Structure–activity relationship studies of novel 3-oxazolidinedione-6-naphthyl-2-pyridinones as potent and orally bioavailable EP3 receptor antagonists

Cui

Journal of Integrative Agriculture

et al. 2019

An elite backcrossed inbred line Z550 with increased grains per panicle was identified from advanced backcrosses between Nipponbare and Xihui 18 by simple sequence repeat (SSR) marker-assisted selection (MAS). Z550 carries 13 substitution segments distributed on chromosomes 1, 6, 7, 8, 9, 10, and 12, with an average substitution length of 1.68 Mb. Compared with the Nipponbare parental line, plant height, panicle length, spikelets per panicle, grains per panicle, and grain weight for Z550 were significantly increased. While the grain width of Z550 was significantly narrower, and the seed setting ratio (81.43%) was significantly lower than that of Nipponbare, it is still sufficient for breeding purposes. Quantitative trait loci (QTLs) mapping for important agronomic traits was conducted with the F 2 population derived from Nipponbare crossed with Z550 using the restricted maximum likelihood (REML) method. A total of 16, including 12 previously unreported QTLs were detected, with contribution rates ranging from 1.46 to 10.49%. Grains per panicle was controlled by 8 QTLs, 5 of which increased number of grains whereas 3 decreased it. qGPP-1, with the largest contribution (10.49%), was estimated to increase grains per panicle by 30.67, while qGPP-9, with the minimum contribution rate (2.47%), had an effect of increasing grains per panicle by 15.79. These results will be useful for further development of single segment substitution lines with major QTLs, and for research of their molecular functions via QTL cloning.

mentioning

confidence: 99%

Identification and QTL mapping of Z550, a rice backcrossed inbred line with increased grains per panicle

Cui

Journal of Integrative Agriculture

et al. 2019

“…These homologues (13−22) possessed both enhanced EP3 binding affinity and functional potency. Compared to the saturated A-ring derivatives (14,15,17,19,21,22), the unsaturated analogues (13,16,18,20) exhibited a much longer T 1/2 in human and rat liver microsomes while maintaining comparable EP3 binding affinity and functional potency. Among the compounds, oxazolidine-2,4-dione 13 seemed to strike the best balance of hEP3 binding affinity (K i of 9.0 nM), antagonistic potency (IC 50 of 21 nM), and metabolic stability (T 1/2 > 180 min in human and rat liver microsomes), warranting further pharmacokinetic and pharmacodynamic characterization.…”

mentioning

confidence: 95%

“…GSK-29, an oxazolidinedione-containing EP3 antagonist, showed in vivo activity in OAB animal models . Two structurally similar amide-based EP3 antagonists ( 2 ) have been described by GSK and Pfizer. , Recently, an amide-based pyridone ( 3 ) was reported to be a potent EP3 antagonist by Pfizer . To date, only DG-041 was reported to have entered phase II clinical trials for atherothrombosis.…”

mentioning

confidence: 99%

“…The mass spectra suggested that bioactivation occurred on the fluoronaphthalene moiety of 14 probably through epoxidation, opening of the epoxide with glutathione, and elimination of hydrogen fluoride (see the Supporting Information). 12,13 Increasing the steric bulk around the α,β-unsaturated carbonyl moiety of 13, as in tetra-substituted alkene 25, reduced the oral exposure (C max = 1227 ng/mL, AUC last = 12 703 h•ng/mL) and increased the clearance (CL = 15.6 mL/min/kg) in the rat. Introduction of a gem-diethyl moiety in place of the isopropyl group effectively blocked NADPH-dependent GSH conjugate addition to the α,β-unsaturated carbonyl moiety of compound 33.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Discovery of a Novel Series of Pyridone-Based EP3 Antagonists for the Treatment of Type 2 Diabetes

Zhang

Zhu

Guo

et al. 2021

ACS Med. Chem. Lett.

A novel series of pyridones were discovered as potent EP3 antagonists. Optimization guided by EP3 binding and functional assays as well as by eADME and PK profiling led to multiple compounds with good physical properties, excellent oral bioavailability, and a clean in vitro safety profile. Compound 13 was identified as a lead compound as evidenced by the reversal of sulprostone-induced suppression of glucosestimulated insulin secretion in INS 1E β-cells in vitro and in a rat ivGTT model in vivo. A glutathione adduction liability was eliminated by replacing the naphthalene of structure 13 with the indazole ring of structure 43.

Synthesis and in vitro cytotoxic evaluation of novel $$N$$ -(3,4,5-trimethoxyphenyl)pyridin-2( $$1H$$ )-one derivatives

Chen

Luo

et al. 2013

Mol Divers

A series of novel [Formula: see text]-(3,4,5-trimethoxyphenyl)pyridin-2([Formula: see text])-one derivatives were designed, synthesized, and evaluated for their in vitro cytotoxicity against human colon cancer cells HCT-116. The key steps involved consecutive Chan-Lam- and Buchwald-Hartwig couplings. Most of these C-6 substituted pyridone derivatives showed moderate antiproliferative activity. The preliminary SAR indicated that the conformationally restricted pyridones exhibited more potent cytotoxicity than the flexible counterparts. In addition, cell cycle analysis of the selected compounds 4b and e showed a G2/M arrest, suggesting a possible antitubulin mechanism for these novel pyridone derivatives.