JNJ-77242113, a highly potent, selective peptide targeting the IL-23 receptor, provides robust IL-23 pathway inhibition upon oral dosing in rats and humans.

The interleukin (IL)-23 pathway is a pathogenic driver in psoriasis, psoriatic arthritis, and inflammatory bowel disease. Currently, no oral therapeutics selectively target this pathway. JNJ-77242113 is a peptide targeting the IL-23 receptor with high affinity (K: 7.

Design, synthesis and preclinical evaluation of bio-conjugated amylinomimetic peptides as long-acting amylin receptor agonists.

Pramlintide is an equipotent amylin analogue that reduces food intake and body weight in obese subjects and has been clinically approved as an adjunctive therapy for the treatment of adult diabetic patients. However, due to its extremely short half-life in vivo, a regimen of multiple daily administrations is required for achieving clinical effectiveness. Herein is described the development of prototypical long-acting pramlintide bioconjugates, in which pramlintide's disulfide-linked macrocycle was replaced by a cyclic thioether motif.

Indazole-based ligands for estrogen-related receptor α as potential anti-diabetic agents.

Estrogen-related receptor α (ERRα) is an orphan nuclear receptor that has been functionally implicated in the regulation of energy homeostasis. Herein is described the development of indazole-based N-alkylthiazolidenediones, which function in biochemical assays as selective inverse agonists against this receptor. Series optimization provided several potent analogues that inhibited the recruitment of a co-activator peptide fragment in vitro (ICs < 50 nM) and reduced fasted circulating insulin and triglyceride levels in a sub-chronic pre-diabetic rat model when administered orally (10 mg/kg).

Discovery of novel potent imidazo[1,2-b]pyridazine PDE10a inhibitors.

Design and optimization of a novel series of imidazo[1,2-b]pyridazine PDE10a inhibitors are described. Compound 31 displays excellent pharmacokinetic properties and was also evaluated as an insulin secretagogue in vitro and in vivo.

Identification of diaryl ether-based ligands for estrogen-related receptor α as potential antidiabetic agents.

Estrogen-related receptor α (ERRα) is an orphan nuclear receptor that has been functionally implicated in the regulation of energy homeostasis. Herein is described the development of diaryl ether based thiazolidenediones, which function as selective ligands against this receptor. Series optimization provided several potent analogues that inhibit the recruitment of a coactivator peptide fragment in in vitro biochemical assays (IC(50) < 150 nM) and cellular two-hybrid reporter assays against the ligand binding domain (IC(50) = 1-5 μM).

Synthesis and evaluation of novel 3,4,6-substituted 2-quinolones as FMS kinase inhibitors.

A series of 3,4,6-substituted 2-quinolones has been synthesized and evaluated as inhibitors of the kinase domain of macrophage colony-stimulating factor-1 receptor (FMS). The fully optimized compound, 4-(4-ethyl-phenyl)-3-(2-methyl-3H-imidazol-4-yl)-2-quinolone-6-carbonitrile 21b, has an IC(50) of 2.5 nM in an in vitro assay and 5.

Potent 2'-aminoanilide inhibitors of cFMS as potential anti-inflammatory agents.

A series of 2'-aminoanilides have been identified which exhibit potent and selective inhibitory activity against the cFMS tyrosine kinase. Initial SAR studies within this series are described which examine aroyl and amino group substitutions, as well as the introduction of hydrophilic substituents on the benzene core. Compound 47 inhibits the isolated enzyme (IC(50)=0.

Crystal structure of the tyrosine kinase domain of colony-stimulating factor-1 receptor (cFMS) in complex with two inhibitors.

The cFMS proto-oncogene encodes for the colony-stimulating factor-1 receptor, a receptor-tyrosine kinase responsible for the differentiation and maturation of certain macrophages. Upon binding its ligand colony-stimulating factor-1 cFMS autophosphorylates, dimerizes, and induces phosphorylation of downstream targets. We report the novel crystal structure of unphosphorylated cFMS in complex with two members of different classes of drug-like protein kinase inhibitors.

Identification of 2-acylaminothiophene-3-carboxamides as potent inhibitors of FLT3.

A series of 2-acylaminothiophene-3-carboxamides has been identified which exhibit potent inhibitory activity against the FLT3 tyrosine kinase. Compound 44 inhibits the isolated enzyme (IC50 = 0.027 microM) and blocks the proliferation of MV4-11 cells (IC50 = 0.

Single-step syntheses of 2-amino-7-chlorothiazolo[5,4-d]pyrimidines: intermediates for bivalent thiazolopyrimidines.

[reaction: see text] A single-step process for the preparation of 2-amino-7-chlorothiazolo[5,4-d]pyrimidines, 2, was achieved by the reaction of the commercially available 4,6-dichloro-5-aminopyrimidine 1 with isothiocyanates. This mild reaction accommodates a variety of functionalized isothiocyanates and proceeds in good to excellent yields. The utility of such intermediates is exemplified by subsequent reaction with alkyl or arylamine nucleophiles to afford novel, differentially functionalized 2,7-diaminothiazolo[5,4-d]pyrimidines, 3.

A tandem Heck-carbocyclization/Suzuki-coupling approach to the stereoselective syntheses of asymmetric 3,3-(diarylmethylene)indolinones.

[reaction: see text] An efficient and versatile method for stereoselective synthesis of (E)-3,3-(diarylmethylene)indolinones by a palladium-catalyzed tandem Heck-carbocyclization/Suzuki-coupling sequence is presented. Factors influencing yield and selectivity, namely catalyst, coordinating ligand, and solvent, are detailed.

2-Hydroxy-4,6-diamino-[1,3,5]triazines: a novel class of VEGF-R2 (KDR) tyrosine kinase inhibitors.

2-Hydroxy-4,6-diamino-[1,3,5]triazines are described which are a novel class of potent inhibitors of the VEGF-R2 (flk-1/KDR) tyrosine kinase. 4-(Benzothiazol-6-ylamino)-6-(benzyl-isopropyl-amino)-[1,3,5]triazin-2-ol (14d) exhibited low nanomolar potency in the in vitro enzyme inhibition assay (IC(50) = 18 nM) and submicromolar inhibitory activity in a KDR-induced MAP kinase autophosphorylation assay in HUVEC cells (IC(50) = 280 nM), and also demonstrated good in vitro selectivity against a panel of growth factor receptor tyrosine kinases. Further, 14d showed antiangiogenic activity in an aortic ring explant assay by blocking endothelial outgrowths in rat aortas with an IC(50) of 1 microM.