Discovery of a Novel Series of Potent and Orally Bioavailable Phosphoinositide 3-Kinase γ Inhibitors

Abstract

The phosphoinositide 3-kinases (PI3Ks) have been linked to an extraordinarily diversified group of cellular functions making these enzymes compelling targets for the treatment of disease. A large body of evidence has linked PI3Kγ to the modulation of autoimmune and inflammatory processes making it an intriguing target for drug discovery. Our high-throughput screening (HTS) campaign revealed two hits that were nominated for further optimization studies. The in vitro activity of the first HTS hit, designated as the sulfonylpiperazine scaffold, was optimized utilizing structure-based design. However, nonoptimal pharmacokinetic properties precluded this series from further studies. An overlay of the X-ray structures of the sulfonylpiperazine scaffold and the second HTS hit within their complexes with PI3Kγ revealed a high degree of overlap. This feature was utilized to design a series of hybrid analogues including advanced leads such as 31 with desirable potency, selectivity, and oral bioavailability.

Recent development of ATP-competitive small molecule phosphatidylinostitol-3-kinase inhibitors as anticancer agents

“…Leahy et al [60] disclosed a novel series of potent and selective PI3Kγ inhibitors (131-136), based on hits 128 and 129, which were identified from HTS of ~4.6 million compounds. The sulfonyl piperazine series (131) of hit 128 had improved potency and selectivity, while with poor pharmacokinetic properties.…”

Spectroscopic and theoretical characterization of 2-(4-methoxyphenyl)-4,5-dimethyl-1H-imidazole 3-oxide

“…À0.0 C 1 -C 6 1.424 C 2 -C 1 -H 7 117.9 C 6 -C 1 -C 2 -H 8 179.9 C 1 -H 7 1.0889 C 6 -C 1 -H 7 120.9 H 7 -C 1 -C 2 -C 3 À180.0 C 2 -C 3 1.4127 4 1.4094 C 3 -C 2 -H 8 118.6 C 2 -C 1 -C 6 -C 16 179.9 C 3 -O 11 1.3956 C 2 -C 3 -C 4 119.7 H 7 -C 1 -C 6 -C 5 180.0 C 4 -C 5 1.4049 C 2 -C 3 -O 11 115.5 H 7 -C 1 -C 6 -C 16 À0.0 C 4 -H 9 1.0855 C 4 -C 3 -O 11 124.8 C 1 -C 2 -C 3 -C 4 0.0 C 5 -C 6 1.4186 C 3 -C 4 -C 5 120.1 C 1 -C 2 -C 3 -O 11 À179.9 C 5 -H 10 1.0845 C 3 -C 4 -H 9 121.0 H 8 -C 2 -C 3 -C 4 À179.9 C 6 -C 16 1.4527 C 5 -C 4 -H 9 118.8 H 8 -C 2 -C 3 -O 11 0.0 C 12 -O 11 1.4569 C 4 -C 5 -C 6 120.8 C 2 -C 3 -C 4 -C 5 0.0 C 12 -H 13 1.0918 C 4 -C 5 -H 10 121.1 C 2 -C 3 -C 4 -H 9 À179.9 C 12 -H 14 1.0988 C 6 -C 5 -H 10 118.1 O 11 -C 3 -C 4 -C 5 179.9 C 12 -C 15 1.0988 C 1 -C 6 -C 5 118.1 O 11 -C 3 -C 4 -H 9 0.0 C 16 -N 17 1.3679 C 1 -C 6 -C 16 120.8 C 2 -C 3 -O 11 -C 12 180.0 C 16 -N 18 1.391 20 1.3511 C 3 -O 11 -C 12 118.6 C 3 -C 4 -C 5 -C 6 À0.0 N 17 -C 21 1.4176 O 11 -C 12 -H 13 105.3 C 3 -C 4 -C 5 -H 10 À180.0 N 18 -H 19 1.0085 O 11 -C 12 -H 14 111.2 H 9 -C 4 -C 5 -C 6 179.9 N 18 -C 22 1.4001 O 11 -C 12 -H 15 111.2 H 9 -C 4 -C 5 -H 10 À0.0 C 21 -C 22 1.383 H 13 -C 12 -H 14 109.7 C 4 -C 5 -C 6 -C 1 0.0 C 21 -C 23 1.4923 H 12 -C 12 -H 15 109.7 C 4 -C 5 -C 6 -C 16 À179.9 C 22 -C 24 1.4988 H 14 -C 12 -H 15 109.6 H 10 -C 5 -C 6 -C 1 180.0 C 23 -H 25 1.097 C 6 -C 16 -N 17 127.8 H 10 -C 5 -C 6 -C 16 0.0 C 23 -H 26 1.0951 C 6 -C 16 179.9 C 21 -C 22 -C 24 -H 28 119.4 C 21 -C 22 -C 24 -H 30 À119.5 Table 2 Observed IR, Raman bands and calculated (scaled) wavenumbers of 2-(4-methoxyphenyl)-4,5-dimethyl-1H-imidazole 3-oxide and assignments. cCC (54) in Raman spectrum and 924 cm À1 in IR spectrum.…”

“…Many drugs contain an imidazole ring, such as antifungal drugs and nitroimidazole [1][2][3]. Imidazole and its derivatives are widely used as intermediates in synthesis of organic target compounds including pharmaceuticals [4][5][6][7][8][9][10], agrochemicals, dyes, photographic chemicals, corrosion inhibitors, epoxy curing agents, adhesives and plastic modifiers [11]. Various biologically active synthetic compounds have five-membered nitrogen-containing heterocyclic ring in their structures [12].…”

Recent syntheses of PI3K/Akt/mTOR signaling pathway inhibitors

“…67 The sulfonyl piperazinyl pyrazines were prepared via a base catalyzed substitution reaction of the sulfonyl piperazine and 2,3-dichloropyrazine ( 214 ) followed by a Pd(II) catalyzed cross coupling reaction with an aromatic boronic acid to replace the 2 nd chloride and produce 216 . The aryl sulfonamidyl pyrazines were prepared via an initial Sandmeyer reaction on bromo anilines ( 217 ).…”