WO2006002022A2

WO2006002022A2 - Compositions and methods useful for the treatment of hyperglycemia

Info

Publication number: WO2006002022A2
Application number: PCT/US2005/020724
Authority: WO
Inventors: Mirta Grifman; Henry Li; James E. Macdonald; Flossie Wong-Staal
Original assignee: Immusol Incorporated
Priority date: 2004-06-15
Filing date: 2005-06-10
Publication date: 2006-01-05
Also published as: WO2006002022A3

Abstract

The present invention provides compositions and methods for the treatment of disorders characterized by hyperglycemia, in particular, Type II diabetes. The invention also provides a method for identifying novel compositions useful for the treatment of such disorders.

Description

COMPOSITIONS AND METHODS USEFUL FOR THE TREATMENT OF HYPERGLYCEMIA

FIELD OF THE INVENTION The present invention relates generally to the field of metabolic disorders and particularly to metabolic disorders characterized by hyperglycemia (elevated amounts of blood glucose). The invention provides compositions and methods for the treatment of such disorders, such as Type II diabetes, and also provides a novel method for identifying additional compositions for the treatment of such disorders. BACKGROUND OF THE INVENTION Hyperglycemia is a condition in which the blood contains an abnormally high level of glucose. If not controlled, high blood glucose levels can damage blood vessels, preventing oxygen and other essential nutrients from reaching vital areas. This can cause complications involving many bodily functions and organs, including the kidneys, the circulation system, nerves and eyes. In a healthy person, the level of glucose in the blood is controlled by, among others, the action of insulin, a hormone secreted by the pancreas. Diabetes Mellitus is a life-threatening condition caused by the body' S₁ inability to either produce sufficient insulin or to properly utilize the insulin it produces to regulate the level of glucose in the blood. In Type I (or insulin-dependent) diabetes, the pancreas simply does not produce the amount of insulin needed by the body to regulate blood glucose levels. In Type II diabetes (or Non-insulin-dependent Diabetes Mellitus ("NIDDM")), the pancreas initially produces a sufficient amount of insulin, but the body cannot properly utilize the insulin for controlling blood glucose levels. Eventually, the pancreas of people who suffer from Type II diabetes also ceases to produce a sufficient amount of insulin. Insulin resistance which is characteristic of Type II diabetes can arise from a number of causes, including defects in insulin signal transduction, changes in the expression of proteins or genes that are targets of insulin action, cross talk with other hormonal systems or metabolic abnormalities. The action of insulin normally modifies the activity of a multitude of proteins within minutes and regulates the expression of about 100 genes in a matter of hours. Among the genes regulated by insulin is glucose-6-phosphatase ("GβPase") and phosphoenolpyruvate carboxykinase ("PEPCK"). These enzymes are positively regulated by glucocorticoids and glucagons, while they are inhibited by insulin. In diabetic patients these enzymes are chronically up-regulated due to failures in insulin signaling, leading to abnormally elevated glucose levels. Modalities for treating Type II diabetes typically include lifestyle changes, especially diet and exercise, as well as the administration of insulin or oral medications to help the body process glucose. Most drugs used to treat Type II diabetes do not contain insulin, and the pancreas still has to make insulin in order for them to be effective. In time, people with Type II diabetes develop "beta-cell failure" or the inability of the pancreas to release insulin in response to high blood glucose levels. Therefore, these people often require insulin injections, in combination with oral medications, or just insulin to manage their diabetes. Among the many medications used in the treatment of diabetes are sulfonylureas, which lower blood glucose by stimulating the pancreas to release more insulin; biguanides, which improve insulin's ability to move glucose into cells, especially muscle, and prevent the liver from releasing stored glucose; thiazolidinediones, which improve insulin resistance in muscle and in fat tissue, lower the amount of glucose released by the liver, and make adipocytes more sensitive to the effects of insulin; alpha-glycosidase inhibitors, which block enzymes that help digest starches, slowing the rise in blood glucose; and meglitinides, which lower blood glucose by stimulating the pancreas to release more insulin. However, for the reasons stated above, these medications are not ideal treatments. Therefore, there is a need for more improved treatments. The present invention addresses this need. SUMMARY OF THE INVENTION The present invention provides compositions and methods for the treatment of disorders characterized by hyperglycemia, in particular, Type II diabetes. The invention also provides a method for identifying novel compositions useful for the treatment of such disorders. The invention is based upon the discovery that the mineralcorticoid receptor (MNR) is expressed in the liver, where both gluconeogensis and glycogen breakdown occur, and that inhibition of the expression of the MNR in liver (hepatoma) cells or blocking its activity results in a decrease in the level of glucose-6-phosphatase ("GόPase"), phosphoenolpyruvate carboxykinase ("PEPCK") and 1, 6 fructose biphosphatase ("FBPl"), enzymes that play a pivotal role in hepatic glucose output. It is known that reducing the level of these enzymes in the liver will result in a reduction of the level of glucose in the blood. Accordingly, the present invention is directed to compounds which inhibit the expression of the MNR or block its activity. Such compounds may be used for treating conditions characterized by hyperglycemia, such as Type II diabetes. The present invention is also directed to a method for identifying a compound which may be useful for treating such conditions, the method involving testing whether such compound is an MNR antagonist by using, for example, the GβPase/luciferase assay disclosed herein. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a bar graph showing validation data for the GβPase/Luciferase assay in accordance with the present invention as applied to HepG2 (hepatoma) cells. Figure 2 is a bar graph showing validation data for the GβPase/Luciferase assay in accordance with the present invention as applied to HuH7 (hepatoma) cells. Figure 3 is a bar graph showing relative mRNA levels of mineralcorticoid in liver, kidney and heart tissue. Figure 4 is bar graph showing relative mRNA levels of mineralcorticoid in HeIa, HuH7 and HepG2 cultured cells, and also in primary human hepatocytes (PHH). Figure 5 is a photograph of a Western Blot gel of mineralcorticoid protein expression in extracts from HepG2 cells and primary human hepatocytes (PHH), using MNR antibody, with IgG antibody as a negative control. Figure 6 is a bar graph showing reduction in expression of GβPase in HepG2 cells, after transfection with five different synthetic siRNAs. Figure 7 is a bar graph showing reduction in expression of GβPase in HepG2 cells, after stable transduction with a single synthetic "hairpin" siRNA. Figure 8 is a bar graph showing relative mRNA levels of mineralcorticoid in HeLa cells after transfection with the same five synthetic siRNAs shown in Figure 6. Figures 9A and 9B are bar graphs showing knock-down of the mRNA level of mineralcorticoid and GβPase, respectively, in a HepG2 cell line stably transduced with a single synthetic "hairpin" siRNA. Figure 10 is a bar graph showing reduction in expression of GβPase in HepG2 cells, after treatment with two different concentrations of the mineralcorticoid antagonist spironolactone. Figure 11 is a bar graph showing relative reduction of mRNA levels of GόPase in HepG2 cells after treatment with 50/zM spironolactone and 100 μM spironolactone. Figure 12 is a bar graph showing reduction in expression of GόPase in HuH7 cells, after treatment with three different concentrations (lμM, lOμM and 50/xM) of the mineralcorticoid antagonist spironolactone. Figure 13 is a bar graph showing reduction in expression of GόPase in HepG2 cells, after treatment with the mineralcorticoid antagonists RU28318 and R305847. Figure 14 is a bar graph showing reduction in levels of the phosphoenolpyruvate carboxy kinase (PEPCK) and 1, 6 fructose biphosphatase (FBPl) enzymes in HepG2 and HuH7 cells, after stable transduction with a lentiviral vector expressing siRNA targeting MNR. DETAILED DESCRIPTION OF THE INVENTION The mineralocorticoid receptor (MNR) MNR (unigene code NR3C2, Genbank accession #: NM_000901) is a member of the nuclear receptor superfamily, which acts as a ligand-dependent transcription factor. Previous to its cloning (Arriza et al., Science. 237:268-75 (1987)), MNR was termed the type-I glucocorticoid receptor or the aldosterone receptor. MNR can bind a variety of ligands including aldosterone, corticosteroids and synthetic compounds, all with high affinity. Mineralocorticoids are mainly implicated in the maintenance of water and salt homeostasis. Over the last 10 years, novel mineralocorticoid functions have been described. A role for aldosterone in cardiac fibrosis has been demonstrated and led to a novel use for mineralocorticoid antagonists, such as spironolactone (aldactone) and eplerenone (Inspra) in cardiac failure (Pitt et al., N Engl J Med.. 341:709-17 (1999)) and chronic hepatitis B. The MNR gene is composed of 10 exons that encode for a 107kDa protein. It has been mapped to chromosome 4q31.1-4q31.2 (Arriza et al., supra). The MNR protein is composed of an amino-terminal region, which displays ligand-independent transcriptional transactivation a DNA-binding region, a proline-rich region and complex C-terminal domain responsible for ligand-dependent transactivation (Arriza et al., supra). An alternatively spliced variant has been reported which acts as a ligand-independent transcription factor modulating corticosteroid action (Zennaro et al., MoI Endocrinol.. 9:1586-98 (2001)). The glucocorticoid (NR3C1) and mineralocorticoid receptors share 57% of their amino-acids in the ligand-binding domain and they are similarly responsive to physiological concentrations of corticosteroids. Both receptors bind to glucocorticoid responsive elements (GREs) to activate transcription. The MNR is expressed in the kidney, brain, intestine, salivary glands, arteries and lung. The results of a screen of the nuclear receptor siRNA library led us to the finding that the MNR gene is also expressed in the liver and consequently to suggest a function for its protein in gluconeogenesis and its potential application in the treatment of Type II diabetes. Accordingly, the present invention provides methods of identifying a compound that can reduce or inhibit hyperglycemia or Type II diabetes. Such method involves testing whether such compound is an MNR antagonist by using, for example, the GόPase/luciferase assay disclosed herein. MNR antagonists Steroidal derivative are one type of MNR antagonist of the present invention, which can be used to reduce or inhibit hyperglycemia or Type II diabetes. Specifically, the present invention is directed to compounds with the core formula (I):

