“Compound 15” is a BACE1 selective inhibitor with a fluoro-olefin replacement for an N-aryl amide without the liability of a potential aniline metabolite. The compound has good oral PK in rodents, which was likely challenging to obtain with the thioamidine core common to BACE1 inhibitors. As usual for Amgen there’s some pretty cool synthetic [...]

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 [...]

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 + [...]

eFT226 (zotatifin) is a beautiful natural product-derived molecule that inhibits the RNA helicase eIF4A by forming a ternary complex between it, eIF4A, and polypurine RNA. Interestingly, the stability of the ternary complex depends on the RNA sequence bound to eIF4A, with greatest activity for AGAGAG-based complexes. The molecule demonstrates [...]

JNJ-54717793 is a selective antagonist of the orexin-1 receptor intended for use in anxiety disorders, in contrast to dual orexin-1/2 inhibitors and orexin-2 inhibitors typically applied for sleep disorders. It’s a surprisingly large molecule (three aromatic rings and a bicycle) for an oral, brain-penetrant clinical candidate with predicted [...]

DS-1971a is a potent, isoform-selective selective arylsulfonamide NaV1.7 inhibitor intended for the treatment of neuropathic pain. It has a surprisingly long residence time on NaV1.7, which the authors suggest contributes to better than predicted in vivo activity. 1971a is a good example of a compound which was successfully advanced to [...]

“Compound 6g” is a potent, selective, and reversible inhibitor of monoacylglycerol lipase (MAGL), which degrades the cannabinoid receptor (CB) agonist 2-arachidononylglycerol (2-AG) to arachadonic acid (AA). Inhibition of MAGL therefore indirectly agonizes CB receptors and reduces inflammatory AA levels, which may be beneficial for a range of [...]

GSK232 is a highly selective cell-penetrant inhibitor of the non-BET CECR2 bromodomain with >500-fold selectivity over BET-family bromodomains identified during a campaign to find selective inhibitors of the bromodomain ATAD2. Since bromodomain-containing complexes are highly modular and have scaffolding functions, their roles in biology are [...]

LEI401 is a selective, brain-penetrant inhibitor of NAPE-PLD, an enzyme involved in the biosynthesis of various N-acylethanolamine (NAE) signaling lipids, and is a potentially useful tool molecule for understanding the basic biology around this target. The compound emerged as the result of an academic collaboration, including an HTS done with [...]

Tucatinib is the third approved HER2 kinase inhibitor (after lapatinib and neratinib), but differentiates itself due to its selectivity against the closely related EGFR, which is hypothesized to be a source of undesired side effects with prior inhibitors. Impressively, it’s also demonstrated activity in HER2+ breast cancers with brain [...]

S6821 is one of two potent and selective TAS2R8 GPCR antagonists disclosed by Firmenich, a fragrance and flavor company. These compounds block bitter taste receptors and don’t have significant systemic exposure, and have been approved as safe for use. I thought it was interesting to see high-quality medicinal chemistry applied in a [...]

April 2020’s molecule, the Mirati KRAS G12C inhibitor MRTX849 , has been a hotly followed compound in development as it is the closest clinical KRAS inhibitor to the likely soon-to-be approved AMG-510 (sotorasib). The KRAS clinical race easily would have been the most followed development story of 2020 had it not been for COVID, due to the [...]

BAY1161909 is one of two clinical candidates disclosed in a single paper from Bayer. The compounds have an interesting anti-cancer mechanism – rather than inhibiting cancer cell growth, they accelerate cancer cell cycle progression, leading to cell death due to a high degree of chromosomal misaggregation. 909 was discovered through an HTS and [...]

ORN0829 is a dual inhibitor of orexins 1 and 2, designed to have a relatively short half life in humans for application in insomnia (to reduce side effects after waking up). Chemically it has an interesting chiral 1,3-oxazinane amide motif, which is resolved in their med. chem. route through an enzymatic resolution.

BMS-986251 is an inverse agonist of RORgt, a hot target in inflammation for a significant period. Unfortunately it looks like development hit a wall in this space, and several publications of various company’s RORgt modulators have appeared in the last several months. Chemically, 251 is interesting with 5 stereocenters, none of which look [...]

GSK2818713 is an HCV NS5A replication complex inhibitor with an interesting biphenylene linker. The crowded, hotly competitive NS5A space has led to a lot of creative chemical scaffolds including this one.

CPI-1612 is a pretty efficient-looking EP300/CBP histone acetyltransferase (HAT) inhibitor tool compound with demonstrated activity in a xenograft model and good higher species PK. While epigenetics targets like HATs have been hot this decade, many programs have run into tolerability challenges and/or difficulty identifying activity [...]

“Compound 19” is a JAK1/TYK2 dual kinase inhibitor from Pfizer, related to its clinical JAK1/TYK2 dual inhibitor, brepocitinib, in Ph. II for a variety of inflammatory diseases. The cyclopropyl amide group was designed to displace a high energy water molecule. It was probably fortunate for their manufacturing colleagues that brepocitinib was [...]