Optimization of drug-like properties of crfbp-CRF2 negative allosteric modulators for alcohol use disorder

Active Project Grant Awarded Last action

Award ID
R01AA030888
Recipient
Awarding agency
Obligated
$4,060,832

Award facts

Assistance listing
93.273 Alcohol Research Programs
Completion date 62% complete
Place of performance
La Jolla, CA 92037, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
This application, "optimization of drug-like properties of crfbp-CRF2 negative allosteric modulators for alcohol use disorder", is in response to PAR-22-031 "drug discovery for nervous system disorders (R01 clinical trials not allowed)". Alcohol use disorder (AUD) remains a huge clinical and public health problem with no effective pharmacological recourse, affecting 28.3 million adults in the united states, and is the 3RD leading preventable cause of death. The only FDA-approved medications for AUD are disulfiram, naltrexone, and acamprosate, all of which exhibit limited efficacy and have limiting contraindications. Hence, there is a critical need to develop more effective therapeutics to treat AUD. While many factors contribute to the development and maintenance of AUD, increasing attention is being paid to potentially druggable targets within the stress system. The primary regulator of the stress response, corticotrophin-releasing factor (CRF), exerts its effects by binding to CRF1 and CRF2 receptors and, also, a secreted 37-KD CRF-binding protein (crfbp). In addition, crfbp undergoes spontaneous cleavage into a 27-KD n-terminal fragment, crfbp(27KD), that binds CRF and a 10- KD c-terminal fragment, crfbp(10KD), that does not. We hypothesize that crfbp has dual excitatory and inhibitory effects on CRF function and, thus, ethanol consumption, and that the crfbp-CRF2 interaction represents a novel pharmacological target for the treatment of AUD. To test this hypothesis, we developed chemical probes specific for the crfbp(10KD)-CRF2 complex in two lead series that act as negative allosteric modulators (nams) of the crfbp-CRF2 complex only in the presence of crfbp(10KD). Our recent structure- activity relationship (SAR) studies have provided crfbp-CRF2 nams with good on-target potency and selectivity profiles in vitro, but additional chemical optimization is required to produce chemical probes that are ready for comprehensive in vivo evaluation. These in vivo probes would allow US to establish the role of crfbp in alcohol consumption and facilitate the development of effective treatments targeting crfbp for AUD. Thus, our overall objective is to develop systemically active crfbp-CRF2 nams suitable for advanced in vivo proof- of-concept studies for the treatment of AUD. Accordingly, our specific aims are: (1) design and synthesize novel crfbp-CRF2 nams with optimal drug-like properties; (2) characterize novel crfbp-CRF2 nams in assays measuring potency, selectivity and drug-like properties; and (3) demonstrate in vivo proof-of-concept for select crfbp-CRF2 nams in rodent models of AUD. The crfbp-CRF2 nams generated will provide powerful in vivo probes for testing the role of the crfbp-CRF2 interaction in vivo. We are well-positioned to develop potent and selective small molecule crfbp-CRF2 nams with excellent pharmacokinetic properties for in vivo proof-of- concept studies in rodent models of AUD. This multidisciplinary research program has the potential for significant scientific and medical impact by contributing to the discovery of new medications for AUD.

Transactions

Action Obligated Date
Amendment $771,544
Amendment $786,961
Amendment $800,043
Amendment $0
Amendment $0
Amendment $851,142
Original award $851,142

Subawards

Subrecipient Amount Awarded
Brown University Dr. Haass-Koffler will support the assay development and in vivo behavioral pharmacology studies to test novel pharmacophore targeting the stress system for… $51,399
University Of California, San Diego Dr. de Guglielmo will be responsible for all behavioral pharmacology aspects of Aim 3. His laboratory will conduct in vivo efficacy studies of the most advanced… $89,998
University Of California, San Diego Dr. de Guglielmo will be responsible for all behavioral pharmacology aspects of Aim 3. His laboratory will conduct in vivo efficacy studies of the most advanced… $83,499
Brown University Dr. Carolina L. Haass-Koffler, overall, will support the assay development, in vivo behavioral pharmacology studies and will coordinate weekly meetings to… $52,461
Universita' Degli Studi DI Camerino Professor Nazzareno Cannella will coordinate and supervise animal behavior experiments. Prof. Cannella is an expert behavioral pharmacologist who has… $87,056
Brown University Dr. Carolina L. Haass-Koffler, overall, will support the assay development, in vivo behavioral pharmacology studies and will coordinate weekly meetings to… $51,287
Universita' Degli Studi DI Camerino Dr. Cannella will coordinate and supervise animal behavioral experiments for pre-clinical screening of the efficacy of CRFBP-CRF2 Negative Allosteric Modulators… $85,953
Brown University Dr. Haass-Koffler will support the assay development and in vivo behavioral pharmacology studies to test novel pharmacophore targeting the stress system for… $51,461

Quick answers

Who received award R01AA030888?

R01AA030888 was awarded to Sanford Burnham Prebys Medical Discovery Institute by National Institute on Alcohol Abuse and Alcoholism (National Institutes of Health) on September 20, 2023.

How much is award R01AA030888 worth?

$4,060,832 has been obligated on R01AA030888.

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