wherein:

the dotted lines denote optional double bonds; X is a carbon atom; R₁ is hydrogen, -C(O)-Y, -C(O)-O-Y, C₁ to C₆ alkyl, C₁ to C₆ substituted alkyl, nitro or amino, and Y is hydrogen, C₁ to C₆ alkyl, C₁ to C₆ substituted alkyl; R₂ is hydrogen or halo; R₃ is hydrogen or hydroxyl; or R₂ and R₃ combine to form -O- (epoxy) or -CH₂- (methylene); R₄ is hydrogen, hydroxyl, C₁ to C₆ alkyl or C₁ to C₆ substituted alkyl; or R₃ and R₄ combine to form -0-CH₂-; R₅ and R₆ are, independently, hydrogen, hydroxyl, -C(O)-Y, -C(O)-O-Y, C₁ to C₆ alkyl, or C₁ to C₆ substituted alkyl, and Y is hydrogen, C₁ to C₆ alkyl, C₁ to C₆ substituted alkyl; or R₅ and R₆ and X of the core formula combine to form

where R₁₃ and R₁₄ are, independently, hydrogen, hydroxyl, oxo, -C(O)-Y, -C(O)-O-Y, C₁ to C₆ alkyl, or C₁ to C₆ substituted alkyl, and Y is hydrogen, C₁ to C₆ alkyl, C₁ to C₆ substituted alkyl ; Z is hydrogen, hydroxyl or oxo; R₇ is hydrogen, hydroxyl or oxo; R₈ is hydrogen, hydroxyl or halo; R₉ is hydrogen, hydroxyl, -C(O)-Y, -C(O)-O-Y, -S-C(O)-Y, -S-C(O)-O-Y, -S-Y, C₁ to C₆ alkyl, or C₁ to C₆ substituted alkyl, and Y is hydrogen, C₁ to C₆ alkyl, C₁ to C₆ substituted alkyl; or R₁₀ is hydrogen, hydroxyl or oxo; or R₉ and R_j0 combine to from methylene or epoxy; R₁₁ is absent, hydrogen, cyano, C₁ Io C₆ alkyl, C₁Io C₆ substituted alkyl, phenyl, substituted phenyl, heteroaryl or substituted heteroaryl; or R₁₀ and R₁₂ and the attached ring depicted form cyclopropyl, cyclobutyl or cyclopentyl, optionally substituted by oxo; or R₁₂ is hydrogen, hydroxyl or oxo; or a pharmaceutically acceptable salt of a compound thereof. In preferred embodiments of core formula (I): There is a double bond between the ring carbons that are attached to R₁₁ and R₁₂; Z is hydrogen; R₁ is hydrogen, methyl, hydroxymethyl or -CHO; R₂ is hydrogen or fluoro; R₃ is hydrogen; or R₂ and R₃ combine to from -O- (epoxy) or -CH₂- (methylene); R₄ is methyl; or R₃ and R₄ combine to form -0-CH₂-; R₅ and R₆ are, independently, hydorgen, hydroxyl, propionate, acetyl or R₅ and R₆ and X of the core formula combine to form

