MEDCHEM DIABETIC DRUG

    Cards (26)

    • Treatment of type II diabetes

      • Diagnosis - levels of glycosylation of haemoglobin (HbA1c), proportional to glucose levels in the bloodstream
      • Diagnosis - glucose tolerance test, in vivo clearance of glucose
      • Treatment - lifestyle changes: diet, weight, physical activity
      • Treatment - medication: monotherapy with metformin or sulfonylureas
      • Treatment - medication: monotherapy with other oral drugs
      • Treatment - medication: combination of oral drugs
      • Treatment - medication: combination of oral drugs and insulin
    • Synthesis and mechanism of action of metformin
      • Inhibition of mitochondrial complex I - reduces ATP levels, increases AMP levels, reduces NAD+ levels
      • Decreased gluconeogenesis
      • Stimulation of AMP-activated protein kinase
      • Inhibition of adenylate cyclase
    • Metformin as a drug
      • Inexpensive and well tolerated at the clinical dose (>1 g daily)
      • Often more effective at reducing glucose levels than other antidiabetic drugs
      • Requires endogenous insulin for action, hence effective only if functional pancreatic islet cells are present
      • Does not cause hypoglycaemia or weight gain
      • Gastrointestinal side-effects and, in rare cases, lactic acidosis
      • Can be used in combination with other oral antidiabetic drugs or insulin
      • Potential benefits against cancer and ageing, popular self-medication
    • Sulfonylureas
      • glibenclamide
      • gliclazide
      • glimepiride
      • glipizide
      • tolbutamide
    • Meglitinides
      • nateglinide
      • repaglinide
    • Mechanism of action of sulfonylurea drugs
      • Pancreatic KATP channels are hetero-octamers of four Kir6.2 subunits, which form the K+ conducting pore, and four regulatory SUR1 subunits
      • Upon glucose stimulation, the ion channel is closed, leading to influx of Ca2+ and insulin secretion
      • Sulfonylureas and meglitinides bind to SUR1 and block the ion channel, having the same effect as glucose to stimulate insulin secretion
    • Sulfonylureas as drugs
      • Inexpensive, first class of oral antidiabetic drugs, in clinical use since the 1940s
      • Major side effects are hypoglycaemia and weight gain
      • Duration of action (short, medium or long acting) can be tailored to patient response
      • Work by stimulating insulin secretion, hence effective only if functional pancreatic islet cells are present
      • Can be used in combination with other oral antidiabetic drugs or insulin
    • Meglitinide antidiabetic drugs
      • Discovered by medicinal chemistry efforts to find alternatives to sulfonylureas that work on the same target (pancreatic KATP channels)
      • Weaker binding and faster dissociation compared to sulfonylureas
      • Similar side effects of weight gain and hypoglycaemia but less pronounced than with sulfonylureas
      • Short-acting, rapid onset of action
    • The structure of starch
      • Polymerisation of glucose through 1,4 and 1,6 linkages gives starch, an energy storage form of glucose
      • Starch is broken down into glucose by two hydrolysing enzymes, a-amylase and a-glucosidase (a-amyloglucosidase)
      • Inhibition of the hydrolysis of dietary starch will reduce the absorption of glucose
    • Acarbose mechanism of action

      • Acarbose mimics the oligosaccharides formed from starch as well as the transition state of the enzyme a-glucosidase
      • Acarbose is a competitive inhibitor of a-glucosidase
    • PPARg agonists
      • pioglitazone
    • SGLT2 inhibitors
      • canagliflozin
      • dapagliflozin
      • empagliflozin
    • Discovery of SGLT1 and SGLT2
      • Used in 1899 to lower glucose levels in a diabetic patient, mechanism unknown
      • The kidney normally reabsorbs all of the filtered glucose (~180 g/day)
      • Reabsorption by two sodium-dependent glucose co-transporters (SGLTs) located on the
    • SGLT2 inhibitors
      Canagliflozin, dapagliflozin, empagliflozin
    • SGLT1 and SGLT2
      • Sodium-dependent glucose co-transporters located on the luminal epithelium in the kidney tubules
      • SGLT2: low affinity, high capacity, in the early proximal tubule, reabsorbs ~90% of the filtered glucose load
      • SGLT1: low capacity, in the more distal regions of the tubule, absorbs the remaining ~10%
      • Rate of reabsorption 20-40% higher in diabetics compared to normal individuals
    • SGLT2 inhibitors as drugs
      • Not associated with weight gain, likely to promote some weight loss due to reduced glucose reabsorption
      • Not associated with hypoglycaemia
      • Effect independent of insulin
      • Results in glycosuria (≥ 50 g/ day)
      • Potential for side-effects due to glycosuria- tiredness, dehydration, urinary tract infections
    • GLP-1, an incretin hormone

