{
  "docId": "019dd923-622c-750b-8b9a-21918ac10c17",
  "docSlug": "f3db2294dcf9",
  "documentTitle": "Harmony Biosciences (HRMY)",
  "authorId": "58_Scorpion_Capital",
  "authorName": "Scorpion Capital",
  "documentKindSlug": "research-note",
  "documentKindLabel": "Research note",
  "sourceTypeSlug": "short_seller",
  "sourceTypeLabel": "Short seller",
  "presentationDate": "2023-03-28 00:00:00",
  "orientation": "landscape",
  "aspectRatio": 1.3333334,
  "pageNumber": 62,
  "pageCount": 366,
  "prevPage": 61,
  "nextPage": 63,
  "slideType": "cite_precedent",
  "function": "cite_precedent",
  "density": "balanced",
  "nDataPoints": 0,
  "notes": "The slide highlights the specific chemical challenge of nitrogen basicity in piperidine rings and the potential for fluorine to modulate pKa for improved safety.",
  "elementsJson": [
    "paragraph",
    "footnote"
  ],
  "metadataConfidence": 0.95,
  "imagePath": null,
  "slideHref": "/slides/019dd923-622c-750b-8b9a-21918ac10c17/62",
  "deckHref": "/decks/019dd923-622c-750b-8b9a-21918ac10c17",
  "deckJsonHref": "/decks/019dd923-622c-750b-8b9a-21918ac10c17.json",
  "deckAnchorHref": "/decks/019dd923-622c-750b-8b9a-21918ac10c17#slide-62",
  "components": [
    {
      "bbox": null,
      "kind": "callout",
      "text": "Molecules containing basic nitrogen atoms tend to be more promiscuous in vivo and can show cardiovascular tox, driven by interaction with the hERG potassium on channel, and phospholipidosis.",
      "attrs": null,
      "subkind": null,
      "toolName": "Visual emphasis",
      "toolSlug": "visual-emphasis",
      "confidence": null,
      "componentId": "019dd953-64d0-7099-9ccd-8187b119a21e",
      "frameworkName": null,
      "frameworkSlug": null
    },
    {
      "bbox": {
        "h": 0.35,
        "w": 0.86,
        "x": 0.07,
        "y": 0.32
      },
      "kind": "paragraph",
      "text": "The modulation of the basicity of the nitrogen atom can have a profound influence on the binding and structural recognition of a piperidine-containing drug and often fluorine substitution is used to this end.2 For example the Merck kinesin spindle protein (KSP) inhibitor shown below (R= 4-exploited a number of times in drug discovery.2 Molecules containing basic nitrogen atoms tend to be more promiscuous in vivo and can show cardiovascular tox, driven by interaction with the hERG potassium ion channel, and phospholipidosis.4 Incorporation of fluorine has been used as a strategy to modulate the pKa of an adjacent basic nitrogen atom and in doing so disrupt binding to the the hERG ion channel and increase cardiovascular safety in vivo. To discovery chemists, fluorine and piperidine are a dynamic duo that can have the potential to get them out of deep water. The challenge is bringing them together.",
      "attrs": null,
      "subkind": "paragraph",
      "toolName": null,
      "toolSlug": null,
      "confidence": null,
      "componentId": "47637429-3cbe-4e1b-b1c3-559838890824",
      "frameworkName": null,
      "frameworkSlug": null
    },
    {
      "bbox": {
        "h": 0.03,
        "w": 0.3,
        "x": 0.07,
        "y": 0.27
      },
      "kind": "paragraph",
      "text": "Paper on piperidine structures in drugs",
      "attrs": null,
      "subkind": "paragraph",
      "toolName": null,
      "toolSlug": null,
      "confidence": null,
      "componentId": "cb7ce015-40f5-4535-ba46-8bb45783865e",
      "frameworkName": null,
      "frameworkSlug": null
    },
    {
      "bbox": null,
      "kind": "quote",
      "text": "“profound influence on the binding and structural recognition of a piperidine-containing drug.” — Scientific Update",
      "attrs": null,
      "subkind": null,
      "toolName": "Authority citation",
      "toolSlug": "authority-citation",
      "confidence": null,
      "componentId": "019dd953-64d0-7099-9ccd-869f67a434f1",
      "frameworkName": null,
      "frameworkSlug": null
    },
    {
      "bbox": {
        "h": 0.04,
        "w": 0.5,
        "x": 0.07,
        "y": 0.93
      },
      "kind": "source-note",
      "text": "Source: https://www.scientificupdate.com/process-chemistry-articles/syn-3-fluoro-4-aminopiperidine-a-story-from-multiple-orientations/",
      "attrs": null,
      "subkind": null,
      "toolName": null,
      "toolSlug": null,
      "confidence": null,
      "componentId": "c9feaa09-5d8f-4b14-bdca-f96070c96587",
      "frameworkName": null,
      "frameworkSlug": null
    },
    {
      "bbox": {
        "h": 0.18,
        "w": 0.86,
        "x": 0.07,
        "y": 0.07
      },
      "kind": "title",
      "text": "A second paper further elaborated on the nitrogen atom in the piperidine ring as core of the problem and its “profound influence on the binding and structural recognition of a piperidine-containing drug.” The nitrogen atoms “tend to be more promiscuous in vivo and can show cardiovascular tox, driven by interaction with the hERG potassium on channel and phospholipidosis.”",
      "attrs": null,
      "subkind": "headline",
      "toolName": null,
      "toolSlug": null,
      "confidence": null,
      "componentId": "f6f86d72-216f-4ce7-a29e-44ecf2fdc109",
      "frameworkName": null,
      "frameworkSlug": null
    }
  ],
  "metrics": [],
  "tools": [],
  "frameworks": [],
  "arcBeats": [
    {
      "to": 70,
      "from": 51,
      "beatId": "f412f440-0381-4eb7-b9f4-292dcebd62be",
      "arcName": "Overcoming the Monster",
      "arcSlug": "overcoming-monster",
      "beatName": "The Victory",
      "beatSlug": null,
      "evidence": "The document presents the conclusion that the company is a house of cards",
      "position": 3,
      "confidence": 0.8,
      "parentBeatName": null,
      "parentBeatSlug": null
    }
  ],
  "loops": [],
  "imagePathAlt": null,
  "thumbSrc": null,
  "thumbSrcAlt": null,
  "locked": true
}