Structure Activity Relationship Of Viglibose

voglibose miglitol

Figure 20.23 • Structures of antihyperglycemic a-glucosidase inhibitors on the market worldwide.

Figure 20.24 • Polysaccharide linkages of relevance to the actions of a-glucosidase inhibitors, and the relationship of inhibitor structures to postulated high-energy intermediates in the hydrolysis of the disaccharide bonds.

activity and two with "maltase-glucoamylase" (MGAM)

activity.65'66 The sucrase activity represents catalytic hydrolysis of the a-(1^2) linkage between glucose C1 and fructose C2 in sucrose.

Acarbose potently and competitively inhibits the MGAM activity,66 and more specifically, the glucoamylase—but not the maltase—activity.67 The former activity was recently shown to reside within the C-terminal subunit of the enzyme, which extends into the intestinal lumen, and to which acarbose binds with considerably higher affinity than it does to the N-terminal subunit.68 The latter subunit is mostly membrane-imbedded, although both subunits are catalyti-cally active and are closely related members of the glycosyl hydrolase family 31. Miglitol potently inhibits glucoamylase and sucrase activities, but not isomaltase activity.69 Voglibose inhibits sucrase and maltase activities70 with such potency that clinically effective doses of voglibose are more than 100-fold lesser than the doses required for acarbose or miglitol.

Structure-activity relationships for molecules inhibiting a-glucosidases were extensively reviewed in 1996 by Junge et al.71; however, interpretations are complicated by substrate-dependent inhibitor binding and inhibition kinetics for these enzymes. These complexities are now understood to arise, in part, as manifestations of allosteric crosstalk between binding sites in these multisubunit enzymes.6872

Acarbose is o^^-dideoxy^-^a^tf^s^m^^-trihydroxy-3-(hydroxymethyl)-2-cyclohexen-1-yl]amino]-a-d-glucopyranosyl-(1 ^4)- o-a-d-glucopyranosyl-(1 ^4)-d-glucose. It is sold as 25-, 50-, and 100-mg tablets (Precose, generics) dosed with the first bite of each meal, up to t.i.d. Acarbose potently inhibits the glucoamylase activity of MGAM a-glucosidases and the sucrase activity of SI a-glucosidases, whereas isomaltase activity is at most moderately inhibited at concentrations in the range of those in the intestinal lumen upon oral dosing, and trehalase and lactase are not significantly inhibited.73 Some inhibition of pancreatic a-amylases may also contribute to the clinical effects.

Based on the structure of acarbose, it should come as no surprise that little intact acarbose reaches the systemic circulation; instead, acarbose is extensively biotransformed by the action of microbes and digestive enzymes in the gut. Only about 35% of the radioactivity in a dose of 14C-labeled acarbose administered orally to men was excreted in the urine, appearing as several metabolites, some of which are phase II conversion products of 4-methylpyrogallol (o-methyl, o-sulfate, or o-glucuronide conjugates)74; the methylpyrogallol fragment arises from the terminal valienamine pseudosugar. That these biotransformation products are mostly formed in the gut is shown by the fact that nearly 90% of an intravenously administered dose of acarbose is excreted intact in urine.

Miglitol is (2tf,3tf,4tf,5s)-1-(2-hydroxyethyl)-2-(hy-droxymethyl)-3,4,5-piperidinetriol, or a-hydroxyethyl-1-deoxynorjirimycin. The drug is available as 25-, 50-, and 100-mg tablets (Glyset), for administration 25 to 100 mg t.i.d. with meals. In contrast to acarbose, miglitol is highly absorbed from a 25-mg oral dose, although absorption is reported to be saturable, and accordingly less complete at higher doses.69 Binding to plasma proteins is minimal, and the volume of distribution (0.18 L/kg, corresponding to 12-13 L in a 70-kg adult) is characteristic of compounds distributed only to blood and extracellular fluids. Practically no systemic biotransformation of miglitol occurs in humans; essentially 100% of an orally administered dose is excreted intact in urine.

