ho ho vildagliptin


Figure 20.28 • Structures of DPP-4 inhibitors on the global market or in advanced stages of clinical development.

binding (—38%), a relatively large volume of distribution (198 L), and a terminal elimination half-life of —12 hours. About 79% of a 100-mg oral dose is excreted unchanged in urine, the balance as trace-level metabolites (CYP3A4, lesser contribution by CYP2C8) in urine or feces: 87% of administered radioactivity is excreted in urine, and 13% in feces. Active tubular excretion is reported to play a key role in renal clearance of unchanged drug, and may be mediated at least in part via the organic anion transporter hOAT-3.

Glucose Elevating Agents

Apart from administration of glucose, either glucagon (rDNA origin) or diazoxide represent therapeutic options for pharmacotherapy of hypoglycemia. Applications are limited and specialized, as will be discussed here.

Glucagon produced by recombinant DNA technology is marketed by Novo Nordisk (glucagon [recombinant] hy-drochloride, GlucaGen HypoKit, GlucaGen Diagnostic Kit) and by Eli Lilly (glucagon [recombinant] Emergency Kit). Details regarding the structure and chemistry of this 29-amino-acid peptide are available in Chapter 27. As discussed earlier in this chapter, endogenous glucagon is produced from the gene-derived protein PG in the a cells of the islets of Langerhans in the pancreas. The core function of this hormone is to renormalize blood glucose levels when they fall too low, by stimulating production from glycogen

Figure 20.29 • Covalently bound imidate intermediate formed with nitrilo-containing DPP-4 inhibitors.
Figure 20.30 • Basis of sitagliptin fused ring system nomenclature, and explicit structure of 1:1 phosphate salt.

stores in liver and muscle, and stimulating hepatic gluconeo-genesis. Glucagon also elicits biochemical processes (such as fatty acid oxidation) that supply the needed precursors for gluconeogenesis. Glucagon supplied exogenously (i.e., injected) in response to emergency hypoglycemia acts rapidly to elicit these same responses. Clinically, glucagon also provides an alternative to cholinergic antagonists for reducing GI motility and secretory activity during radiologic imaging procedures.

Diazoxide is 7-chloro-3-methyl-4H-benzo[e][1,2,4] thiadiazine-1,1-dioxide (structure Fig. 20.31), and is currently available in the United States only as a 50-mg/mL oral suspension (Proglycem); discontinued formulations included capsules for oral administration, and injectable forms that typically found use for indications other than hypo-glycemic conditions. Diazoxide is a cyclic benzenesulfon-amide, although the free acid in solution can exist in three tautomeric forms, and the 4H tautomer most likely predominates to a very high proportion.114 Partly because of the additional nitrogen in the quinazoline ring structure, the molecule is somewhat more acidic (pKa —8.4,115 8.6116) than benzenesulfonamide (pKa —10).

Diazoxide acts as an ATP-sensitive potassium channel opener, thus inhibiting basal insulin secretion. This action may be viewed as the reverse of the insulin secretagogue actions of the sulfonylureas discussed earlier in this chapter; however, diazoxide is much less selective for SUR1 over SUR2A, SUR2B, or SUR2C receptor types,117 acts on mitochondrial ATP-sensitive potassium channels,118 and exerts various extrapancreatic effects that will not be discussed here.119 The action of diazoxide on ¡-islet cells may trigger glucagon release from a-islet cells via paracrine pathways.120

Structurally, diazoxide closely resembles (Fig. 20.31) hy-drochlorthiazide, a diuretic that inhibits the sodium chloride symporter in the distal convoluted tubule. Diazoxide does not act as a diuretic, however, instead exerting an antidiuretic effect. The discovery/creation/development of pancreas-selective ATP-sensitive potassium channel openers continues to be an area of ongoing investigation.121-123

Diazoxide binds extensively (>90%) to serum proteins, which greatly retards its renal excretion, by which route this drug is almost exclusively eliminated, with a terminal elimination half-life about 28 ± 8 hours. Lacking this serum binding (or active tubular reuptake), the hydrophilicity of this molecule would otherwise confer a much more rapid rate of renal excretion.