R₇ is hydrogen or oxo; R₈ is hydrogen or hydroxyl; R₉ is hydrogen, propyl, hydroxyl, -C(O)-O-methyl or -S-C(O)-methyl; R₁₀ is hydrogen; or R₉ and R₁₀ combine to form methylene; R₁₁ is absent, hydrogen or cyano; or R₁₀ and R₁₂ and the attached ring depicted form cyclobutyl, optionally substituted with oxo; or R₁₂ is hydrogen. Spironolactone (aldactone) is an example of a preferred compound of the present invention, specifically depicted by core formula (I), where: There is a double bond between the ring carbons that are attached to R₁₁ and R₁₂; R₁ is methyl; R₂ is hydrogen; R₃ is hydrogen; R₄ is methyl; R₅ and R₆ and X of the core formula combine to form

Z and R₇ are each hydrogen; R₈ is hydrogen; R₉ is -S-C(O)-methyl; R₁₀ is hydrogen; R₁₁ is hydrogen; and R₁₂ is hydrogen. Spironolactone is the most widely used MNR antagonist, with the primary indication hypertension. Due to some undesired side-effects like its anti-androgenic action, many attempts have been made to obtain a more specific antagonist that will display in vivo anti-hypertensive properties. These antagonists, including their potassium salts, which are all additional preferred compounds of the present invention include: canrenoic acid (the principal in vivo metabolite of spironolactone), RU- 28318, potassium prorenoate, ketoprogesterone the highly specific eplerenone (Inspra) and others (Wambach and Casals-Stenzel, Biochem Pharmacol.. 32:1479-85 (1983); Hofmann et al., J Pharmacol Exp Ther.. 94:450-6 (1975); and de Gasparo et al., J Pharmacol Exp Ther.. 240:650-6 (1987)). Methods of making the steroidal compounds of the present invention are disclosed in the above-cited references. Canrenoic acid is specifically depicted by core formula (I), where: There is a double bond between the ring carbons that are attached to R₁₁ and R₁₂ and R₉ and R₁₀, respectively, R₁ is methyl; R₂ is hydrogen; R₃ is hydrogen; R₄ is methyl; one of R₅ and R₆ is hydroxyl and the other is propionate; Z and R₇ are each hydrogen; R₈ is hydrogen; R₉ is hydrogen; R₁₀ is hydrogen; R₁₁ is hydrogen; and R₁₂ is hydrogen. RU- 28318 is specifically depicted by core formula (I), where: There is a double bond between the ring carbons that are attached to R₁₁ and R₁₂; R₁ is methyl; R₂ is hydrogen; R₃ is hydrogen; R₄ is methyl; one of R₅ and R₆ is hydroxyl and the other is propionate; Z and R₇ are each hydrogen; R₈ is hydrogen; R₉ is propyl; R₁₀ is hydrogen; R₁₁ is hydrogen; and R₁₂ is hydrogen. Prorenoate (or the potassium salt thereof) is specifically depicted by core formula (I), where: There is a double bond between the ring carbons that are attached to R₁₁ and R₁₂; R₁ is methyl; R₂ is hydrogen; R₃ is hydrogen; R₄ is methyl; one of R₅ and R₆ is hydroxyl and the other is propionate; Z and R₇ are each hydrogen; R₈ is hydrogen; R₉ and R₁₀ combine to form methylene; R₁₁ is hydrogen; and R₁₂ is hydrogen. R30584-7 is specifically depicted by core formula (I), where: There is a double bond between the ring carbons that are attached to R₁₁ and R₁₂; R₁ is methyl; R₂ is hydrogen; R₃ is hydroxyl; R₄ is methyl; R₅ and R₆ and X of the core formula combine to form

Z and R₇ are each hydrogen; R₈ is hydrogen; R₉ is -C(O)-O-methyl; R₁₀ is hydrogen; R₁₁ is hydrogen; and R₁₂ is hydrogen. Another example of a compound of the invention is the highly specific eplerenone, which is specifically depicted by core formula (I), where: There is a double bond between the ring carbons that are attached to R₁₁ and R₁₂; R₁ is methyl; R₂ and R₃ combine to from epoxy; R₄ is methyl; R₅ and R₆ and X of the core formula combine to form

Z and R₇ are each hydrogen; R₈ is hydrogen; R₉ is -C(O)-O-methyl; R₁₀ is hydrogen R₁₁ is hydrogen; and R₁₂ is hydrogen. Another preferred compound of the present invention is ketoprogesterone. Another class of MNR antagonists of the present invention has the core formula (II):

