Indalpine

Indalpine
IUPAC name

3-(2-piperidin-4-ylethyl)-1H-indole
Identifiers
CAS number 63758-79-2 Y
PubChem 44668
ChemSpider 40643 Y
ChEMBL CHEMBL276520 Y
Jmol-3D images Image 1
Properties
Molecular formula C15H20N2
Molar mass 228.33 g mol−1
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Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa)
Infobox references

Indalpine (Upstène, LM-5008) is an SSRI class drug that was discovered in 1977 by the pharmacologists Le Fur and Uzan at Pharmuka, a small Paris based pharmaceutical firm, who credit Baron Shopsin and the innovative body of basic and clinical research carried out with colleagues at NYU-Bellevue/NYU School of Medicine in New York as directly responsible for their search to come up with more specific and potent serotonergic neuromodulating molecules for new antidepressant drug development. It was the series of "synthesis inhibitor studies" carried out by Shopsin's team during the early to mid 70's, and in particular, the high impact clinical report by Shopsin et al.(1976)[1] relating to PCPA's rapid reversal of antidepressant response to tranylcyptomanine in depressed patients that furnished the proof of principle needed to delineate a pivotal role for serotonin (5-HT) as the brain monoaminergic neurotransmitter accountable for the therapeutic effects of the then available tricyclic and MAOI class antidepressants. The studies led to widespread recognition of a serotonin hypothesis of depression, displacing the data insupportable, but stubbornly entrenched theories that promoted the role of norepinephrine.

History

Indalpine: the first worldwide marketeed SSRI and Designated Blockbuster:

While Citalopram (Lundbeck) and Zimelidine (Astra Pharmaceuticals) were developed in the early 70s, it was Pharmuka's indalpine that was first to reach market of all existing SSRIs, and first designated as 'Blockbuster" antidepressant. Dr. Shopsin was recruited as consultant to Pharmuka throughout a timely and orderly R & D process that resulted in the marketing of Indalpine in France and then worldwide, in 1982...save the United States. The enormous therapeutic success, public excitement and media attention in France relating to Upstène (Indalpine)spread worldwide where patient demand and widepread physician prescribing of this new SSRI antidepressant drug led to another indalpine first: its designation as "Blockbuster" breaking all records for the sale of any antidepressant up to that point in time. With FDA approval of Pharmuka's IND submission to conduct clinical studies with indalpine and Viqueline, Dr. Shopsin carried out and published the first clinical trials with these drugs in depressed outpatients in the U.S.[2] Astra's SSRI Zimelidine was marketed within a year (1983), but the next crop of SSRI's didn't become commercially available until the 1986 marketing of Fluvoxamine in Belgium by Duphar, followed by approval in the United States later that year. Lily's Fluoxetine (Prozac) burst on the scene in the US, in 1987, an event occurrence five yrs after the advent worldwide marketing of Pharmuka's indalpine.

Indalpine withdrawn and Fluoxetine (Prozac) marketed in 1987

Meanwhile, Zimelidine had been withdrawn soon after its marketing in 1983 due to the emergence of Guillain–Barré syndrome, a serious neurological disease. In a smoldering climate of lingering concerns among some Common Market countries and activist groups about the potential of SSRIs to induce adverse effects, the ill timed occurrence of Indalpine associated hematological effects during the dislocating aftermath of Pharmuka's take over by the pharmaceutical giant Rhône Poulenc under industry nationalization by the socialist Mitterrand government, generated the "The Perfect Storm" sealing Indalpine's fate. In or about 1987, Rhône Poulenc abruptly blindsighted the regulatory authorities, the medical community and patients alike, by pulling Indalpine off the market to the astonishment and protestations of all concerned. David Healey the renowned British psychiatrist characterized the hapless fate of 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.[3] In line with Indalpine's fate, R & D was halted relating to the 2 other 4-alkyl-piperidine derivatives developed by Pharmuka, Viqueline (a 5-HT reuptake inhibitor & 5-HT releaser)and Pipequeline (a 5-HT post-receptor agonist), both in different stages of development at the time.

Recently, revision of this molecular motif yielded SERT inhibitors with nanomolar and subnanomolar IC50 values.[4]

See also

References

  1. ^ Shopsin, B; Friedman, E; Gershon, S (1976). "Parachlorophenylalanine reversal of tranylcypromine effects in depressed patients". Archives of general psychiatry 33 (7): 811–9. PMID 133650. 
  2. ^ Shopsin B, Lefebvre C, Maulet C (1983). "Indalpine (LM-5008): An open study in depressed outpatients". Curr Ther Res 34 (1): 239–252. 
  3. ^ 3. From Book Let Em Eat Prozac by David Healy, 2004
  4. ^ Marcin, LR; Mattson, RJ; Gao, Q; Wu, D; Molski, TF; Mattson, GK; Lodge, NJ (2010). "Synthesis and hSERT activity of homotryptamine analogs. Part 6: 3+2 dipolar cycloaddition of 3-vinylindoles". Bioorganic & medicinal chemistry letters 20 (3): 1027–30. doi:10.1016/j.bmcl.2009.12.043. PMID 20034793.