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Recently, we had identified an unexplored pocket adjacent to the known binding site of allosteric MEK inhibitors which allowed us to design highly potent and in vivo efficacious novel inhibitors. We now report that our initial preclinical candidate, featuring a phenoxy side chain with a sulfamide capping group, displayed human carbonic anhydrase off-target activity and species-dependent blood cell accumulation, which prevented us from advancing this candidate further. Since this sulfamide MEK inhibitor displayed an exceptionally favorable PK profile with low brain penetration potential despite being highly oral bioavailable, we elected to keep the sulfamide capping group intact while taming its unwanted off-target activity by optimizing the structural surroundings. Introduction of a neighboring fluorine atom or installation of a methylene linker reduced hCA potency sufficiently, at the cost of MEK target potency. Switching to a higher fluorinated central core reinstated high MEK potency, leading to two new preclinical candidates with long half-lives, high bioavailabilities, low brain penetration potential and convincing efficacy in a K-Ras-mutated A549 xenograft model. [ABSTRACT FROM AUTHOR]

The article presents the discussion on repurposing approved or clinically pretested drugs against Covid-19. Topics include raising concerns about drug candidates showing antiviral activity in hypothesis-free cellular screens; potent sigma receptor drugs not inducing phospholipidosis showing no antiviral activity; and effecting cationic amphiphilic drugs (CADs) known to inhibit the production of many other viruses in cell culture.

Abstract: Using PD325901 as a starting point for identifying novel allosteric MEK inhibitors with high cell potency and long-lasting target inhibition in vivo, truncation of its hydroxamic ester headgroup was combined with incorporation of alkyl and aryl ethers at the neighboring ring position. Whereas alkoxy side chains did not yield sufficient levels of cell potency, specifically substituted aryloxy groups allowed for high enzymatic and cellular potencies. Sulfamide 28 was identified as a highly potent MEK inhibitor with nanomolar cell potency against B-RAF (V600E) as well as Ras-mutated cell lines, high metabolic stability and resulting long half-lives. It was efficacious against B-RAF as well as K-Ras driven xenograft models and showed—despite being orally bioavailable and not a P-glycoprotein substrate—much lower brain/plasma exposure ratios than PD325901. [Copyright &y& Elsevier]

This article presents information on stereochemical assignment of intermediates in the rifamycin biosynthetic pathway by precursor-directed biosynthesis. Natural and semisynthetic rifamycins are potent inhibitors of bacterial DNA-dependent RNA polymerase and are used for the treatment of tuberculosis and AIDS-associated mycobacterial infections. The parent compound, rifamycin B 1, is biosynthesized by the soil bacterium Amycolatopsis mediterranei employing the assembly line methodology of a modular polyketide synthase (PKS). The first of five PKS enzymes is primed with 3-amino-5-hydroxybenzoic acid (AHBA), which is derived from the amino-shikimate pathway. The last step of this pathway comprises the aromatization of amino-DHS catalyzed by AHBA synthase.

Background and Purpose: First‐generation soluble guanylate cyclase (sGC) stimulators have shown clinical benefit in pulmonary hypertension (riociguat) and chronic heart failure (vericiguat). However, given the broad therapeutic opportunities for sGC stimulators, tailored molecules for distinct indications are required. Experimental Approach: We report the high‐throughput screening (HTS)‐based discovery of a second generation of sGC stimulators from a novel imidazo[1,2‐a]pyridine lead series. An intense medicinal chemistry programme resulted in the discovery of the sGC stimulator BAY 1165747 (BAY‐747). The pharmacokinetic profile of BAY‐747 was determined in different species, and it was broadly characterized in pharmacological model systems relevant for vasodilatation and hypertension. Key Results: BAY‐747 is a highly potent sGC stimulator in vitro. In addition, BAY‐747 showed an excellent pharmacokinetic profile with long half‐life and low peak‐to‐trough ratio. BAY‐747 was investigated in experimental in vivo models of malignant and resistant hypertension (rHT). In spontaneously hypertensive (SH) rats, BAY‐747 caused a dose‐related and long‐lasting decrease in mean arterial blood pressure (MAP). Oral treatment over 12 days resulted in a persistent decrease. BAY‐747 provided additional benefit when dosed on top of losartan, amlodipine or spironolactone and even on top of triple combinations of frequently used antihypertensive drugs. In a new canine model of rHT, BAY‐747 caused a dose‐related and long‐lasting (>6 h) MAP decrease. Conclusion and Implications: BAY‐747 is a potent, orally available sGC stimulator. BAY‐747 shows long‐acting pharmacodynamic effects with a very low peak‐to‐trough ratio. BAY‐747 could be a treatment alternative for patients with hypertension, especially those not responding to standard‐of‐care therapy. [ABSTRACT FROM AUTHOR]