wherein: R₁ is C₁ to C₁₂ alkyl, C₂ to C₆ alkenyl, C₂ to C₆ alkynyl, C₁ to C₁₂ substituted alkyl, C₂ to C₆ substituted alkenyl, C₂ to C₆ substituted alkynyl, C₃ to C₇ cycloalkyl, C₃ to C₇ substituted cycloalkyl, C₅ to C₇ cycloalkenyl, C₅ to C₇ substituted cycloalkenyl, heterocycle, substituted heterocycle, heteroaryl, substituted heteroaryl, C₇ to C₁₈ phenylalkyl, C₇ to C₁₈ substituted phenylalkyl, phenyl, substituted phenyl, naphthyl, substituted naphthyl, cyclic C₂ to C₇ alkylene, substituted cyclic C₂ to C₇ alkylene, cyclic C₂ to C₇ heteroalkylene, substituted cyclic C₂ to C₇ heteroalkylene or - CH₂COR₇; R₂ is C₁ to C₁₂ alkyl, C₁ to C₁₂ substituted alkyl, C₃ to C₇ cycloalkyl, C₃ to C₇ substituted cycloalkyl, or -(CH₂)_n-phenyl, wherein n is 0, 1 or 2, and said phenyl is optionally substituted one, two or three times with hydroxyl, C₁ to C₄ alkyl, C₁ to C₄ alkoxy, halo, nitro, amino, -NH(C_j to C₆)alkylamine, N₅N-(C₁ to C₄)dialkylamine, - NH-(C₁ to C₄)alkylsulfonyl, -NH-acyl, or said phenyl has a fused heterocylic ring attached to it; R₃ is phenyl, which is optionally substituted one, two or three times with hydroxyl, C₁ to C₄ alkyl, C₁ to C₄ alkoxy, halo, nitro, amino, -NH(C₁ to C₆)alkylamine or N₅N-(C₁ to C₄)dialkylamine; R₄ and R₅ are, independently, hydrogen, halo, hydroxyl, C₁ to C₄ alkyl, C₁ to C₄ alkoxy, C₃ to C₅ cycloalkyl, CF₃, OCF₃, CHF₂, OCHF₂, CF₂CF₃, cyano, nitro, amino, - NH(C₁ to C₆)alkylamine, or N₁N-(C₁ to C₆)dialkylamine; and R₇ is C₁ to C₆ alkyl, C₃ to C₇ cycloalkyl, -NH-(C₃ to C₇ cycloalkyl), C₁ to C₄ alkoxy, phenyl, substituted phenyl, heterocycle or substituted heterocycle; or a pharmaceutically acceptable salt thereof. Preferred compounds with core formula (II) are those where: R₁ is a substituted phenyl, substituted heterocycle, C₁ to C₄ alkyl-substituted phenyl, specifically, substituted one or two times. More preferred are compounds where R₁ is 4-methoxybenzyl, 3-methoxybenzyl, 4-hydroxybenzyl, 4-fluorobenzyl, 2- fluorobenzyl, 4-bromobenzyl, 2,6-difluorobenzyl, 2-bromobenzyl, 3-bromobenzyl, 2,4-difluorobenzyl, 2,3-difluorobenzyl, 2-chlorobenzyl, 3-chlorobenzyl, 3,4- dichlorobenzyl, 2,6-dichlorobenzyl, 2-chloro-6-fluorobenzyl, 4-bromo-2- fluorobenzyl, 4-chloro-2-fluorobenzyl, 2-methylbenzyl, 2,6-dimethylbenzyl, 2- cyanobenzyl, 4-methoxycarbonylbenzyl, 3-methoxycarbonylbenzyl, A- methanesulfonylbenzyl, 4-tert-butylbenzyl, 2-difluoromethoxybenzyl, 2- trifluormethylbenzyl, 3-trifluormethoxybenzyl, 3-trifluoromethylbenzyl, A- trifluorormethylbenzyl, 4-trifluoromethoxybenzyl, 2,4-Bis-trifluoromethylbenzyl, 3,5- Bis-trifluoromethylbenzyl, 2-fluoro-3-methylbenzyl, 2, fluoro-5- trifluoromethylbenzyl, 4-nitrobenzyl, 2-nitrobenzyl, 3-nitrobenzyl, 2-aminobenzyl, 3- aminobenzyl, 4-aminobenzyl, 4-benzoylbenzyl, 4-benzyloxybenzyl, l-biphenyl-2- ylmethyl or 4-[l,2,3]thiadiazol-4-yl-benzyl. Preferred compounds are also where, in R₂, n is 0. Also preferred is where the phenyl ring in R₂ is hydrogen or substituted with hydroxyl, C₁ to C₄ alkyl, halo, nitro, amino -NH-COCH₃, or -NH-SO₂CH₃. More preferred compounds are where R₂ is 4-hydroxy-3,5-dimethylphenyl, 4- hydroxy-3-ethylphenyl, 4-hydroxy-3-methylphenyl, 4-hydroxyphenyl, 4-hydroxy-3,5- dichlorophenyl, 4-amino-3,5-dimethylphenyl, 4-aminophenyl, 4-nitrophenyl, 2- hydroxy-3 ,4-dimethylphenyl, 2-hydroxy-3 ,5-dimethylphenyl, 2-hydroxy-4,5- dimethylphenyl, 2-hydroxy-5-methylphenyl, 3,4-dihydroxy-5-methylphenyl, 4- hydroxy-3-methyl-5-propylphenyl, 3,4-dimethylphenyl, 3,4,5-trimethylphenyl, 4- amino-3-chloro-5-methylphenyl, 4-amino-3-methylphenyl, 2,4-dihydroxyphenyl, 2,4- dihydroxy-3-methylphenyl, 2-hydroxy-3-ethylphenyl, 2-hydroxyphenyl, 4- NH(SO₂)CH₃-phenyl or 4-NH(CO)CH₃-phenyl. Other preferred compounds include those where R₃ is 4-hydroxy-3,5- dimethylphenyl, 4-hydroxy-3-ethylphenyl, 4-hydroxy-3-methylphenyl, 4-hydroxy- 3,5-dichlorophenyl, 3,5-dimethylphenyl or 3,4,5-trimethylphenyl. In yet other preferred compounds, R₄ and R₅ are, independently, hydrogen, halo, hydroxyl, C₁ to C₄ alkyl, C₁ to C₄ alkoxy, CF₃, OCF₃, CHF₂, OCHF₂, CF₂CF₃, cyano, nitro or amino and, even more specifically, bromo, chloro, methyl, ethyl or methoxy. Compounds with core formula (II), as described above, can be made as disclosed, for example, in WO 03/078394 (PCT/US03/06152). When the above-described compounds include one or more chiral centers, the stereochemistry of such chiral centers can independently be in the R or S configuration, or a mixture of the two. The chiral centers can be further designated as R or S or R,S or d,D, 1,L or d,l, D,L. Regarding the compounds and combinatorial libraries described herein, the suffix "ene" added to any of the described terms means that two parts of the substituent are each connected to two other parts in the compound (unless the substituent contains only one carbon, in which case such carbon is connected to two other parts in the compound, for example, methylene). The term "C₁ to C₁₂ alkyl" denotes such radicals as methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, amyl, tert-amyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl and the like. Preferred "C₁ to C₁₂ alkyl" groups are methyl, ethyl, iso-butyl, sec-butyl and iso-propyl. Similarly, the