(R)-Norfluoxetine is a pharmacologically active metabolite of Fluoxetine that is a selective serotonin reuptake inhibitor. (R)-Norfluoxetine was being investigated by Eli Lilly and Company for treatment pain and drug abuse, but future development was discontinued.

LY-3039478 is an orally bioavailable, novel small molecule inhibitor of Notch signaling pathway, developed Eli Lilly and Company for cancer treatment. The Notch receptor, on the surfaces of progenitor cells and cancer cells, binds neighboring cell-surface ligands DLL or JAGGED. On ligand binding, the intramembrane protease γ-secretase cleaves the Notch intracellular domain (NICD). LY-3039478 is an exquisitely potent inhibitor of Notch-1 intracellular domain (N1ICD) cleavage with an IC50 of ∼1nM in most of the tumor cell lines tested. LY3039478 also potently inhibits mutant Notch receptor activity. Treatment with a gamma-secretase inhibitor, LY3039478, significantly inhibited the growth of 2 CCRCC(Clear cell renal cell carcinoma) cell lines in a concentration-dependent manner. LY3039478 treatment also led to decreased expression of Myc and Cyclin A1, two genes that were part of the NOTCH driven proliferative signature in murine and human model systems. LY3039478 treatment also led to G0/G1 cell cycle arrest in CCRCC cells. In a xenograft tumor model, LY3039478 inhibited N1ICD cleavage and expression of Notch-regulated genes in the tumor microenvironment. The inhibition of Notch cleavage also resulted in the induction of apoptosis in a Notch-dependent xenograft model. In immunodeficient NSG mice xenografted with 769-P CCRCC cells, LY3039478 treatment resulted in significantly increased survival and delayed tumor growth in independent cohorts of mice demonstrating in vivo efficacy in CCRCC. LY3039478 is being investigated in a clinical trial in patients with T-cell acute lymphoblastic leukemia or T-cell lymphoblastic lymphoma in combination with Dexamethasone.

Adomeglivant, also known as LY2409021, is a potent and selective glucagon receptor antagonist. Adomeglivant lowers blood glucose in healthy people and in those with type 2 diabetes. Blockade of glucagon signalling in patients with type 2 diabetes is well tolerated and results in substantial reduction of fasting and postprandial glucose with minimal hypoglycaemia, but with reversible increases in aminotransferases. Adomeglivant had been in phase II clinical trials by Eli Lilly for the treatment of type 2 diabetes mellitus. However, this research has been discontinued.

LY-2456302 or CERC-501 (now JNJ-67953964) is a non-peptide, centrally-penetrant, potent, short-acting kappa opioid receptor (KOR)-selective antagonist with pharmacokinetic properties favorable for clinical development and activity in animal models predictive of efficacy in mood and addictive disorders. It is under development for depression and substance abuse disorders.

LY3023414, an investigational drug, is a small molecule that that demonstrates activity against PI3K, mTOR, and DNA-PK in tumor cells, thereby inducing cell-cycle effects and inhibiting cancer cell viability. As shown in vitro LY3023414 inhibits the ability of PI3K and mTOR to phosphorylate substrates in the PI3K/mTOR pathway, one of the most frequently mutated pathways in cancer, leading to cancer progression and resistance to existing treatments. Downstream target inhibition by LY3023414 occurs rapidly via an intermittent “on/off” mechanism that may enhance the drug's clinical tolerability, which may in turn allow LY3023414 to overcome some of the toxicities associated with PI3K/mTOR inhibitors and potentially reduce the emergence of feedback mechanisms leading to resistance. The physicochemical and absorption properties of LY3023414 are favorable, as evidenced by the molecule's high solubility across a wide pH range and high oral bioavailability. On the basis of these findings, LY3023414 is currently being evaluated in clinical trials in patients with advanced cancer such as metastatic prostate cancer and non-small cell lung cancer in combination with other chemotherapeutic agents and in endometrial cancer as a monotherapy.

LY2608204 is a activator of glucokinase (GK) with EC50 of 42 nM. Eli Lilly is developing LY 2608204 as an orally administered, once-daily therapy for type 2 diabetes. LY-2608204 is in phase I clinical trials for the treatment of type 2 diabetes.

Malethamer is the generic name of a new synthetic hydrocarbon copolymer with extraordinary water-binding properties, being able to absorb 200 times its weight of water. It is physically and chemically binds poliovirus 1 and certain bacterial enterotoxins. Ethylene-maleic anhydride copolymers and their derivatives have come to be considered for a number of applications generally involving the formation of insoluble complexes with proteins and viruses. The copolymer is not absorbed from the gastrointestinal tract and is pharmacologically inert. Malethamer, because of its water absorbing quality, is an effective compound for the symptomatic control of diarrhea, both organic and functional.

LY2886721 is a BACE inhibitor used for the treatment of Alzheimer's Disease. LY2886721 did not inhibit other aspartyl proteases such as cathepsin D, pepsin, and renin, and reduced Aβ in a dose-dependent manner in HEK293Swe cells and in primary neurons from PDAPP transgenic mice. LY2886721 was the first BACE inhibitor to reach Phase 2 clinical research. Lilly completed six Phase 1 studies of LY2886721’s safety, tolerability, and pharmacology in a total of 150 healthy volunteers and people with Alzheimer’s disease at doses of 1–70 mg. Single and multiple ascending oral dosing was accompanied by repeat CSF sampling in the hours and days thereafter. This was done to assess CSF penetration and target engagement by way of measuring levels of the drug, BACE1 substrate, and BACE1 cleavage products. The compound lowered CSF Aβ40, Aβ42, and sAPPβ concentrations while increasing sAPPα, consistent with expectations for BACE1 inhibition. Fourteen days of daily dosing reduced BACE1 activity by 50–75 percent, and CSF Aβ42 by 72 percent. No safety concerns were apparent in dosing up to six weeks

LY2452473 is a selective androgen receptor modulator (SARM), with potential tissue-selective androgenic/anti-androgenic activity. Upon oral administration, LY2452473 acts as an agonist in select tissues and organs, including skeletal muscle, bone and the penis, thereby binding to and activating androgen receptor (AR) while acting as an antagonist in the prostate, thereby blocking AR activation and AR-mediated cellular proliferation. This may improve muscle mass and strength, bone formation, and erectile dysfunction while not stimulating growth of the prostate. Eli Lilly was developing LY 2452473/tadalafil combination for the treatment of erectile dysfunction. In addition, Eli Lilly is studying the use of a targeted LY 2452473 therapy, as a possible improvement in quality of life for prostate cancer patients who have undergone radical prostatectomy.

LY377604 is a human β3-adrenergic receptor agonist and β1- and β2-adrenergic receptor antagonist with no sympathomimetic activity at the β1- and β2-adrenergic receptors. Combination of LY377604 and a norepinephrine-serotonin uptake inhibitor (sibutramine) was studied in the treatment of obesity. LY377604 would ameliorate side effect of sibutramine treatment (increase in blood pressure and heart rate due to activation of the sympathetic nervous system).