BAY 2413555 is a M2R PAM that has the potential to counter parasympathetic withdrawal and restore autonomic balance in heart failure patients. The preclinical and clinical data of BAY 2413555 showed it has positive effects on heart rate and heart rate variability and a relatively long human t1/2 of 37 h. The Ph. I trial, however, was terminated in March 2024 due to findings from a chronic toxicology study. This article covers the discovery of BAY 2413555, presented by Alexandros Vakalopoulos of Bayer at the EFMC-ISMC 2024 conference in Rome and published in the Journal of Medicinal Chemistry.

Novartis' NLRP3 inhibitor, NVP-DFV890, features a unique sulfonimidamide motif designed to reduce hydrolysis relative to traditional sulfonylureas. This potent compound, with promising PK in humans, is advancing through multiple clinical studies, including Ph. II trials for coronary heart disease and knee osteoarthritis. Presented by Angela Mackay at the EFMC-ISMC 2024 joint conference in Rome, this overview covers NVP-DFV890's discovery, as well as its preclinical PK and PD data.

Recently, a surge of (pre)clinical compounds inhibiting the NLRP3 inflammasome, often featuring a hexahydroindacene ring system, has emerged, including Nodthera’s ND-0796. In a push for new chemotypes, AZ and Mitsubishi Tanabe have disclosed their clinical compound, AZD4144, which is currently in Ph. I trials in healthy volunteers. The discovery story detailed their efforts to overcome PLD (phospholipidosis), genotoxicity, and hERG inhibition in a non-classical pharmacophore series. The discovery was presented by Anders Johansson at the EFMC-ISMC 2024 Meeting in Rome.

Pfizer disclosed the structure and discovery of their oral small molecule BDK inhibitor/degrader, PF-07328948, during the ACS Fall 2024 First-Time Disclosures session in Denver. The team identified a thiophene carboxylic acid-based hit targeting an allosteric pocket on BDK. Through optimization, they overcame challenges such as potential IADRs and BDK-E2 complex stabilization. By manipulating the dihedral angle of the methoxy group, they enhanced binding interactions, verifying PF-07328948's unexpected mechanism of action in vivo. PF-07328948 is currently Ph. I trials.

Nerandomilast (BI 1015550) is Boehringer Ingelheim’s PDE4B inhibitor with demonstrated clinical potential in treating IPF.

Compound 20 is a galactose-based monosaccharide Gal-3 inhibitor from Bristol Myers Squibb that shows potential in targeting fibrotic diseases.

AstraZeneca recently disclosed the structure and discovery journey of their oral small molecule PCSK9 inhibitor, AZD0780, during the ACS Fall 2024 First Time Disclosures session in Denver. Discover how the team identified a fragment hit targeting a previously unexplored pocket, verified its novel mechanism of action, and successfully advanced it into a clinical compound now in Ph. II trials for patients with dyslipidemia.

NT-0796 is NodThera's pro-drug inhibitor of the NLRP3 inflammasome. NT-0796 is currently in a Ph. Ib/IIa trial in obese individuals at risk of developing atherosclerotic cardiovascular diseases. NT-0796 has the potential to reduce neuroinflammation in Parkinson’s disease. The NLRP3 inflammasome has emerged as a hot target due to its connection to Alzheimer’s disease, Parkinson’s disease, gout, and other diseases. Here is a detailed review of the role of NLRP3 inhibition in treating atherosclerosis, how NT-0796 was identified, and what makes it special, clinical development, and more.

Acoramidis (AG10), an oral, second-generation stabilizer of the tetrameric transthyretin (TTR) protein, was submitted for FDA approval on Dec. 5, 2023 by BridgeBio for the treatment of transthyretin amyloid cardiomyopathy (ATTR-CM). The rare but potentially fatal disease is characterized by amyloid deposits in heart muscle. The molecule has the potential to be best-in-class relative to Pfizer’s $2.4B+/yr blockbuster tafamidis. This story highlights early experiments validating TTR stabilization, why enthalpy of binding was key, how it binds TTR, its 30-mo clinical data, and more.

BAY 1165747 (BAY-747) is a new, structurally distinct, soluble guanylate cyclase (sGC) stimulator with potential in the treatment of resistant hypertension . Identified through ultrahigh-throughput screening, it features an imidazo[1,2-a]pyridine core, distinct from the [...]