term "C₁ to C₁₂ alkylene" denotes radicals of 1 to 12 carbons connected to two other parts in the compound. In light of the above, the meaning of terms using shorter alkyls or alkylenes (such as C₁ to C₆ alkyl or shorter versions of other moieties) are understood. The term "C₂ to C₁₂ alkenyl" denotes such radicals as vinyl, allyl, 2-butenyl, 3- butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5- hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, (as well as octenyl, nonenyl, decenyl, undecenyl, dodecenyl radicals attached at any appropriate carbon position and the like) as well as dienes and trienes of straight and branched chains. The term "C₂ to C₁₂ alkynyl" denotes such radicals as ethanol, propynyl, 2- butynyl, 2-pentynyl, 3-pentynyl, 2- hexynyl, 3-hexynyl, 4-hexynyl, 2-heptynyl, 3- heptynyl, 4- heptynyl, 5-heptynyl (as well as octynyl, nonynyl, decynyl, undecynyl, dodecynyl radicals attached at any appropriate carbon position and the like) as well as di- and tri-ynes of straight and branched chains. The terms "C₁ to C₁₂ substituted alkyl," "C₂ to C₁₂ substituted alkenyl," "C₂ to C₁₂ substituted alkynyl," "C₁ to C₁₂ substituted alkylene," "C₂ to C₁₂ substituted alkenylene" and "C₂ to C₁₂ substituted alkynylene" denote groups are substituted by one or more, and preferably one or two, halogen, hydroxy, protected hydroxy, oxo, protected oxo, C₃ to C₇ cycloalkyl, phenyl, naphthyl, amino, protected amino, (monosubstituted)amino, protected (monosubstituted)amino, (disubstituted)amino, guanidino, protected guanidino, heterocyclic ring, substituted heterocyclic ring, imidazolyl, indolyl, pyrrolidinyl, C₁ to C₁₂ alkoxy, C₁ to C₁₂ acyl, C₁ to C₁₂ acyloxy, nitro, carboxy, protected carboxy, carbamoyl, carboxamide, protected carboxamide, N-(C₁ to C₁₂ alkyl)carboxamide, protected N-(C₁ to C₁₂ alkyl)carboxamide, N,N-di(C_! to C₁₂ alkyl)carboxamide, cyano, methylsulfonylamino, thiol, C₁ to C₁₀ alkylthio or C₁ to C₁₀ alkylsulfonyl groups. The substituted alkyl groups may be substituted once or more, and preferably once or twice, with the same or with different substituents. Examples of the above substituted alkyl groups include the 2-oxo-prop-l-yl, 3-oxo-but-l-yl, cyanomethyl, nitromethyl, chloromethyl, hydroxymethyl, tetrahydropyranyloxymethyl, trityloxymethyl, propionyloxymethyl, aminomethyl, carboxymethyl, allyloxycarbonylmethyl, allyloxycarbonylaminomethyl, methoxymethyl, ethoxymethyl, t-butoxy methyl, acetoxymethyl, chloromethyl, bromomethyl, iodomethyl, trifluoromethyl, 6-hydroxyhexyl, 2,4-dichloro(n-butyl), 2- aminopropyl, 1-chloroethyl, 2-chloroethyl, 1- bromoethyl, 2-chloroethyl, 1- fluoroethyl, 2-fluoroethyl, 1- iodoethyl, 2-iodoethyl, 1-chloropropyl, 2-chloropropyl, 3- chloropropyl, 1-bromopropyl, 2-bromopropyl, 3-bromopropyl, 1-fluoropropyl, 2- fluoropropyl, 3-fluoropropyl, 1- iodopropyl, 2-iodopropyl, 3-iodopropyl, 2- aminoethyl, 1- aminoethyl, N-benzoyl-2-aminoethyl, N-acetyl-2-aminoethyl, N- benzoyl-1-aminoethyl, N-acetyl-1 -aminoethyl and the like. Examples of the above substituted alkenyl groups include styrenyl, 3-chloro- propen-1-yl, 3-chloro-buten-l-yl, 3-methoxy-propen-2-yl, 3-phenyl-buten-2-yl, 1- cyano-buten-3-yl and the like. The geometrical isomerism is not critical, and all geometrical isomers for a given substituted alkenyl can be used. Examples of the above substituted alkynyl groups include phenylacetylen-1- yl, l-phenyl-2-propyn-l-yl and the like. The term "oxo" denotes a carbon atom bonded to two additional carbon atoms substituted with an oxygen atom doubly bonded to the carbon atom, thereby forming a ketone moiety. The term "protected oxo" denotes a carbon atom bonded to two additional carbon atoms substituted with two alkoxy groups or twice bonded to a substituted diol moiety, thereby forming an acyclic or cyclic ketal moiety. The term "C₁ to C₁₂ alkoxy" as used herein denotes groups such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy and like groups. A preferred alkoxy is methoxy. The term "C₁ to C₁₂ substituted alkoxy" means the alkyl portion of the alkoxy can be substituted in the same manner as in relation to C₁ to C₁₂ substituted alkyl. Similarly, the term "C₁ to C₁₂ phenylalkoxy" as used herein means "C₁ to C₁₂ alkoxy" bonded to a phenyl radical. The term "C₁ to C₁₂ acyloxy" denotes herein groups such as formyloxy, acetoxy, propionyloxy, butyryloxy, pivaloyloxy, pentanoyloxy, hexanoyloxy, heptanoyloxy, octanoyloxy, nonanoyloxy, decanoyloxy, undecanoyloxy, dodecanoyloxy and the like. Similarly, the term "C₁ to C₁₂ acyl" encompasses groups such as formyl, acetyl, propionyl, butyryl, pentanoyl, pivaloyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, benzoyl and the like. Preferred acyl groups are acetyl and benzoyl. The term "C₁ to C₁₂ substituted acyl" denotes the acyl group substituted by one or more, and preferably one or two, halogen, hydroxy, protected hydroxy, oxo, protected oxo, cyclohexyl, naphthyl, amino, protected amino, (monosubstituted)amino, protected (monosubstituted)amino, (disubstituted)amino, guanidino, heterocyclic ring, substituted heterocyclic ring, imidazolyl, indolyl, pyrrolidinyl, C₁ to C₁₂ alkoxy, C₁ to C₁₂ acyl, C₁ to C₁₂ acyloxy, nitro, C₁ to C₁₂ alkyl