Bromodomains (BD) are readers of lysine acetylation marks present in numerous proteins associated with chromatin. Here we describe a dual inhibitor of the bromodomain and PHD finger (BRPF) family member BRPF2 and the TATA box binding protein-associated factors TAF1 and TAF1L. These proteins are found in large chromatin complexes and play important roles in transcription regulation. The substituted benzoisoquinolinedione series was identified by high-throughput screening, and subsequent structure-activity relationship optimization allowed generation of low nanomolar BRPF2 BD inhibitors with strong selectivity against BRPF1 and BRPF3 BDs. In addition, a strong inhibition of TAF1/TAF1L BD2 was measured for most derivatives. The best compound of the series was BAY-299, which is a very potent, dual inhibitor with an IC50 of 67 nM for BRPF2 BD, 8 nM for TAF1 BD2, and 106 nM for TAF1L BD2. Importantly, no activity was measured for BRD4 BDs. Furthermore, cellular activity was evidenced using a BRPF2- or TAF1-histone H3.3 or H4 interaction assay. [ABSTRACT FROM AUTHOR]

Protein lysine methyltransferases have recently emerged as a new target class for the development of inhibitors that modulate gene transcription or signaling pathways. SET and MYND domain containing protein 2 (SMYD2) is a catalytic SET domain containing methyltransferase reported to monomethylate lysine residues on histone and nonhistone proteins. Although several studies have uncovered an important role of SMYD2 in promoting cancer by protein methylation, the biology of SMYD2 is far from being fully understood. Utilization of highly potent and selective chemical probes for target validation has emerged as a concept which circumvents possible limitations of knockdown experiments and, in particular, could result in an improved exploration of drug targets with a complex underlying biology. Here, we report the development of a potent, selective, and cell-active, substrate-competitive inhibitor of SMYD2, which is the first reported inhibitor suitable for in vivo target validation studies in rodents. [ABSTRACT FROM AUTHOR]

The first studies on the regioselectivity of Rh(l)-catalyzed (5 + 2) cycloadditions between vinylcyclopropanes (VCPs) and alkynes have been conducted experimentally and analyzed using density functional theory (DFT). The previously unexplored regiochemical consequences for this catalytic, intermolecular cycloaddition were determined by studying the reactions of several substituted VCPs with a range of unsymmetrical alkynes. Experimental trends were identified, and a predictive model was established. VCPs with terminal substitution on the alkene reacted with high regioselectivity (>20:1), as predicted by a theoretical model in which bulkier alkyne substituents prefer to be distal to the forming C-C bond to avoid steric repulsions. VCPs with substitution at the internal position of the alkene reacted with variable regioselectivity (ranging from >20:1 to a reversed 1:2.3), suggesting a refined model in which electron-withdrawing substituents on the alkyne decrease or reverse sterically controlled selectivity by stabilizing the transition state in which the substituent is proximal to the forming C-C bond. [ABSTRACT FROM AUTHOR]

The synthesis of a masked northern half of the natural product disorazole D1 and a cyclopropane analog of the masked northern half of disorazole A1 is described. The synthesis involves in both cases as key steps a Z-selective Wittig olefination and a Sonogashira cross-coupling reaction. [Copyright &y& Elsevier]