      • Incretins are GI hormones that are secreted in response to nutrient stimuli and stimulate glucose-dependent insulin secretion
      • GLP-1 itself is rapidly cleaved (t1/2 1-2 min) to an inactive form by the serine protease dipeptidyl peptidase 4 (DPP-4)
      • Increase insulin production and secretion
      • Decrease glucagon secretion
      • Slow gastric emptying
      • Promote weight loss by inducing satiety
    • GLP-1 signaling in the b-cell

      • GLP-1 binds to the GLP-1 receptor, a GPCR coupled to adenylyl cyclase
      • Triggers Epac2, EGFR, PI3K and CHOP pathways to induce insulin secretion, proliferation of b-cells and suppression of apoptosis
    • Extending the lifetime of GLP-1 signaling
      • Modify the structure of GLP-1 so that it is less easily broken down
      • Replacing the alanine by glycine decreases cleavage by DPP-4
      • Modify the structure of GLP-1 so that it hides from DPP-4
      • Binding GLP-1 to albumin or other proteins increases stability
      • Inhibit the protease DPP-4
      • DPP-4 inhibition increases the lifetime of endogenous GLP-1
    • Albiglutide, an albumin conjugate of human GLP-1
      • Two copies of GLP-1 modified to increase resistance to DPP4, conjugated with albumin protein
      • Once weekly administration by subcutaneous injection
      • Produced by fermentation in recombinant strain of baker's yeast Saccharomyces cerevisiae
    • Dulaglutide, an IgG conjugate of human GLP-1
      • Two copies of GLP-1, modified to increase resistance to DPP4, conjugated with IgG4 Fc fragment
      • Once weekly administration by subcutaneous injection, plasma half-life ~5 days
      • Manufactured by cell fermentation, marketed by Lilly
    • Irreversible DPP-4 inhibitors
      • Cyanopyrrolidines found to be proline mimetics that covalently bind to DPP-4 via the active site Ser
      • Stability improved by steric shielding of the amine
      • Vildagliptin (Novartis): MW 303, Clog P 1.1, HBA 4, HBD 2, nrot 3, TPSA 76 Å2
      • Saxagliptin (Bristol-Myers Squibb): MW 315, Clog P 0.9, HBA 4, HBD 2, nrot 2, TPSA 90 Å2
    • Reversible DPP-4 inhibitors- sitagliptin
      Sitagliptin (Januvia, Merck)- first in class DPP-4 inhibitor, launched in 2006, blockbuster drug: MW 407, Clog P 2.0, HBA 4, HBD 1, nrot 5, TPSA 77 Å2
    • Reversible DPP-4 inhibitors- linagliptin and alogliptin
      • Linagliptin (FDA approval 2011, EMEA approval 2012): MW 473, Clog P 2.6, HBA 7, HBD 1, nrot 5, TPSA 114 Å2
      • Alogliptin (FDA/EMEA approval 2013): MW 339, Clog P 0.7, HBA 5, HBD 1, nrot 3, TPSA 94 Å2
    • GLP-1 agonists and DPP-4 inhibitors as drugs
      • Dual effect of promoting insulin production in b-cells and inhibiting glucagon production in a-cells
      • Not associated with weight gain, in fact GLP-1 agonists are associated with weight loss
      • Low risk of hypoglycaemia
      • GLP-1 agonists are injectable whereas DPP-4 inhibitors are oral
      • Drug overdose is more problematic with GLP-1 agonists compared to DPP-4 inhibitors
      • Small but statistically significant risk of pancreatitis and pancreatic cancer
    • Mechanism of action of antidiabetic drugs
      • Insulin secretagogues: sulfonylureas, metiglinides, GLP-1 agonists, DPP-4 inhibitors
      • Decrease glucose absorption: a-glucosidase inhibitors
      • Decrease glucose reabsorption: SGLT2 inhibitors
      • Decrease gluconeogenesis: metformin, PPARg agonists
      • Increase glucose uptake: metformin, PPARg agonists
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