ester, carboxy, protected carboxy, carbamoyl, carboxamide, protected carboxamide, N-(C₁ to C₁₂ alkyl)carboxamide, protected N-(C₁ to C₁₂ alkyl)carboxamide, NjN-CIi(C₁ to C₁₂ alkyl)carboxamide, cyano, methylsulfonylamino, thiol, C₁ to C₁₀ alkylthio or C₁ to C₁₀ alkylsulfonyl groups. The substituted acyl groups may be substituted once or more, and preferably once or twice, with the same or with different substituents. Examples of C₁ to C₁₂ substituted acyl groups include 4-phenylbutyroyl, 3- phenylbutyroyl, 3-phenylpropanoyl, 2- cyclohexanylacetyl, cyclohexanecarbonyl, 2- furanoyl and 3-dimethylaminobenzoyl. The substituent term "C₃ to C₇ cycloalkyl" includes the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl rings. Similarly, a substituent that can be C₃ to C₇ cycloalkyl" can also be "C₅ to C₇ cycloalkyl," which includes the cyclopentyl, cyclohexyl or cycloheptyl rings. The substituent term "C₃ to C₇ substituted cycloalkyl" or "C₅ to C₇ substituted cycloalkyl" indicates the above cycloalkyl rings substituted by one or two halogen, hydroxy, protected hydroxy, C₁ to C₁₀ alkylthio, C₁ to C₁₀ alkylsulfoxide, C₁ to C₁₀ alkylsulfonyl, C₁ to C₁₀ substituted alkylthio, C₁ to C₁₀ substituted alkylsulfoxide, C₁ to C₁₀ substituted alkylsulfonyl, C₁ to C₁₂ alkyl, C₁ to C₁₂ alkoxy, C₁ to C₁₂ substituted alkyl, C₁ to C₁₂ alkoxy, oxo, protected oxo, (monosubstituted)amino, (disubstituted)amino, trifluoromethyl, carboxy, protected carboxy, phenyl, substituted phenyl, phenylthio, phenylsulfoxide, phenylsulfonyl, amino, or protected amino groups. The term "cycloalkylene" means a cycloalkyl, as defined above, where the cycloalkyl radical is bonded at two positions connecting together two separate additional groups. Similarly, the term "substituted cycloalkylene" means a cycloalkylene where the cycloalkyl radical is bonded at two positions connecting together two separate additional groups and further bearing at least one additional substituent. The term "C₅ to C₇ cycloalkenyl" indicates a 1,2, or 3-cyclopentenyl ring, a 1,2,3 or 4-cyclohexenyl ring or a 1,2,3,4 or 5-cycloheptenyl ring, while the term "substituted C₅ to C₇ cycloalkenyl" denotes the above C₅ to C₇ cycloalkenyl rings substituted by a C₁ to C₁₂ alkyl radical, halogen, hydroxy, protected hydroxy, C₁ to C₁₂ alkoxy, trifluoromethyl, carboxy, protected carboxy, oxo, protected oxo, (monosubstituted)amino, protected (monosubstituted)amino, (disubstituted)amino, phenyl, substituted phenyl, amino, or protected amino. The term "C₅ to C₇ cycloalkenylene" is a cycloalkenyl ring, as defined above, where the cycloalkenyl radical is bonded at two positions connecting together two separate additional groups. Examples of C₅ to C₇ cycloalkenylenes include 1,3-cyclopentylene and 1,2-cyclohexylene. Similarly, the term "substituted C₅ to C₇ cycloalkenylene" means a cycloalkenylene further substituted by halogen, hydroxy, protected hydroxy, C₁ to C₁₀ alkylthio, C₁ to C₁₀ alkylsulfoxide, C₁ to C₁₀ alkylsulfonyl, C₁ to C₁₀ substituted alkylthio, C₁ to C₁₀ substituted alkylsulfoxide, C₁ to C₁₀ substituted alkylsulfonyl, C₁ to C₁₂ alkyl, C₁ to C₁₂ alkoxy, C₁ to C₁₂ substituted alkyl, C₁ to C₁₂ alkoxy, oxo, protected oxo, (monosubstituted)amino, (disubstituted)amino, trifluoromethyl, carboxy, protected carboxy, phenyl, substituted phenyl, phenylthio, phenylsulfoxide, phenylsulfonyl, amino, or protected amino group. Examples of substituted C₅ to C₇ cycloalkenylenes include 4-chloro-l,3-cyclopentylene and 4-methyl-l ,2-cyclohexylene. The term "heterocycle" or "heterocyclic ring" denotes optionally substituted five-membered to eight-membered rings that have 1 to 4 heteroatoms, such as oxygen, sulfur and/or nitrogen, in particular nitrogen, either alone or in conjunction with sulfur or oxygen ring atoms. These five-membered to eight-membered rings may be saturated, fully unsaturated or partially unsaturated, with fully saturated rings being preferred. Preferred heterocyclic rings include morpholino, piperidinyl, piperazinyl, 2-amino-imidazoyl, tetrahydrofurano, pyrrolo, tetrahydrothiophen-yl, hexylmethyleneimino and heptylmethyleneimino. The term "substituted heterocycle" or "substituted heterocyclic ring" means the above-described heterocyclic ring is substituted with, for example, one or more, and preferably one or two, substituents which are the same or different which substituents can be halogen, hydroxy, protected hydroxy, cyano, nitro, C₁ to C₁₂ alkyl, C₁ to C₁₂ alkoxy, C₁ to C₁₂ substituted alkoxy, C₁ to C₁₂ acyl, C₁ to C₁₂ acyloxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, amino, protected amino, (monosubstituted)amino, protected (monosubstituted)amino, (disubstituted)amino carboxamide, protected carboxamide, N-(C₁ to C₁₂ alkyl)carboxamide, protected N- (C₁ to C₁₂ alkyl)carboxamide, N, N-Oi(C₁ to C₁₂ alkyl)carboxamide, trifluoromethyl, N-((C_! to C₁₂ alkyl)sulfonyl)amino, N-(phenylsulfonyl)amino, heterocycle or substituted heterocycle groups. The term "heteroaryl" means a heterocyclic aromatic derivative which is a five-membered or six-membered ring system having from 1 to 4 heteroatoms, such as oxygen, sulfur and/or nitrogen, in particular nitrogen, either alone or in conjunction with sulfur or oxygen