Peptidic GLP-1R agonists have received significant media coverage over the past year for their astounding efficacy in several indications. While most of the recent fanfare has been related to their role in weight loss, GLP-1R agonists have been a mainstay of the type 2 diabetes treatment landscape for the past 2 decades. GLP-1R agonists have also recently shown efficacy in reducing heart disease risk and treating certain chronic kidney diseases. Here’s a recap of the March 14th, 2024, Flash Talk, from Oliver Philps.

We asked the global drug discovery community to nominate and vote on their favorite molecule from 2023, and the results are in. The 2023 winner, with the most votes between ten molecules, is Merck’s oral macrocyclic peptide inhibitor of PCSK9, MK-0616, derived from mRNA display technology and shown to have clinical efficacy. Herein, we highlight what makes MK-0616 so impressive to the drug discovery community.

Peptidic GLP-1R agonists have received significant media coverage over the past year for their astounding efficacy in several indications. GLP-1R agonists now appear to be efficacious in reducing heart disease risk and in treating certain chronic kidney diseases, expanding their likely future use. This review by Oliver Philps provides an overview of GLP-1 agonists and where they fit in the treatment of diabetes, how the peptide drugs evolved over time to today’s weight loss medications, and what to expect next...

Chugai’s PCO371 is an oral, biased agonist and "molecular wedge" of the class B GPCR, PTHR1, that first entered development for hypoparathyroidism in 2015 (NCT02475616). While Class A GPCRs, which typically have compact ligandable pockets are the most common targets for approved drugs, Class B GPCRs like PTHR1, GLP-1R, and CGRP are notoriously difficult to drug since they normally bind large peptides with long transmembrane tunnels that are not easily bound by small molecules. This article explains what makes PCO371 a big deal for GPCR drug discovery.

Peptidic GLP-1R agonists have received significant media coverage over the past year. Shortages of the semaglutide-based injectable diabetes medication Ozempic, which accounts for 40% of GLP-1R agonist US market share, have even emerged, driven by overwhelming demand for the weight loss formulation Wegovy, both for treatment of obesity and for short-term weight loss popularized by celebrities on social media. This article reviews the science of danuglipron, recent news, and what makes it different.

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.

Orforglipron is an oral non-peptide glucagon-like peptide-1 (GLP-1) receptor partial agonist that entered Ph. III for obesity and type-2-diabetes mellitus (T2DM). This 2020 and 2023 Molecule of the Year nominee (nominated initially back when it was still in Ph. I) was first discovered by Chugai Pharmaceuticals under the name OWL833, then licensed by Eli Lilly for worldwide development under the name LY3502970. The article discusses where it sits in the GLP-1R agonist landscape, why it’s scientifically notable, how it works with illustrations from cryo-EM structures, its synthesis, and more.

Merck’s macrocyclic PCSK9 protein-protein interaction (PPI) inhibitor, MK-0616, is a once-daily PCSK9-lowering and LDL-cholesterol-lowering small molecule that has recently demonstrated antibody-like efficacy as an oral agent in the clinic. The program highlights numerous technical achievements at the forefront of modern drug discovery, and will set a standard for modern “classics in drug discovery” for some time.

ACT-777991, an oral and insurmountable CXCR3 antagonist discovered by Idorsia (formerly Actelion), is under investigation for the treatment of Type 1 Diabetes (T1D). Despite the complex history of CXCR3 antagonists, ACT-777991 has shown promise with [...]

Finally, December’s molecule, the Novo Nordisk oral insulin analog OI338, is the first oral insulin to demonstrate similar outcomes to insulin glargine injection in a Ph. II clinical trial. The molecule has an ultralong PK profile (t1/2 = 70 h) due to the inclusion of an albumin-binding long-chain fatty acid. [...]

November’s molecule, the Chugai/Lilly GLP-1R agonist LY3502970, is a highly potent and selective, oral, biased partial agonist of the GLP-1R GPCR. GLP-1R agonists have been approved for many years now to treat Type II diabetes mellitus, due to their ability to stimulate insulin secretion in pancreatic beta-cells. [...]

January’s molecule, a Novartis FXR partial agonist (LMB763 (nidufexor)), modulates the farnesoid X nuclear receptor (FXR), a hot target for NASH due to promising prior clinical activity with bile acid-derived FXR agonists such as OCA. OCA, however, showed significant rates of side effects including itching (likely due to GPBAR1 bile acid receptor agonism) and elevated LDL cholesterol levels, which is problematic for the more heart-disease-susceptible NASH patient population. [...]

