VK2809

Thyroid hormone receptor β (TRβ, THRβ or THR-β) agonists have seen a surge of interest in non-alcoholic steatohepatitis (NASH) and non-alcoholic fatty liver disease (NAFLD), largely thanks to impressive Ph. III clinical data from resmetirom, a Breakthrough Therapy and 2022 Molecule of the Year candidate developed by Madrigal and originated at Roche. If its recently accepted NDA is approved, resmetirom could become the first drug to achieve accelerated approval for NASH after decades of research effort.

Thyroid hormone receptor β (TRβ, THRβ or THR-β) agonists have seen a surge of interest in non-alcoholic steatohepatitis (NASH) and...

LY03005

While SNRIs and selective serotonin reuptake inhibitors (SSRIs) have been hugely successful in treating major depressive disorder (MDD), many patients remain resistant to treatment or do not experience full symptom relief. The majority of current treatments for MDD increase levels of synaptic serotonin and/or norepinephrine by inhibiting their reuptake transporters SERT and NET, respectively.

While SNRIs and selective serotonin reuptake inhibitors (SSRIs) have been hugely successful in treating major depressive disorder ...

OBI-3424

A diaziridine-based tumor-activated prodrug for AKR1C3-expressing cancers from a defunct Bay Area biotech. OBI-3424 (formerly TH-3424) is a tumor-activated prodrug in Ph. II that releases DNA-crosslinking diaziridine phosphamide (remniscent of thioTEPA) upon activation by the NAD(P)H-dependent aldoketoreductase, AKR1C3, which is differentially expressed in many cancers. The molecule was originated at...

A diaziridine-based tumor-activated prodrug for AKR1C3-expressing cancers from a defunct Bay Area biotech. OBI-3424 (formerly TH-3...

Terlipressin: Longer Peptide Effect Half-Life via an Active Metabolite

On Monday, Mar. 27th (12:15 PM ET), our Drug Hunter team will be sponsoring a luncheon at ACS Spring 2023 in Indianapolis with a presentation on scientific gems from 2022’s drug approvals ( request an invitation here ). Each newly approved drug has an interesting scientific story, and you can see our overview of all 36 of the novel small [...]

On Monday, Mar. 27th (12:15 PM ET), our Drug Hunter team will be sponsoring a luncheon at ACS Spring 2023 in Indianapolis with a p...

SPR720

SPR720 (pVXc-486) is an oral prodrug of a dual inhibitor of the bacterial DNA gyrase and topoisomerase IV ATPase catalytic domains, GyrB and ParE . The molecule was in-licensed by Spero Therapeutics , a 2014 “Fierce 15” startup , from Vertex ( WO2014014845A1 , US20140031318 ), and is now Spero’s lead development program after [...]

SPR720 (pVXc-486) is an oral prodrug of a dual inhibitor of the bacterial DNA gyrase and topoisomerase IV ATPase catalytic domains...

A Prodrug Bioactivated in the Eye for Ocular Hypertension: Omidenepag

Omidenepag isopropyl (Omlonti) is a prodrug of a prostaglandin E2 (EP2) receptor agonist that reduces pressure in the eye. Upon topical administration to the eye, the molecule penetrates the lipophilic and negatively charged corneal epithelium and is converted to the pharmacologically active form by the enzyme carboxylesterase-1. The [...]

Omidenepag isopropyl (Omlonti) is a prodrug of a prostaglandin E2 (EP2) receptor agonist that reduces pressure in the eye. Upon to...

sirpiglenastat

A first-in-class diazo-prodrug for the treatment of solid tumors. Sirpiglenastat (DRP-104) (Johns Hopkins/Dracen Pharmaceuticals) is a dual prodrug of 6-diazo-5-oxo-l-norleucine (DON), a diazoketone-based glutamine irreversible antagonist used to suppress cancer cell metabolism. Rapidly growing cancer cells depend on glutamine as an energy [...]

A first-in-class diazo-prodrug for the treatment of solid tumors. Sirpiglenastat (DRP-104) (Johns Hopkins/Dracen Pharmaceuticals) ...

