Chemistry:RX871024
RX871024 is an experimental drug containing an imidazoline moiety, developed by Reckitt Benckiser.[1] The development of RX871024 was discontinued in 1997. It is known for its potent ability to enhance insulin action. RX871024 stimulates insulin secretion from pancreatic beta cells through multiple mechanisms.[2]
Mechanism of action
Unlike traditional sulfonylureas, RX871024 not only closes ATP-sensitive potassium (KATP) channels—leading to membrane depolarization, opening of voltage-gated calcium channels, and increased intracellular calcium—but also directly stimulates exocytosis of insulin-containing granules, even under conditions where calcium levels are held constant.[3][4]
This compound inhibits several potassium channels, including KATP, KCa, and delayed rectifier potassium channels, and interacts specifically with the Kir6.2 (KCNJ11) subunit of the KATP channel, distinguishing its mode of action from sulfonylureas, which target the sulfonylurea receptor 1 (ABCC8).[4][5] Additionally, RX871024 mobilizes calcium from intracellular, thapsigargin-sensitive stores via redox-dependent pathways involving cytochrome P-450.[3] Its insulinotropic effect is further enhanced by activation of protein kinase C and increases in diacylglycerol (DAG) levels, while protein kinase A activity appears to play a permissive role.[5][6] RX871024 also modulates the phosphorylation of cytosolic proteins such as nonmuscle myosin heavy chain-A, which may be involved in insulin secretion signaling.[6]
Collectively, these multifaceted actions make RX871024 a potential lead compound for the development of novel antidiabetic therapies.
Synthesis
Ex 1: The reaction between ethyl 1-phenyl-1H-indole-2-carboxylate [20538-24-3] (1) and ethylenediamine (2) gives RX871024 (3).
Prec:[7] Patent:[8] Also, reaction of 1-phenylindole-2-carbonitrile, PC20095505 with ethylenediamine monotosylate [14034-59-4] gives higher yield.
References
- ↑ "RX 871024". AdisInsight. Springer Nature Switzerland AG. https://adisinsight.springer.com/drugs/800003412.
- ↑ "Two generations of insulinotropic imidazoline compounds". Diabetes 51 (Suppl 3): S448–S454. December 2002. doi:10.2337/diabetes.51.2007.s448. PMID 12475789.
- ↑ 3.0 3.1 "RX871024 induces Ca2+ mobilization from thapsigargin-sensitive stores in mouse pancreatic beta-cells". Diabetes 47 (2): 211–218. February 1998. doi:10.2337/diab.47.2.211. PMID 9519715.
- ↑ 4.0 4.1 "Imidazoline compounds stimulate insulin release by inhibition of K(ATP) channels and interaction with the exocytotic machinery". Diabetes 45 (11): 1610–1618. November 1996. doi:10.2337/diab.45.11.1610. PMID 8866568.
- ↑ 5.0 5.1 "Effector systems involved in the insulin secretory responses to efaroxan and RX871024 in rat islets of Langerhans". European Journal of Pharmacology 350 (2–3): 251–258. June 1998. doi:10.1016/S0014-2999(98)00245-3. PMID 9696415.
- ↑ 6.0 6.1 "Multiple effector pathways regulate the insulin secretory response to the imidazoline RX871024 in isolated rat pancreatic islets". British Journal of Pharmacology 127 (5): 1279–1287. July 1999. doi:10.1038/sj.bjp.0702656. PMID 10455276.
- ↑ "2-Alkylidene-2H-indole intermediates. Thermolysis of 2-hydroxydiphenylmethylindole.". The Journal of Organic Chemistry 34 (10): 2988–2993. October 1969. doi:10.1021/jo01262a042.
- ↑ Chapleo CB, Fagan GP, "Imidazolinyl indole derivatives useful in the treatment of diabetes", US patent 5385919, issued 1995
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