MC4R antagonism to help gain weight. PF-07258669 is a melanocortin-4 receptor (MC4R) antagonist intended to help increase weight gain, in contrast to MC4R agonists which have been studied extensively in the industry for weight loss (and have notable side effects such as priapism ). The peptidic MC4R agonist, setmelanotide , for example, was [...]

Resmetirom is an oral, liver-targeting, once-daily THRβ-selective agonist, which in December 2022 became the first drug to meet its primary endpoints in Ph. III for NASH, demonstrating both NASH resolution and no worsening of fibrosis by biopsy over placebo in 316 test patients. Madrigal will file an NDA for resmetirom in 2023, allowing it to [...]

What is it? Baxdrostat ( RO6836191 , CIN-107) is an oral aldosterone synthase (CYP11B2) inhibitor in several Ph. II trials (0.5-2 mg QD) for hypertension, CKD, and primary aldosteronism. The molecule is highly selective ( >100x ) against a cortisol synthesis enzyme, CYP11B1, allowing it to avoid negative effects due to cortisol reduction in [...]

PF-6870961 is a growth hormone secretagogue receptor 1a (GHSR1a) inverse agonist biased for inhibition of 𝜷-arrestin signaling, in contrast to its parent compound, PF-5190457, an unbiased GHSR1a inverse agonist. PF-6870961 was discovered as a major metabolite of [...]

On Mar. 14th, 2024, resmetirom (REZDIFFRA™) became the first and only medicine approved by the FDA for the treatment of NASH (non-alcoholic steatohepatitis, aka MASH). Resmetirom, an oral, liver-targeting, once-daily THR-β-selective agonist originally discovered at Roche Nutley, was first highlighted as a Molecule of the Month in Dec. 2022. Now, with the FDA’s accelerated approval, this 2023 Molecule of the Year nominee reflects a historic milestone for liver drug discovery. This article reviews how the molecule works, how it was discovered, and why it’s a big deal.

Toward a first-in-class DGAT2 inhibitor for the treatment of NASH. Hepatic triglyceride (TG) accumulation is a symptom of non-alcoholic fatty liver disease ( NAFLD ), which can progress to non-alcoholic steatohepatitis ( NASH ), which is characterized by hepatocyte damage, inflammation and collagen deposits (fibrosis). NASH has been estimated [...]

Revisiting AMPK activation with β2-AMPK isoform potency. “ Compound 14d ” (Shionogi & Co.) is a highly potent, dose-dependent adenosine monophosphate activated protein kinase (AMPK) activator being investigated for its blood-glucose-lowering effects. AMPK became a target-of-interest for the treatment of diabetes due to its role in regulating [...]

Context. AZD1656 (AstraZeneca)is an oral glucokinase (GK) activator (GKA) for hyperglycemia in type 2 diabetes mellitus. Despite GK being first reported more than 50 years ago and subsequent extensive research efforts , a GKA is yet to be approved. Most GKAs have failed in clinical development owing to an increased risk of hypoglycemia and [...]

Context. Upacicalcet (Sanwa Kagaku Kenkyusho Co) is a calcium-sensing receptor (CaSR) agonist being developed for secondary hyperparathyroidism (SHPT). The IV drug, first identified in "kokumi-flavor" studies of γ-glutamyl peptides, was approved for SHPT in Japan in 2021 and is currently being developed for the US and other markets [...]

Context. GB1211 (Galecto Biotech) is an oral galectin-3 inhibitor under development for fibrotic disease. First described in 1971, galectin-3 , a unique subtype of a 15-member family of carbohydrate-binding proteins, has been implicated in a host of different diseases, such as cancer, liver cirrhosis, and atherosclerosis. Incredibly, over [...]

Context. “ Compound 3f ” (Janssen) is an oral Factor XIa (FXIa) inhibitor being developed for thromboembolic diseases. The suitability of FXIa as a target in the development of anticoagulation agents stems from observations that the coagulation factor contributes significantly to pathological blood clotting (thrombosis) but plays a negligible [...]

Context. “ Compound 14 ” (Shionogi Pharmaceuticals) is a nicotinamide N -methyltransferase (NNMT) inhibitor. For some “difficult to drug” targets such as protein-protein interactions , peptides are attractive therapeutic modalities due to their high binding specificity and synthetic accessibility. Macrocyclization of peptides may help improve [...]

Context. BMS-986339 (BMS) is an oral farnesoid X receptor (FXR) agonist being developed for nonalcoholic steatohepatitis (NASH) . Considered the master regulator of bile acid homeostasis, the nuclear receptor FXR may be an attractive target for diseases such as NASH, where bile acid dysregulation has been implicated. Currently, the only [...]