ring atoms. Examples of heteroaryls include pyridinyl, pyiϊmidinyl, and pyrazinyl, pyridazinyl, pyrrolo, furano, oxazolo, isoxazolo, phthalimido, thiazolo and the like. The term "substituted heteroaryl" means the above-described heteroaryl is substituted with, for example, one or more, and preferably one or two, substituents which are the same or different which substituents can be halogen, hydroxy, protected hydroxy, cyano, nitro, C₁ to C₁₂ alkyl, C₁ to C₁₂ alkoxy, C₁ to C₁₂ substituted alkoxy, C₁ to C₁₂ acyl, C₁ to C₁₂ substituted acyl, C₁ to C₁₂ acyloxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, amino, protected amino, (monosubstituted)amino, protected (monosubstituted)amino, (disubstituted)amino, carboxamide, protected carboxamide, N-(C₁ to C₁₂ alkyl)carboxamide, protected N-(C₁ to C₁₂ alkyl)carboxamide, N, N-Oi(C₁ to C₁₂ alkyl)carboxamide, trifluoromethyl, N-((Cj to C₁₂ alkyl)sulfonyl)amino or N- (phenylsulfonyl)amino groups. The term "C₇ to C₁₈ phenylalkyl" denotes a C₁ to C₁₂ alkyl group substituted at any position within the alkyl chain by a phenyl. The definition includes groups of the formula: -phenyl-alkyl, -alkyl-phenyl and -alkyl-phenyl-alkyl. Examples of such a group include benzyl, 2-phenylethyl, 3-phenyl(n-propyl), 4-phenylhexyl, 3-phenyl(n- amyl), 3-phenyl(sec-butyl) and the like. Preferred C₇ to C₁₈ phenylalkyl groups are any one of the preferred alkyl groups described herein combined with a phenyl group. Similarly, the term "C₁ to C₁₂ heterocycloalkyl" denotes a C₁ to C₁₂ alkyl group substituted at any position within the alkyl chain by a "heterocycle," as defined herein. The definition includes groups of the formula: -heterocyclic-alkyl, -alkyl- heterocyclic and -alkyl-heterocyclic-alkyl. Examples of such a group include 2- pyridylethyl, 3-piperydyl(n-propyl), 4-furylhexyl, 3-piperazyl(n-amyl), 3- morpholyl(sec-butyl) and the like. Preferred C₁ to C₁₂ heterocycloalkyl groups are any one of the preferred alkyl groups described herein combined with any one of the preferred heterocycle groups described herein. The terms "C₇ to C₁₈ substituted phenylalkyl" and "C₁ to C₁₂ substituted heterocycloalkyl" denote a C₇ to C₁₈ phenylalkyl group or C₁ to C₁₂ heterocycloalkyl substituted (on the alkyl or, where applicable, phenyl or heterocyclic portion) with one or more, and preferably one or two, groups chosen from halogen, hydroxy, protected hydroxy, oxo, protected oxo, amino, protected amino, (monosubstituted)amino, protected (monosubstituted)amino, (disubstituted)amino, guanidino, protected guanidino, heterocyclic ring, substituted heterocyclic ring, C₁ to C₁₂ alkyl, C₁ to C₁₂ substituted alkyl, C₁ to C₁₂ alkoxy, C₁ to C₁₂ substituted alkoxy, C₁ to C₁₂ acyl, C₁ to C₁₂ substituted acyl, C₁ to C₁₂ acyloxy, nitro, carboxy, protected carboxy, carbamoyl, carboxamide, protected carboxamide, N-(C₁ to C₁₂ alkyl)carboxamide, protected N-(C₁ to C₁₂ alkyl)carboxamide, N, N-(C₁ to C₁₂ dialkyl)carboxamide, cyano, N-(C₁ to C₁₂ alkylsulfonyl)amino, thiol, C₁ to C₁₀ alkylthio, C₁ to C₁₀ alkylsulfonyl groups; and/or the phenyl group may be substituted with one or more, and preferably one or two, substituents chosen from halogen, hydroxy, protected hydroxy, cyano, nitro, C₁ to C₁₂ alkyl, C₁ to C₁₂ substituted alkyl, C₁ to C₁₂ alkoxy, C₁ to C₁₂ substituted alkoxy, C₁ to C₁₂ acyl, C₁ to C₁₂ substituted acyl, C₁ to C₁₂ acyloxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, amino, protected amino, (monosubstituted)amino, protected (monosubstituted)amino, (disubstituted)amino, carboxamide, protected carboxamide, N-(C₁ to C₁₂ alkyl)carboxamide, protected N- (C₁ to C₁₂ alkyl)carboxamide, N, N-di(C_x to C₁₂ alkyl)carboxamide, trifluoromethyl, N-((C₁ to C₁₂ alkyl)sulfonyl)amino, N-(phenylsulfonyl)amino, cyclic C₂ to C₁₂ alkylene or a phenyl group, substituted or unsubstituted, for a resulting biphenyl group. The substituted alkyl, phenyl or heterocyclic groups may be substituted with one or more, and preferably one or two, substituents which can be the same or different. Examples of the term "C₇ to C₁₈ substituted phenylalkyl" include groups such as 2-phenyl-l-chloroethyl, 2-(4-methoxyphenyl)ethyl, 4-(2,6-dihydroxy phenyl)n- hexyl, 2-(5-cyano-3-methoxyphenyl)n-pentyl, 3-(2,6-dimethylphenyl)n-propyl, 4- chloro-3-aminobenzyl, 6-(4-methoxyphenyl)-3-carboxy(n-hexyl), 5-(4- aminomethylphenyl)- 3-(aminomethyl)n-pentyl, 5-phenyl-3-oxo-n-pent-l-yl and the like. The term "C₇ to C₁₈ phenylalkylene" specifies a C₇ to C₁₈ phenylalkyl, as defined above, where the phenylalkyl radical is bonded at two different positions connecting together two separate additional groups. The definition includes groups of the formula: -phenyl-alkyl-, -alkyl-phenyl- and -alkyl-phenyl-alkyl-. Substitutions on the phenyl ring can be 1,2, 1,3 or 1,4. C₇ to C₁₈ phenylalkylenes include, for example, 1,4-tolylene and 1,3-xylylene. Similarly, the term "C₁ to C₁₂ heterocycloalkylene" specifies a C₁ to C₁₂ heterocycloalkyl, as defined above, where the heterocycloalkyl radical is bonded at two different positions connecting together two separate additional groups. The definition includes groups of the formula: -heterocyclic-alkyl-, -alkyl-heterocyclic and -alkyl-heterocyclic-alkyl-. The