 | |
| Clinical data | |
|---|---|
| Trade names | Upstène |
| Other names | LM-5008 |
| Identifiers | |
| |
| CAS Number | |
| PubChemCID | |
| DrugBank |
|
| ChemSpider |
|
| UNII | |
| ChEMBL | |
| CompTox Dashboard(EPA) | |
| ECHA InfoCard | 100.058.569 |
| Chemical and physical data | |
| Formula | C15H20N2 |
| Molar mass | 228.339 g·mol−1 |
| 3D model (JSmol) | |
| |
| |
Indalpine, sold under the brand nameUpstène, is aselective serotonin reuptake inhibitor (SSRI) that was briefly marketed as anantidepressant for treatment ofdepression.[1][2][3][4] It was marketed inFrance and a few otherEuropean countries.[4]
Indalpine is aselective serotonin reuptake inhibitor (SSRI) andantihistamine.[2]
Indalpine was invented by 1977 and was introduced for medical use inFrance in 1983.[2][3] Two years later, in 1985, it was withdrawn from the market due totoxicity.[2][4] Indalpine has sometimes been said to be the first SSRI.[2][3] However, it was preceded by the SSRIzimelidine (Zelmid), which was invented in 1969 and was introduced to the market in 1981 (then similarly withdrawn due to toxicity in 1983).[2][5][4]
Indalpine is aselective serotonin reuptake inhibitor (SSRI) andantihistamine.[2]
Indalpine is anindole and isstructurally similar totryptamines but is not a tryptamine itself.
Metalation ofindole (1) usingmethyl magnesium iodide forms the organo-magnesium derivative (2) which reacts with 1-benzyloxycarbonyl-4-piperidyl-acetyl chloride (3) to give (4). Acid-catalyzed removal of thebenzyloxycarbonyl (Cbz)protecting group gives theketone (5).Reduction withlithium aluminium hydride yields indalpine.[6][7]
Apatent for indalpine was filed in 1976 and granted in 1977.[2] It was marketed by Fournier Frères-Pharmuka inFrance in 1983.[2][3][5] The drug was withdrawn from the market due totoxicity, includingneutropenia oragranulocytosis andhepaticcarcinogenicity, 2 years later in 1985.[2][3][5][4] The drug was never introduced in theUnited States.[2] Indalpine was derived fromstructural modification ofantihistamines.[4]
It was invented in 1977 by the pharmacologists Le Fur and Uzan at Pharmuka, a small French pharmaceutical firm, who credit Baron Shopsin and his colleagues at NYU-Bellevue orNYU School of Medicine in New York with providing the basis for their work. They were particularly influenced by the series of "synthesis inhibitor studies" carried out by Shopsin's team during the early to mid 1970s, and in particular, the clinical report by Shopsin et al. (1976)[8] relating toPCPA's rapid reversal of antidepressant response totranylcypromine indepressed patients. This led to an understanding of the role of themonoamine neurotransmitterserotonin (5-hydroxytryptamine, or 5HT) in the therapeutic effects of the availabletricyclic andMAOI class antidepressants. The studies led to widespread recognition of a serotonin hypothesis of depression, contradicting theories that promoted the role ofnorepinephrine.
Whilecitalopram andzimelidine were developed in the early 1970s, it was Pharmuka's indalpine that was first to reach the market. Baron Shopsin was recruited as consultant to Pharmuka throughout a research and development process that resulted in the marketing of indalpine in France and then worldwide, in 1982. With FDA approval of Pharmuka'sInvestigational New Drug (IND) submission to conduct clinical studies with indalpine andviqualine, Shopsin carried out and published the first clinical trials with these drugs in depressed outpatients in the United States.[9] Astra's SSRI zimelidine was marketed within a year (1983), but the next crop of SSRIs didn't become commercially available until the 1986 marketing offluvoxamine in Belgium by Duphar, followed by approval in the United States later that year. Lilly'sfluoxetine (Prozac) was approved in the United States in 1987.
Meanwhile, zimelidine had been withdrawn soon after its marketing in 1983 due to the emergence ofGuillain–Barré syndrome, a serious neurological disease. With lingering concerns among some Common Market countries and activist groups about the potential of SSRIs to induce adverse effects, and the reported association between indalpine and hematological effects, which emerged in the aftermath of Pharmuka's take over byRhône Poulenc, indalpine was abruptly taken off the market by Rhône Poulenc. Irish psychiatristDavid Healy characterized indalpine as being "born at the wrong time" during a period when "indalpine and psychiatry was under siege" by different interest groups in some of the Common Market countries.[5] In line with indalpine's fate, research and development was halted relating to the two other 4-alkylpiperidine derivatives developed by Pharmuka,viqualine (aserotonin releasing agent) andpipequaline (aGABAA receptorpositive allosteric modulator), both in different stages of development at the time.[citation needed]
In 2010, revision of this molecular motif yielded SERT inhibitors with nanomolar and subnanomolarIC50 values.[10]
Indalpine is thegeneric name of the drug and itsINNTooltip International Nonproprietary Name andBANTooltip British Approved Name.[1] It was also known by its developmental code nameLM-5008.[1][11] The drug was sold under the brand name Upstène.[1][11]
It now seems clomipramine is useful for OCD because of its action on the 5HT system. This leads on to a Rhône-Poulenc drug which as I understand it was the first SSRI to be released clinically – Upstene, Indalpine. Can you tell me anything about it? Br: Well it wasn't made in Rhône-Poulenc. It was Fournier Freres, who were part of Pharmuka, who in turn became part of Rhône-Poulenc. Indalpine was launched in 1983. Gr: It was withdrawn because of side effects, neutropenia supposedly but that was not all. This drug had been launched before all the carcinogenicity results were in and when they were all available the drug had to be withdrawn. [...] Of 500,000 patients treated in 1984, the Pharmacovigilance committee had reports of 30 cases of neutropenia. Upstene in fact won the Prix Galien for pharmaceutical innovation in 1983.