“Compound 6f” is a potent macrocyclic factor XIa inhibitor (<1 nM) that is highly selective against other serine proteases and has excellent oral PK (high bioavailability, low clearance). The BMS team was able to troubleshoot metabolic instability through met. ID, which revealed a hotspot outside of the macrocycle.

Mavacamten is a first-in-class oral, selective, allosteric cardiac myosin inhibitor, discovered by Myokardia and acquired by BMS in 2020 in a whopping $13.1B transaction. In 2022 , it was approved by the FDA to treat obstructive hypertrophic cardiomyopathy (HCM) in adults and, thanks to its use, led to improvements in functional capacity and [...]

In this update of small molecules in the news for February 2023, we will cover recent: - Molecules in Motion : clinical trial updates and FDA filings - Negative Readouts : halted, discontinued or altered clinical trials - Million-Dollar Molecules : recent M&A’s, IPOs, and other fundraising - Potential Approvals : recent NDA filings and [...]

Bexotegrast is a dual-selective αvβ6-αvβ1 integrin inhibitor with surprising efficacy and safety data from a Ph. II trial in idiopathic pulmonary fibrosis (IPF). The αv integrins have been studied for decades in indications such as cancer and IPF. Both small molecule and antibody-based integrin inhibitors have demonstrated preclinical toxicities in non-human primates. This article highlights the unmet need for effective therapies for IPF and related conditions, a comparison of bexotegrast with other integrin binders, and possible reasons why bexotegrast is different in terms of safety.

Our latest roundup of small molecules in the news includes two potential upcoming approvals: rezafungin Rezafungin (CD-101) is a once-weekly IV antifungal agent and next-generation echinocandin (glucan synthase inhibitor) that demonstrated non-inferiority vs. standard of care caspofungin (IV QD) (NCT03667690). An FDA AdCom voted 14 to 1 in [...]

Context. Obicetrapib (Monash University and NewAmsterdam Pharma) is an oral selective cholesteryl ester transfer protein (CETP) inhibitor being developed for dyslipidemia. Patients with high cardiovascular risk typically aim to lower cholesterol with a combination of statins, diet, and exercise, but this is often not enough . A foundational [...]

Context. SPH3127 (Mitsubishi Tanabe and Shanghai Pharmaceuticals) is an oral direct renin inhibitor (DRI) being developed for hypertension. The renin-angiotensin-aldosterone system is responsible for regulating blood pressure. Existing drugs treat hypertension by targeting angiotensin-converting enzyme (ACE) and the angiotensin II receptor [...]

Context. AZD4831 (AstraZeneca) is an oral covalent myeloperoxidase (MPO) inhibitor being developed for heart failure. Almost half of chronic heart disease patients suffer from heart failure with a preserved ejection fraction (HFpEF) and have an estimated five-year mortality rate of 75% . Improvement in vascular structure could help these [...]

Context. “ Compound 33 ” (Merck) is a cGMP-dependent protein kinase G1α (PKG1α) activator cGMP modulation is considered one of the most promising approaches for cardiovascular drug discovery with >30 agents either approved for use or in various stages of clinical development. Although PKGs are the main effector of cGMP, cardiovascular drug [...]

Context. BMS-986120 is an oral protease-activated receptor 4 (PAR4) inhibitor that was being developed for arterial thrombosis . PAR4 was long considered a redundant “backup” receptor to the more popular and well-researched PAR1 receptor, owing in part to the higher thrombin levels required for activation and the slower signaling response the [...]

Context. MK-0159 (Mitobridge) is an oral CD38 inhibitor being developed for cardiovascular diseases. D ue to its NADP + depleting activity, which has implications for calcium homeostasis, the cell surface marker CD38 has attracted attention as a suitable target for developing cardiovascular disease agents. Although two monoclonal antibodies [...]

A first-in-class intravenous kappa opioid receptor (KOR) agonist, an oral soluble guanylate cyclase (sGC) stimulator, a first-in-class subcutaneous complement C3 inhibitor, and an oral contraceptive comprising a synthetic progesterone (drospirenone) and a plant-based estrogen (estetrol) make up the final group of novel drugs from 2021 that we [...]

Context. Lenrispodun (Intra-Cellular Therapies) is a phosphodiesterase (PDE) type 1 (PDE1) inhibitor being developed for CNS and non-CNS disorders, including heart failure, and cancer. Studies to identify PDE inhibitors date back at least 30 years, and at least 10 drugs have been approved targeting other PDE proteins (spearheaded by the PDE5 [...]

