PDE4B Inhibitors For Treating Major Depression

DESCRIPTION (provided by applicant): Inflammatory Bowel Disease (IBD), a chronic, recurring disease of the gastrointestinal tract, afflicts over 1.4 million people in the U.S. Curret therapies for IBD are modestly successful and result with significant adverse side effects, including immune suppression and malignancies. Recently, we have identified Lanthionine Synthetase Component C-Like 2 (LANCL2) as a novel therapeutic target and specifically have found that 61610, a compound of the class of bis(benzimidazoyl)terephthalanilides, exerts potent anti-inflammatory activity in mouse models of IBD. The specific aims for the proposed SBIR Phase I are: Aim One will validate LANCL2 as a novel therapeutic target for IBD. Site-specific, atomic-resolution receptor-ligand binding studies will provide the most detailed information related to drug-therapeutic target binding and facilitate a rational design and discovery of novel agonists. Isothermal titration calorimetry (ITC), a label-free thermodynamic technique, and afluorescence-based assay will be used to quantify binding affinity and reaction stoichiometry between LANCL2 and its ligands (i.e., abscisic acid (ABA) and 61610). Previously, our group and others found that ABA binds to LANCL2 and activates cAMP production and activates protein kinase A (PKA). Thus, we will explore downstream effects of administering 61610 on cAMP/PKA signaling. Aim Two will evaluate the efficacy of the bis(benzimidazoyl)terephthalanilides class of anti- inflammatory compounds for treatinggut inflammation. To optimize drug efficacy of bis(benzimidazoyl)terephthalanilides for anti-inflammatory effects in IBD, we will (1) generate 20-50 derivatives and analogs of 61610, (2) perform compound screening based on LANCL2 binding, cAMP/PKA signaling and exclusion of PPAR gamma activation to select 3 lead derivatives/analogs for further development in vivo, and (3) compare the oral administration efficacy of 3 lead compounds against the parent compound 61610 and prednisolone, a steroid used by IBD patients, in mouse models of IBD. SBIR Phase II will optimize two of the lead compounds with demonstrated efficacy in mouse model of gut inflammation and advance them along the regulatory pathway, including efficacy, mode of action, absorption, distribution, metabolism and excretion (ADME), phamacokinetics/pharmacodynamics (PK/PD), toxicokinetics (TK) analysis and toxicity assessment working towards the testing required to submit an investigational new drug (IND) application in preparation for human clinicaltrials. To optimize drug delivery in the gut we will develop more water-soluble 61610-based pro-drugs and test their efficacy and safety. Long Term Goal: For moderate to severe cases of IBD, the goal of BioTherapeutics technology will be to provide an oral therapeutic alternative to existing treatments that costs less and provides greater efficacy with reduced adverse side effects. The technology will address the overlying health problem with patients suffering with IBD and will provide a significant commercialization potential estimated to be over 800M. PUBLIC HEALTH RELEVANCE PUBLIC HEALTH RELEVANCE: Inflammatory bowel disease (IBD) afflicts over 1.4 million people in the United States with a worldwide prevalence reaching up to 396/100,000 persons. This Phase I SBIR will develop a novel class of potent anti- inflammatory drugs for IBD. The proposed feasibility studies will lay the groundwork for creating new chemical entities and discovering how bis(benzimidazoyl)terephthalanilides modulate immune and inflammatory responses in humans.