Context. Apararenone (Mitsubishi Tanabe) is an oral nonsteroidal mineralocorticoid receptor (MR) antagonist . Agents with the ability to modulate the nuclear receptor MR have been pursued for at least 80 years. Spironolactone , the first-in-class MR (steroidal) antagonist, was approved in 1960, with the more selective eplerenone (also [...]

Context. RLX-33 (Research Triangle Institute) is a nonpeptide relaxin-3/RXFP3 system antagonist . Evidence over the last 2 decades, since the discovery of relaxin‐3 in 2001 , suggests that the protein, through its receptor RXFP3, regulates responses to stress, anxiety-related and motivated behaviors, circadian rhythms, learning and memory [...]

Context. INCB13739 (Incyte) is an oral 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) antagonist . Inhibition of the tissue-specific generation of cortisol using agents that antagonize 11β-HSD1, the key metabolic enzyme involved in the conversion of inactive glucocorticoids to active ones, has been considered a desirable therapeutic strategy [...]

Dorzagliatin (Hua Medicine) is an oral dual-acting full glucokinase (GK) activator being developed for type 2 diabetes . More than 50 years since the first report of the role of GK in glucose metabolism, no agents targeting this enzyme have been approved, although not for lack of trying. We recently covered a partial GK activator [...]

There were two novel small molecules approved in May 2022: vonoprazan (Voquezna) : a potassium-competitive acid blocker (PCAB) tapinarof (Vtama) : an aryl hydrocarbon receptor (AhR) agonist And one novel large molecule approval: tirzepatide (Mounjaro) : a glucose-dependent insulinotropic polypeptide (GIP) receptor and glucagon-like peptide-1 [...]

In 2021, the FDA approved two new drugs for endocrinology-related indications, including severe hypoglycemia in diabetes, and chronic kidney disease (CKD) associated with type 2 diabetes. This article and slide deck explores each in more detail, including but not limited to their: target rationale discovery disease context original patents [...]

Context. DS69910557 (Daiichi Sankyo) is an oral inhibitor of parathyroid hormone (PTH) type 1 receptor (PTHR1) being developed as a calcium-lowering drug. The well-characterized secretin class receptor PTH1R is a principal regulator of bone remodeling and calcium ion homeostasis which makes it an attractive target for some endocrinopathies [...]

“Compound 10” (AstraZeneca) is an oral CDK5-mediated PPARγ phosphorylation inhibitor and partial PPARγ agonist being developed as an antidiabetic drug . Although widely used PPARγ agonists such as rosiglitazone and pioglitazone are effective antidiabetics, they are limited by [...]

Context. BMS-820132 (Bristol Myers Squibb) is an oral glucokinase (GK) partial activator intended for diabetes. GK activators for diabetes were hotly pursued in the late 2000’s, with well over 100 industry patents on GK activators by 2009. The pursuit was triggered by the discovery of the first allosteric activators of glucokinase from an [...]

Context. GCC5694A (GC Pharma (Green Cross)) is an oral SGLT2 inhibitor. SGLT2 inhibitors help glycemic control in diabetes by preventing reabsorption of glucose in the kidney. Dapagliflozin was the first SGLT2 inhibitor approved in the EU (2012), and canagliflozin was the first to be approved in the US (2013). We recently highlighted [...]

Compound 15 is a gut-restricted inhibitor of NaPi2b, a sodium-dependent phosphate transport protein in the solute carrier (SLC) family. NaPi2b is expressed on the apical side of the small intestine and contributes to absorption of inorganic phosphate in the diet. Chronic kidney disease patients have elevated serum phosphate levels and need [...]

MK-0616 is a macrocyclic PCSK9 inhibitor with demonstrated once-daily PCSK9-lowering and LDL-cholesterol-lowering activities in a human clinical trial (<300 mg QD). Currently PCSK9-targeting therapies are only available by injection, and the cost-benefit of using large molecules to lower cholesterol has been hotly debated. Identification of [...]

The Lilly glucagon-like peptide-1 receptor (GLP-1R) agonist ( LSN3318839 ) is a positive allosteric modulator intended to treat type 2 diabetes. This drug candidate has an interesting proposed mechanism as a molecular glue between GLP-1R and GLP peptide, enhancing endogenous peptide activity. GLP-1 agonism is a well-established mechanism for [...]

Retinol-binding protein 4 (RBP4) is the sole carrier for retinol (vitamin A). It may also play a role in diabetes and reduction of RBP4 may be beneficial for the ocular disease AMD. Belite Bio had a Ph. III trial ongoing for an oral RBP4 antagonist (LBS-008, tinlarebant ) in Stargardt Disease and intends to start a Ph. III trial for AMD in [...]