Amylin Analogs

Amylin is a circulating hormone released along with insulin from normally functioning pancreatic [ cells. This 37-amino-acid polypeptide (Fig. 20.25) incorporates one intramolecular disulfide bridge between cysteine residues at positions 2 and 7. The physiological and biochemical roles of amylin are at present only rather vaguely understood, but some of these are discussed here. Amylin, in excess, causes amyloidogenesis. The ramifications of this fact, in terms of [ cell loss in pancreatic islets or progressive amyloid tangle formation associated with Alzheimer disease, is an active area of investigation. The observation, though, that this property is not shared by rat amylin75-77 was exploited in the design of pramlintide, which differs from human amylin at only three positions toward the c-terminal end, namely substitution in each case with proline (Fig. 20.25).

Pramlintide is the 25-l-proline-28-l-proline-29-l-pro-line trisubstitution product of human amylin. The marketed formulation (Symlin) is an acetate salt, the exact composition of which may not be public-domain knowledge, although salts containing up to four acetic acid molecules per pramlintide molecule would be possible by virtue of the free amino terminus and Lys1, Arg11, and His18 residues. The carboxyl terminus of pramlintide, as in amylin, is amidated, and there are no appreciably acidic moities in the structure; thus, in solution at the pH of blood and tissues pramlintide would be present almost entirely as one or the other of two significant molecular species, one having a +3 charge (histidine imidazole deprotonated and uncharged) predominating modestly over the quadruply protonated (+4) species.

Pramlintide's labeled pharmacotherapeutic uses are (a) as an adjunct in type 1 diabetics who require mealtime insulin injections and yet fail to achieve desired glucose control (15 fig initially, titrated to 30 or 60 fig as tolerated); and (b) as an adjunct in type 2 diabetics who require mealtime insulin injections and yet fail to achieve desired glucose control (60 fig initially, increased after 3-7 days to 120 fig if tolerated), with or without ongoing management with metformin or a sulfonylurea. Pramlintide functions as an amylinomimetic; its administration slows gastric emptying, suppresses glucagon secretion (in turn inhibiting liver glucose output), and reduces the amount of food consumed via centrally mediated appetite suppression or satiety enhancement. Abnormal postprandial glucagon secretion occurs in diabetics, exacerbating hyperglycemic excursions, and pramlintide's glucagon-suppressing action serves to normalize this response. The multiple effects of pramlintide (and by analogy, endogenous amylin) are mediated directly or indirectly, or by some combination thereof, mechanistic understanding of which remains modest or even poor in many aspects.

Amylin receptors consist of short-form calcitonin receptors (CT[a]) in hetero-oligomeric complex with receptor activity-modifying proteins (RAMP1, RAMP2, RAMP3), thereby generating three subtypes of receptor complexes (AMY1(a), AMY2(a), and AMY3(a), or simply AMY1, AMY2, and AMY3).78,79 CT receptors are G-protein-coupled receptors (GPCRs), and the short-form CTr is a splice variant lacking a 16-amino-acid insert in the first intracellular loop (thus, it is also known as "insert negative"). Compared with many other GPCRs, particularly those that are targets of currently marketed or late-stage investigational pharmacotherapeutic agents, characterization of anatomical distributions and tissue- and system-level functions of amylin receptors remain but lightly addressed in open literature reports.

Pramlintide's effects upon administration to patients almost certainly arise in significant measure from direct AMY-mediated actions within the brainstem.80 Amylin receptors are abundant in the circumventricular organs, including the subfornical organ (where AMYi(a) receptors are known to be expressed in relative abundance), the organum vasculosum lateralis terminalis, and the area postrema (AMY3(a)), where the action of pramlintide (or of [-cell-secreted amylin) is not precluded by a diffusional BBB. Amylin receptors are also expressed in various other brain areas, in particular the nucleus accumbens, but neither amylin or pramlintide circulating in the bloodstream are likely to exert any action at these BBB-shielded locations. Direct amylin receptor-mediated actions of pramlintide in

Pramlintide: Human Amylin: Rat amylin:

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