There were two novel small molecules approved in April 2022: mavacamten (Camzyos), an oral cardiac myosin inhibitor oteseconazole (Vivjoy), an oral antifungal ( jump to section ) This deep dive explores each drug in more detail, including the industry context, the clinical data, the target rationale, mechanisms of action, and drug origins [...]

Merck’s oral, macrocyclic PCSK9 inhibitors are among the 12 candidates for 2021's "Molecule of the Year" and have already gotten quite a few votes for 2021’s “Molecule of the Year.” They’ve been called “gamechangers” by readers, with impressive human proof-of-concept. MK-0616 is a macrocyclic PCSK9 inhibitor with demonstrated once-daily [...]

asundexian (BAY2433334) is a reversible Factor XIa active site inhibitor previously disclosed at the 2021 EFMC-ISMC conference . This article highlights the Ph. I data of asundexian in healthy volunteers, showing that the drug is well tolerated, with no clinically relevant bleeding-related adverse events or any relevant CYP3A4 modulation. The [...]

The Cytokinetics next-generation myosin inhibitor, aficamten , is a phase II candidate for genetic hypertrophic cardiomyopathies, and is orally dosed between 5-30 mg QD. It follows BMS’s mavacamten ( acquired from Myokardia in a $13.1B deal), whose NDA is under review by the FDA. This class of molecules is intended to address hypertrophic [...]

The Merck bicyclic macrocyclic peptide PCSK9 inhibitor, “ compound 44 ,” is a highly potent (Ki = 0.00239 nM) and orally bioavailable (cyno %F = 2.9, t1/2 = 10 h) agent against a notoriously difficult target for small molecules, demonstrating target engagement comparable to approved PCSK9 antibodies. The discovery of this molecule is an [...]

The Sanofi S1P1 agonist, SAR247799 , is a biased agonist of the S1P1 sphingosine receptor, preferentially activating G-protein signaling over the β-arrestin and internalization pathways. Commercial S1P1 modulators such as fingolimod and ozanimod exert their immunosuppressive effects in multiple sclerosis and other diseases primarily by [...]

The BMS factor XIa inhibitor, milvexian (BMS-986177), is an oral antithrombotic with a Ki of 0.11 nM. A member of this macrocyclic series was previously highlighted as one of 2020’s Molecules of the Year . Poor pharmaceutic properties from previous preclinical molecules such as solubility were addressed resulting in this candidate. Milvexian [...]

The Merck CETP inhibitor backup, MK-8262 , is potential best-in-class CETP inhibitor, which was only discontinued as a backup due to the success of its predecessor, anacetrapib in Ph. III. Reviewer Kim Huard thought this CETP inhibitor was a great piece of work from Merck, and is a great example how to deal with a very lipophilic binding site [...]

BAY 1217224 (Bayer oral non-prodrug thrombin (Factor IIa) inhibitor)

“compound 12” is a selective inhibitor of integrin αvβ5, a potential target for sepsis due to its potential role in regulating vascular leakage. Selectivity among integrin family members can be challenging to achieve and can have significant safety implications – hence, most integrin drugs have been selective biologics. Since the biological [...]

“compound 23” is an oral, selective Factor XIa inhibitor intended as an anticoagulation agent. Since the clinical translatability of FXIa inhibition in preclinical models hasn’t been established, this program was driven by activity in in vitro human plasma coagulation assays. The team was able to turn a 0.6 uM hit originally from a complement [...]

BI-0115 inhibits the C-type lectin family member lectin-like oxidized LDL-receptor-1 (LOX-1) by stabilizing an inactive tetrameric form of the protein. Interestingly, co-crystollography demonstrates that inter-ligand interactions between two BI-0115 molecules contribute to the dimerization of LOX-1 homodimers.

“Compound 6f” is a potent macrocyclic factor XIa inhibitor (<1 nM) that is highly selective against other serine proteases and has excellent oral PK (high bioavailability, low clearance). The BMS team was able to troubleshoot metabolic instability through met. ID, which revealed a hotspot outside of the macrocycle.

BMS-986235/LAR-1219 is an FPR1-sparing FPR2-selective agonist intended to help resolve chronic inflammation/promote wound healing to prevent serious complications like heart failure. It’s a very efficient molecule and is orally efficacious in a mouse myocardial infarction model at doses as low as 0.3 mg/pk, despite having 3 N-H donors (urea + [...]