In contrast to the acute clinical uses of glucagon, diazoxide finds use in chronic hypoglycemic conditions: inoperable islet cell adenoma or carcinomas, extrapancreatic malignancies of insulin-secreting cells, or islet cell hyperplasias. In children, additional indications include congenital hyperinsu-linemia124 and leucine sensitivity. Experimentally, diazoxide is among an array of ATP-sensitive potassium channel openers being studied for intermittently bringing about jS-cell rest (see discussion of j-cell "fatigue" earlier in this chapter).125


As discussed elsewhere in this book (Chapters 25 and 27), the term gonadotropin encompasses three large-peptide

Figure 20.31 • Diazoxide structure. The 4H structure shown predominates in di-methylsulfoxide and is thought to predominate in aqueous solutions (although the solubility of the free acid is very low). Canonical (resonance) structures represent delocalization of the negative charge in the anionic conjugate base. Structures of the conjugate base of the sulfonylurea tolbutamide, and of the diuretic hydrochlorthi-azide, are provided for comparison.

tolbutamide (conjugate base)

Figure 20.31 • Diazoxide structure. The 4H structure shown predominates in di-methylsulfoxide and is thought to predominate in aqueous solutions (although the solubility of the free acid is very low). Canonical (resonance) structures represent delocalization of the negative charge in the anionic conjugate base. Structures of the conjugate base of the sulfonylurea tolbutamide, and of the diuretic hydrochlorthi-azide, are provided for comparison.

hormones: luteinizing hormone (LH), follicle-stimulating hormone (FSH), and chorionic gonadotropin (CG). LH and FSH are produced by the anterior pituitary, CG by the placenta during pregnancy; human CG is more commonly denoted as hCG. In broad brushstrokes sufficient for the needs of the information that follows, the major actions of LH and FSH in women are encapsulated by Figure 25.9 (Chapter 25). Release of LH and FSH by the pituitary is stimulated by gonadotropin-releasing hormone (GnRH, also known as luteinizing hormone-releasing hormone (LHRH), or simply—but less commonly—gonadoliberin). GnRH is produced in the arcuate nucleus and preoptic areas of the hypothalamus, and upon its release, is carried to the pituitary via the portal circulation. Although LH and FSH are named for their actions on the ovaries during the estrus cycle of women (see Chapter 25, Fig. 25.11), these hormones similarly regulate spermatogenesis in the testes of men (see Fig. 25.10). GnRH acts in the pituitary on cells known as gonadotropes, binding to seven-transmembrane-segment GPCRs (GnRH-Rs)126 and activating them, thereby triggering signaling pathways involving phospho-lipase C, ultimately bringing about an increase in cytoplas-mic calcium concentrations, which in turn prompts LH or FSH release.127 The control of pituitary release of either LH or FSH or both, in disparate amounts and timings (as depicted in Fig. 25.11) with only one hypothalamic releasing hormone, is made possible via variations in magnitude and frequency of the pulsatile release of GnRH, in conjunction with feedback regulation by circulating estrogens, progestins, and androgens. (For further details, the reader is referred to other information sources, as the focus herein is intended to be the medicinal chemistry rather than the intricacies of physiology; see, e.g., Knobil,128 and references given in Chapter 25.) A relatively thorough understanding of these pathways and systems, gained over nearly a century at least, now allows for their therapeutic exploitation despite their complexities, although new findings regularly alter clinical practice as well as drug discovery directions.

Inadequate production by the pituitary of gonadotropins causes hypogonadism, the consequences of which include infertility. Exogenously administered gonadotropins thus provide one means of fertility enhancement (see Chapter 27). Functional deficits in the gonads diminish production of estrogen, progestin, and testosterone (depending on gender and cycle stage), which otherwise inhibit release of LH or FSH from the pituitary, and also of GnRH from the hypothalamus (negative feedback loops). Gonadotropin (LH, FSH) levels rise, so that in the hypothalamus, the net impacts on GnRH release are relatively complex.

Gonadotropin-Releasing Hormone Agonists

Upon acute administration, GnRH agonists produce an initial stimulation of either LH release (called the "flare" response) or FSH release (in this case to stimulate ovulation), but upon chronic administration, the effect is to downregu-late pituitary release of gonadotropins. In turn, during the initial flare response there is an increase in gonadal steroido-genesis (testosterone and dihydrotestosterone in men, estrone and estradiol in premenopausal women). Following the flare response, steroidogenesis decreases over the next

2 to 4 weeks. Examples of therapeutic applications (see Table 20.6) include controlling timing of estrus cycle events in women and—in veterinary medicine—female animals to allow for artificial insemination or in vitro fertilization; suppression of precocious puberty; inducing ovarian suppression and a hypoestrogenic state in women when beneficial (e.g., menorrhagia, endometriosis, adenomyosis, or uterine fibroids); induction of hypogonadal states in oncology (notably, prostate cancer); and fertility suppression in male dogs. For chronic administration, long-lasting depot injections enable monthly or quarterly administration, and im-plantable devices allow release for as long as a year.

TABLE 20.6 GnRH Agonists


Volume of Protein Serum

Drug Indications Dosing Distribution Binding Time-course Elimination

TABLE 20.6 GnRH Agonists

Leuprolide acetate


, B, C, D

Injection, implant,

27 La


(Bolus dose)

Not fully

(Lupron, Eligard,

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