GS-621763

The Gilead SARS-CoV-2 drug, GS-621763, is an oral prodrug of the parent nucleoside of remdesivir (GS-441524) which demonstrated therapeutic and prophylactic efficacy in a ferret model of SARS-CoV-2 infection, significantly reducing viral load to near-undetectable levels with twice-daily administration. Remdesivir is already FDA [...]

The Gilead SARS-CoV-2 drug, GS-621763, is an oral prodrug of the parent nucleoside of remdesivir (GS-441524) which demonstrated th...

compound 10

The BMS TGFβR inhibitor prodrug, “ compound 10 ,” demonstrates antitumor efficacy comparable to the parent compound ( BMS-986260 ) in a syngeneic model with once-weekly dosing, while reducing the systemic exposure of BMS-986260. Reducing the systemic exposure of a TGFβR inhibitor is important due to previously observed mechanism-based cardiac [...]

The BMS TGFβR inhibitor prodrug, “ compound 10 ,” demonstrates antitumor efficacy comparable to the parent compound ( BMS-986260 )...

AL-611

AL-611 is a prodrug to a nucleoside inhibitor of HCV NS5B polymerase. While there have been very successful nucleoside drugs (e.g. sofosbuvir), several nucleoside inhibitors of HCV previously failed in the clinic due to severe toxicities, in some cases due to incorporation of the nucleosides into host RNA. The Janssen Biopharma (formerly [...]

AL-611 is a prodrug to a nucleoside inhibitor of HCV NS5B polymerase. While there have been very successful nucleoside drugs (e.g....

"compound 9"

“compound 9” is an investigational prodrug of pibrentasvir (ABT-530), a key component of AbbVie’s marketed HCV combination Mavyret. Pibrentasvir (PIB) is the largest approved oral small molecule since 1983 (MW = 1113, not including the peptide semaglutide at MW = 4113), and came with some solubility issues (aq. sol. pH 7 = <0.0001 mg/mL). The [...]

“compound 9” is an investigational prodrug of pibrentasvir (ABT-530), a key component of AbbVie’s marketed HCV combination Mavyret...

"compound 3d"

“compound 3d” is a prodrug which is phosphorylated in vivo to form a potent sphingosine-1-phopshate receptor modulator. BMS took two previous compounds into the clinic for MS with the goal of differentiating from fingolimod on safety. One potential issue for a previous compound was an overly long (12 day) half-life which could be undesirable [...]

“compound 3d” is a prodrug which is phosphorylated in vivo to form a potent sphingosine-1-phopshate receptor modulator. BMS took t...

MGS0274

MGS0274 is a prodrug of an mGlu2/3 receptor agonist with ca. 15x greater oral exposure than the parent. The ester is believed to be cleaved pre-systemically by liver carboxyesterases to release the innocuous byproducts acetaldehyde, CO2, and menthol. The parent is also an interesting looking molecule prepared in a few steps from [...]

MGS0274 is a prodrug of an mGlu2/3 receptor agonist with ca. 15x greater oral exposure than the parent. The ester is believed to b...

ETX0282

ETX0282 is an oral prodrug of a class A, C, and D serine β-lactamase inhibitor in clinical development for drug-resistant enterobacterial infections in combination with the beta-lactam drug cefpodoxime proxetil. Impressively ETX0282 had no observed adverse effect levels (NOAELs) of 500 mg/kg/day and 400 mg/kg/day in rat and dog, respectively, [...]

ETX0282 is an oral prodrug of a class A, C, and D serine β-lactamase inhibitor in clinical development for drug-resistant enteroba...

NLG802

NLG802 is a prodrug of the IDO1 inhibitor indoximod with significantly enhanced oral exposure. Both the acid and amine functionalities of indoximod are protected as an ethyl ester and leucine amide, respectively. Prodrugs are generally difficult to develop so it’s interesting that two biotransformations are employed. The molecule is first [...]

NLG802 is a prodrug of the IDO1 inhibitor indoximod with significantly enhanced oral exposure. Both the acid and amine functionali...