug discovery and the subsequent identification of more advanced therapeutic candidates poised for preclinical studies. The traditional approach to small molecule drug discovery is to identify individual compounds through in vitro HTS assays, before selected compounds are tested in vivo. However, such a late transition to animal testing fosters a high rate of attrition that is costly in both time and research dollars. To circumvent this problem, this proposal utilizes a novel translational approach capable of eliminating non-efficacious compounds at the earliest stage. The long-term goal of these studies is to apply in vivo HTS to accelerate drug discovery in multiple therapeutic areas. As the first step towards that goal, the specific objective in the present application applies this technique to address the need for potent, but inherently safer, analgesic compounds. Marketed opioid analgesics are both potent and effective, but are strongly addictive with potentially life- threatening side effects. This proposal will identify new chemical entities (NCEs) with the potential to advance to human clinical trials and, if successful, improve patients' quality of life while reducing the societal problems posed by nonmedical use of opioid analgesics. The potential of this proposal is clearly supportive of the mission of NIDA, "to lead the Nation in bringing the power of science to bear on drug abuse and addiction." The research design uses a method of screening large, mixture-based libraries in vivo to identify compounds that are active in an in vivo mouse model of nociception. A total of 37 available, in-house, small molecule library mixtures (representing over 7 million small molecules) will be screened in vivo with animal models of antinociception to identify additional scaffolds for development, complementing a previously identified scaffold. Individual compounds selected from these three scaffolds will be synthesized and purified for additional development which will include in vitro analysis, pharmaceutical profiling, and additional in vivo models. Ultimately, we will examine multiple scaffolds and select 2-3 new chemical entities to initiate preclinical studies. By the end of the proposed study, we will have clearly demonstrated the utility of combining large mixture- based libraries of small molecules with in vivo screening (in vivo HTS) to identify therapeutic hits and leads with demonstrated efficacy and minimized side effects. By utilizing in vivo HTS, compounds may be identified with in vivo efficacies that function through previously unidentified biological pathways, providing potential advances in both the clinical and scientific realms.


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: 2017 ( Subtotal = $0 )
2017	2015	TORREY PINES INSTITUTE FOR MOLECULAR STUDIES, INC.	3550 GENERAL ATOMICS CT	SAN DIEGO	CA	92121	SAN DIEGO	USA	Drug Use and Addiction Research Programs	000	5	9/29/2017	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2015 ( Subtotal = $369,833 )
2015	2015	TORREY PINES INSTITUTE FOR MOLECULAR STUDIES	3550 GENERAL ATOMICS COURT	SAN DIEGO	CA	92121	SAN DIEGO	USA	Drug Use and Addiction Research Programs	000	5	7/24/2015	NON-COMPETING CONTINUATION	$369,833
														Subtotal = $369,833

Issue Date FY: 2014 ( Subtotal = $437,704 )
2014	2014	TORREY PINES INSTITUTE FOR MOLECULAR STUDIES	3550 GENERAL ATOMICS COURT	SAN DIEGO	CA	92121	SAN DIEGO	USA	Drug Use and Addiction Research Programs	000	4	5/21/2014	NON-COMPETING CONTINUATION	$437,704
														Subtotal = $437,704

Issue Date FY: 2013 ( Subtotal = $511,211 )
2013	2013	TORREY PINES INSTITUTE FOR MOLECULAR STUDIES	3550 GENERAL ATOMICS COURT	SAN DIEGO	CA	92121	SAN DIEGO	USA	Drug Use and Addiction Research Programs	000	3	5/13/2013	NON-COMPETING CONTINUATION	$511,211
														Subtotal = $511,211

Issue Date FY: 2012 ( Subtotal = $501,681 )
2012	2012	TORREY PINES INSTITUTE FOR MOLECULAR STUDIES	3550 GENERAL ATOMICS COURT	SAN DIEGO	CA	92121	SAN DIEGO	USA	Drug Use and Addiction Research Programs	000	2	5/24/2012	NON-COMPETING CONTINUATION	$501,681
														Subtotal = $501,681

Issue Date FY: 2011 ( Subtotal = $407,964 )
2011	2011	TORREY PINES INSTITUTE FOR MOLECULAR STUDIES	3550 GENERAL ATOMICS COURT	SAN DIEGO	CA	92121	SAN DIEGO	USA	Drug Use and Addiction Research Programs	000	1	7/18/2011	NEW	$407,964
														Subtotal = $407,964

Grand Total All Awards = $2,228,393

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High throughput in vivo screening: translational generation of novel analgesics

Award Number: R01DA031370

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2011

PERIOD OF PERFORMANCE END DATE: 05/31/2017

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