Novel Macrocyclic NLRP3 Inhibitors.

Aberrant activation of NLRP3 due to persistent tissue damage, misfolded proteins or crystal deposits has been linked to multiple chronic inflammatory disorders such as cryopyrin-associated periodic syndrome (CAPS), neurodegenerative diseases, gouty arthritis, and numerous others. Hence, there has been an increasing interest in NLRP3 inhibitors as therapeutics. A first generation of NLRP3 inhibitors bearing a sulfonylurea core such as MCC950 (developed by Pfizer) were discovered by phenotypic screening, however their mode of action was only elucidated later.

Discovery of ASTX029, A Clinical Candidate Which Modulates the Phosphorylation and Catalytic Activity of ERK1/2.

Aberrant activation of the mitogen-activated protein kinase pathway frequently drives tumor growth, and the ERK1/2 kinases are positioned at a key node in this pathway, making them important targets for therapeutic intervention. Recently, a number of ERK1/2 inhibitors have been advanced to investigational clinical trials in patients with activating mutations in B-Raf proto-oncogene or Ras. Here, we describe the discovery of the clinical candidate ASTX029 () through structure-guided optimization of our previously published isoindolinone lead ().

Targeting the p300/CBP Axis in Lethal Prostate Cancer.

Resistance to androgen receptor (AR) blockade in castration-resistant prostate cancer (CRPC) is associated with sustained AR signaling, including through alternative splicing of AR (AR-SV). Inhibitors of transcriptional coactivators that regulate AR activity, including the paralog histone acetyltransferase proteins p300 and CBP, are attractive therapeutic targets for lethal prostate cancer. Herein, we validate targeting p300/CBP as a therapeutic strategy for lethal prostate cancer and describe CCS1477, a novel small-molecule inhibitor of the p300/CBP conserved bromodomain.

Fragment-Based Discovery of a Potent, Orally Bioavailable Inhibitor That Modulates the Phosphorylation and Catalytic Activity of ERK1/2.

Aberrant activation of the MAPK pathway drives cell proliferation in multiple cancers. Inhibitors of BRAF and MEK kinases are approved for the treatment of BRAF mutant melanoma, but resistance frequently emerges, often mediated by increased signaling through ERK1/2. Here, we describe the fragment-based generation of ERK1/2 inhibitors that block catalytic phosphorylation of downstream substrates such as RSK but also modulate phosphorylation of ERK1/2 by MEK without directly inhibiting MEK.

and Efficacy of a Novel and Long-Acting Fungicidal Azole, PC1244, on Aspergillus fumigatus Infection.

The antifungal effects of the novel triazole PC1244, designed for topical or inhaled administration, against were tested in a range of and studies. PC1244 demonstrated potent antifungal activities against clinical isolates ( = 96) with a MIC range of 0.016 to 0.

Base-Controlled Diastereoselective Synthesis of Either anti- or syn-β-Aminonitriles.

Deprotonation of secondary alkane nitriles with nBuLi and addition to aryl imines gives kinetic anti-β-aminonitriles. Use of LHMDS allows reversible protonation of the reaction intermediate to give syn-β-aminonitriles. The pure diastereosiomers can be isolated in good yields, and the mechanism was elucidated.

and Antifungal Profile of a Novel and Long-Acting Inhaled Azole, PC945, on Aspergillus fumigatus Infection.

The profile of PC945, a novel triazole antifungal designed for administration via inhalation, was assessed in a range of and studies. PC945 was characterized as a potent, tightly binding inhibitor of sterol 14α-demethylase (CYP51A and CYP51B) activity (50% inhibitory concentrations [ICs], 0.23 μM and 0.

Reductive conjugate addition nitro-Mannich route for the stereoselective synthesis of 1,2,3,4-tetrahydroquinoxalines.

A concise, high yielding and structurally divergent synthesis of complex 1,2,3,4-tetrahydroquinoxalines with excellent diastereoselectivity is described. A wide array of nitroalkenes and imines derived from commercially available aromatic aldehydes and 2-chloroanalines were subjected to a key reductive conjugate addition nitro-Mannich reaction to give diastereomerically pure β-nitro amines. Sequential reduction of the nitro function followed by Pd-catalyzed intramolecular N-arylation of the resultant primary amine onto the 2-chloroanailine gives highly substituted 1,2,3,4-tetrahydroquinoxalines.

Stereoselective synthesis of 1,2-diamine containing indolines by a conjugate addition nitro-Mannich reaction.

A conjugate addition nitro-Mannich reaction followed by nitro reduction and intramolecular N-arylation gives diastereomerically pure substituted 1,2-diamine containing indolines. Placing the N-arylation cyclisation handle on the imine precursor derived from an ortho-bromine substituted aromatic aldehyde gave the corresponding β-nitroamines in 55-72% yields as single diastereoisomers. Nitro reduction was effected with modified quantities of Zn/HCl and a subsequent Pd(0) catalysed Buchwald Hartwig cyclisation gave indoline products in 40-70% yields as single diastereoisomers.

On the scope of trimethylaluminum-promoted 1,2-additions of ArZnX reagents to aldehydes.

A practical asymmetric 1,2-addition of functionalised arylzinc halides to aromatic and aliphatic aldehydes is described by the use of aminoalcohol catalysis in the presence of AlMe(3). The process is simple to carry out, uses only commercially available reagents/ligands and provides moderate to good (80-96 % ee) enantioselectivities for a wide range of substrates. Either commercial ArZnX reagents or those prepared in situ from low cost aryl bromides can be used.

Combinatorial chemistry in the agrosciences.

Combinatorial chemistry and high throughput screening have had a profound effect upon the way in which agrochemical companies conduct their lead discovery research. The article reviews recent applications of combinatorial synthesis in the lead discovery process for new fungicides, herbicides and insecticides. The role and importance of bioavailability guidelines, natural products, privileged structures, virtual screening and X-ray crystallographic protein structures on the design of solid- and solution-phase compound libraries is discussed and illustrated.

Direct asymmetric catalytic 1,2-addition of RZnX to aldehydes promoted by AlMe3 and reversal of expected stereochemistry.

Addition of AlMe3 to commercial THF solutions of RZnX (R = aryl, functionalised aryl, vinyl; X = Br, I) simultaneously promotes Schlenk equilibria (leading to competent nucleophiles) and the formation of an Al-Zn-ligand catalyst delivering 80-90% ee for Ar(1)CH(OH)Ar(2) formation from aldehydes.

Demonstration of promoted zinc Schlenk equilibria, their equilibrium values and derived reactivity.

The presence of promoted Schlenk equilibria for organozinc halide species has been explicitly demonstrated by 13C NMR studies. Thus, addition of methylaluminoxane (MeAlO)n, MAO, to RZnX (R=Et, Bn, ArCH2, (CH2)3CO2Et; X=Cl, Br) leads to the formation of ZnR2 and ZnX2MAO. For EtZnCl, equilibration of ZnEt2 and ZnX2MAO is rapid at -35 degrees C; a K value of 0.