Gout is caused by the buildup of uric acid. The main treatments are drugs that increase uric acid secretion (uricosurics, e.g. probenecid ) and xanthine oxidase inhibitors which inhibit uric acid production (e.g. allopurinol ). URAT1 inhibitors like lesinurad (Ironwood Pharmaceuticals) and dotinurad are emerging treatments, inhibiting uric [...]

The ImmunoMet OXPHOS modulator (PC1 inhibitor), IM156 , is a derivative of the long-used biguanide diabetes drug, metformin, that appears to have activity in lung fibrosis models. The therapeutic hypothesis for IPF is that myofibroblasts play an essential role in extracellular matrix remodeling and fibrogenesis that lead to loss of pulmonary [...]

1.The Lilly glucagon-like peptide-1 receptor (GLP-1R) agonist (LSN3318839) is a positive allosteric modulator intended to treat type 2 diabetes. This drug candidate has an interesting proposed mechanism as a molecular glue between GLP-1R and GLP peptide, enhancing endogenous peptide activity. The starting point was identified from a 220k [...]

The Kissei SGLT2 inhibitor prodrug, remogliflozin etabonate , is an SGLT1-sparing oral drug launched in 2019 in India for the treatment of type 2 diabetes.  Interestingly, the lead for this drug was a metabolite identified from mouse urine after treatment with a Wyeth-Ayerst antihyperglycemic agent of previously unknown mechanism.

Novo oral insulin analog

Chugai/Lilly clinical oral non-peptide GLP-1R GPCR partial agonist

OATD-01 (OncoArendi Therapeutics oral, first-in-class CHIT1/AMCase chitinase inhibitor clinical candidate)

PF-06882961 is an oral small molecule agonist of the glucagon-like peptide-1 receptor (GLP-1R). GLP-1R agonists increase the production of insulin and are highly useful in the treatment of diabetes. However, until the recent introduction of an oral formulation of semaglutide, GLP-1 agonists were all peptides requiring inconvenient injections. [...]

PF-05221304 is a liver targeted inhibitor of acetyl-CoA carboxylase (ACC). ACC is a key regulator of lipid metabolism, and there has been significant interest in ACC inhibitors for the treatment of multiple indications including NASH and diabetes. Pfizer previously took a systemic ACC inhibitor into the clinic (PF-05175157), which was found [...]

PF-06835919 is an oral first-in-class clinical candidate for NAFLD/NASH targeting ketohexokinase (KHK), an enzyme which initiates the metabolism of fructose. The authors describe a very elegant structure-based design campaign to improve a modestly active, quickly cleared lead molecule into this highly potent, permeable, bioavailable, and [...]

SCO-267 is a full agonist of the GPCR GPR40, whose activation stimulates secretions of insulin and incretin. Since no crystal structures were available, the authors used conformational modeling to rationally improve the ligand from a weak lipophilic initial starting point (0.4 uM, clogP 9.4) to a more lipophilically efficient candidate (12 nM [...]

“compound 12j” is a potent agonist of the ghrelin hormone receptor, activation of which stimulates growth hormone secretion and appetite among other activities. Ghrelin receptor antagonists have previously been explored to treat disorders related to obesity such as diabetes, but an agonist could be useful in treating atrophic disorders like [...]

dotinurad (FYU-981) potently inhibits uric acid uptake by renal proximal tubule epithelial cells, increasing uric acid urinary secretion which can help hyperuricemic conditions like gout. The mechanism of action is believed to be inhibition of the URAT1 organic anion transporter which mediates uric acid reabsorption. Benzbromarone has been [...]

“compound 6g” is an oral inhibitor of the sodium-glucose co-transporters (SGLTs) 1 and 2, intended for the treatment of hyperglycemia. SGLT2 selective inhibitors (gliflozins) are approved for treatment of type 2 diabetes, and an SGLT1/2 dual inhibitor is expected to result in greater glycemic control. Like other SGLT inhibitors, this molecule [...]

GS-9688 (selgantolimod) is a potent and selective TLR8 agonist sparing related receptor TLR7, and is intended to induce better immune responses in chronic hepatitis B. Since systemic activation of TLR8 was undesirable, selgantolimod was designed to have high first-pass hepatic clearance to induce effective antiviral immunity in the liver but [...]

LMB763 (nidufexor) (Novartis (GNF) oral in vivo selective FXR partial agonist)

GNF2133 (Novartis (GNF) oral in vivo GSK3-beta-sparing DYRK1A kinase inhibitor)