Ranirestat

Ranirestat
Names

Preferred IUPAC name (3R)-2′-[(4-Bromo-2-fluorophenyl)methyl]-1′H-spiro[pyrrolidine-3,4′-pyrrolo[1,2-a]pyrazine]-1′,2,3′,5(2′H)-tetrone
Identifiers
CAS Number	147254-64-6^Y
3D model (JSmol)	Interactive image
ChemSpider	135685^N
PubChem CID	153948
UNII	Z26P56GFTV^Y
CompTox Dashboard (EPA)	DTXSID80163642
InChI InChI=1S/C17H11BrFN3O4/c18-10-4-3-9(11(19)6-10)8-21-14(24)12-2-1-5-22(12)17(16(21)26)7-13(23)20-15(17)25/h1-6H,7-8H2,(H,20,23,25)/t17-/m1/s1^N Key: QCVNMNYRNIMDKV-QGZVFWFLSA-N^N InChI=1/C17H11BrFN3O4/c18-10-4-3-9(11(19)6-10)8-21-14(24)12-2-1-5-22(12)17(16(21)26)7-13(23)20-15(17)25/h1-6H,7-8H2,(H,20,23,25)/t17-/m1/s1 Key: QCVNMNYRNIMDKV-QGZVFWFLBS
SMILES c1cc2n(c1)[C@@]3(CC(=O)NC3=O)C(=O)N(C2=O)Cc4ccc(cc4F)Br
Properties
Chemical formula	C₁₇H₁₁BrFN₃O₄
Molar mass	420.189 g/mol
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa). N verify (what is ^YN ?) Infobox references

Chemical compound

Ranirestat (also known as AS-3201) is an aldose reductase inhibitor being developed for the treatment of diabetic neuropathy by Dainippon Sumitomo Pharma and PharmaKyorin. It has been granted orphan drug status. The drug is to be used orally.

Trials

A Canadian Phase III clinical trial has been completed. Phase III trials in Europe and the US started in June 2009 and are expected to complete in April 2013.

Mechanism of action

Ranirestat is aldose reductase inhibitor that acts by reducing sorbitol accumulation in cells. Aldose reductase is an enzyme that catalyzes one of the steps in sorbitol (polyol) pathway which is responsible for formation of fructose from glucose. Aldose reductase activity is increased, parallel to glucose blood levels, in tissues that are not insulin sensitive, including lenses, peripheral nerves and renal glomeruli. Sorbitol does not diffuse through cell membranes easily and therefore accumulates in these tissues, causing osmotic damage, leading to retinopathy and neuropathy.

Efficacy

Results from a Canadian double-blind, placebo-controlled biopsy Phase III clinical trial, involving total of 549 patients with diabetic sensorimotor polyneuropathy (DSP) randomly assigned to treatment with placebo or 10, 20, or 40 mg/day ranirestat for 52 weeks, showed that ranirestat appears to have effect on motor nerve function in mild to moderate DSP, but failed to show statistically significant difference in sensory nerve function. Efficacy of ranirestat was evaluated by nerve conduction studies, the modified Toronto Clinical Neuropathy Score (mTCNS), and quantitative sensory tests (QSTs).^[1]

References

^ Bril, V.; Hirose, T.; Tomioka, S.; Buchanan, R.; Ranirestat Study, G. (2009). "Ranirestat for the Management of Diabetic Sensorimotor Polyneuropathy". Diabetes Care. 32 (7): 1256–1260. doi:10.2337/dc08-2110. PMC 2699746. PMID 19366965.

Oral diabetes medication, insulins and insulin analogs, and other drugs used in diabetes (A10)

Insulins/insulin analogs

fast-acting	Insulin aspart Insulin glulisine Insulin lispro
short-acting	Regular insulin^#
long-acting	Insulin detemir^# Insulin glargine^# (+lixisenatide) NPH insulin Lente insulin^‡ Ultralente insulin^‡
ultra-long-acting	Insulin degludec^# (+insulin aspart, +liraglutide) Insulin icodec^† (+semaglutide)
inhalable	Exubera^‡ Afrezza

^#WHO-EM
^‡Withdrawn from market
Clinical trials:
- ^†Phase III
- ^§Never to phase III

Non-insulins

Insulin sensitizers

Biguanides	Buformin^‡ Metformin^# Phenformin^‡
TZDs/"glitazones" (PPAR)	Ciglitazone^§ Darglitazone^§ Englitazone^§ Lobeglitazone Netoglitazone^§ Pioglitazone Rivoglitazone^† Rosiglitazone Troglitazone^‡
Dual PPAR agonists	Aleglitazar^† Muraglitazar^§ Saroglitazar Tesaglitazar^§
Amylin analogs and DACRAs	Cagrilintide^§ Pramlintide

Secretagogues

K⁺_ATP

Sulfonylureas	1st generation: Acetohexamide Carbutamide Chlorpropamide Glycyclamide Metahexamide Tolazamide Tolbutamide 2nd generation: Glibenclamide (glyburide) Glibornuride Glicaramide Gliclazide^# Glimepiride Glipizide Gliquidone Glisoxepide Glyclopyramide
Meglitinides/"glinides"	Mitiglinide Nateglinide Repaglinide

GLP-1 receptor agonists

GLP1 poly-agonist peptides	Mazdutide (GLP-1/GCGR) Retatrutide^§ (GLP-1/GIP/GCGR) Tirzepatide (GLP-1/GIP)

DPP-4 inhibitors/"gliptins"

Other

Aldose reductase inhibitors	Epalrestat Fidarestat^§ Ranirestat^† Tolrestat^‡ Zenarestat^§
Alpha-glucosidase inhibitors	Acarbose Miglitol Voglibose
SGLT2 inhibitors/"gliflozins"	Canagliflozin Dapagliflozin Empagliflozin^# Ertugliflozin Ipragliflozin Luseogliflozin Remogliflozin^§ Sergliflozin^§ Sotagliflozin Tofogliflozin^† Velagliflozin
Other	Benfluorex^‡ Bromocriptine Imeglimin