terms "C₇ to C₁₈ substituted phenylalkylene" and "C₁ to C₁₂ substituted heterocycloalkylene" means a C₇ to C₁₈ phenylalkylene or C₁ to C₁₂ heterocycloalkylene as defined above that is further substituted by halogen, hydroxy, protected hydroxy, C₁ to C₁₀ alkylthio, C₁ to C₁₀ alkylsulfoxide, C₁ to C₁₀ alkylsulfonyl, C₁ to C₁₀ substituted alkylthio, C₁ to C₁₀ substituted alkylsulfoxide, C₁ to C₁₀ substituted alkylsulfonyl, C₁ to C₁₂ alkyl, C₁ to C₁₂ alkoxy, C₁ to C₁₂ substituted alkyl, C₁ to C₁₂ alkoxy, oxo, protected oxo, (monosubstituted)amino, (disubstituted)amino, trifluoromethyl, carboxy, protected carboxy, phenyl, substituted phenyl, phenylthio, phenylsulfoxide, phenylsulfonyl, amino, or protected amino group on the phenyl ring or on the alkyl group. The term "substituted phenyl" specifies a phenyl group substituted with one or more, and preferably one or two, moieties chosen from the groups consisting of halogen, hydroxy, protected hydroxy, cyano, nitro, C₁ to C₁₂ alkyl, C₁ to C₁₂ substituted alkyl, C₁ to C₁₂ alkoxy, C₁ to C₁₂ substituted alkoxy, C₁ to C₁₂ acyl, C₁ to C₁₂ substituted acyl, C₁ to C₁₂ acyloxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, amino, protected amino, (monosubstituted)amino, protected (monosubstituted)amino, (disubstituted)amino, carboxamide, protected carboxamide, N-(C₁ to C₁₂ alkyl)carboxamide, protected N-(C₁ to C₁₂ alkyl)carboxamide, N, N-di(C_x to C₁₂ alkyl)carboxamide, trifluoromethyl, N-^C₁ to C₁₂ alkyl)sulfonyl)amino, N- (phenylsulfonyl)amino or phenyl, wherein the phenyl is substituted or unsubstituted, such that, for example, a biphenyl results. Examples of the term "substituted phenyl" includes a mono- or di(halo)phenyl group such as 2, 3 or 4-chlorophenyl, 2,6-dichlorophenyl, 2,5-dichlorophenyl, 3,4- dichlorophenyl, 2, 3 or 4-bromophenyl, 3,4-dibromophenyl, 3-chloro-4-fluorophenyl, 2, 3 or 4-fluorophenyl and the like; a mono or di(hydroxy)phenyl group such as 2, 3 or 4-hydroxyphenyl, 2,4-dihydroxyphenyl, the protected-hydroxy derivatives thereof and the like; a nitrophenyl group such as 2, 3 or 4-nitrophenyl; a cyanophenyl group, for example, 2, 3 or 4-cyanophenyl; a mono- or di(alkyl)phenyl group such as 2, 3 or 4-methylphenyl, 2,4-dimethylphenyl, 2, 3 or 4-(iso-propyl)phenyl, 2, 3 or 4- ethylphenyl, 2, 3 or 4-(n-propyl)phenyl and the like; a mono or di(alkoxyl)phenyl group, for example, 2,6-dimethoxyphenyl, 2, 3 or 4-methoxyphenyl, 2, 3 or 4-ethoxyphenyl, 2, 3 or 4-(isoρropoxy)phenyl, 2, 3 or 4-(t-butoxy)phenyl, 3-ethoxy-4- methoxyphenyl and the like; 2, 3 or 4-trifluoromethylphenyl; a mono- or dicarboxyphenyl or (protected carboxy)phenyl group such as 2, 3 or 4-carboxyphenyl or 2,4-di(protected carboxy)phenyl; a mono-or di(hydroxymethyl)phenyl or (protected hydroxymethyl)phenyl such as 2, 3, or 4-(protected hydroxymethyl)phenyl or 3,4-di(hydroxymethyl)phenyl; a mono- or di(aminomethyl)phenyl or (protected aminomethyl)phenyl such as 2, 3 or 4-(aminomethyl)phenyl or 2,4-(protected aminomethyl)phenyl; or a mono- or di(N-(methylsulfonylamino))phenyl such as 2, 3 or 4-(N-(methylsulfonylamino))phenyl. Also, the term "substituted phenyl" represents disubstituted phenyl groups wherein the substituents are different, for example, 3-methyl-4-hydroxyphenyl, 3-chloro-4-hydroxyphenyl, 2-methoxy-4- bromophenyl, 4-ethyl-2-hydroxyphenyl, 3-hydroxy-4-nitrophenyl, 2-hydroxy 4- chlorophenyl and the like. The term "phenoxy" denotes a phenyl bonded to an oxygen atom, wherein the binding to the rest of the molecule is through the oxygen atom. The term "substituted phenoxy" specifies a phenoxy group substituted with one or more, and preferably one or two, moieties chosen from the groups consisting of halogen, hydroxy, protected hydroxy, cyano, nitro, Q to C₁₂ alkyl, C₁ to C₁₂ alkoxy, C₁ to C₁₂ substituted alkoxy, C₁ to C₁₂ acyl, C₁ to C₁₂ acyloxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, amino, protected amino, (monosubstituted)amino, protected (monosubstituted)amino, (disubstituted)amino, carboxamide, protected carboxamide, N-(C₁ to C₁₂ alkyl)carboxamide, protected N-(C₁ to C₁₂ alkyl)carboxamide, N, N-CIi(C₁ to C₁₂ alkyl)carboxamide, trifluoromethyl, N-^C₁ to C₁₂ alkyl)sulfonyl)amino and N- (phenylsulfonyl)amino. Examples of substituted phenoxy include 2-methylphenoxy, 2-ethylphenoxy, 2-propylphenoxy, 2-isoρropylphenoxy, 2-sec-butylphenoxy, 2-tert-butylphenoxy, 2- allylphenoxy, 2-propenylphenoxy, 2-cyclopentylρhenoxy, 2-fluorophenoxy, 2-(trifluoromethyl)phenoxy, 2-chlorophenoxy, 2-bromophenoxy, 2-methoxyphenoxy, 2-ethoxyphenoxy, 2-isopropoxyphenoxy, 3-methylphenoxy, 3-ethylphenoxy, 3-isopropylρhenoxy, 3-tert-butylphenoxy, 3-pentadecylphenoxy, 3- (trifluoromethyl)phenoxy, 3-fluorophenoxy, 3-chlorophenoxy, 3-bromophenoxy, 3-iodophenoxy, 3-methoxyphenoxy, 3-(trifluoromethoxy)phenoxy, 4-methylphenoxy, 4-ethylphenoxy, 4-propylphenoxy, 4-isopropylphenoxy, 4-sec-butylphenoxy, 4-tert- butylphenoxy, 4-tert-amylphenoxy, 4-nonylphenoxy, 4-dodecylphenoxy, 4-cyclopenylphenoxy, 4-(trifluoromethyl)phenoxy, 4-fluorophenoxy, 4- chlorophenoxy, 4-bromophenoxy, 4-iodophenoxy, 4-methoxyphenoxy, 4-(trifluoromethoxy)phenoxy, 4-ethoxyphenoxy, 4-propoxyphenoxy, 4- butoxyphenoxy, 4-hexyloxyphenoxy, 4-heptyloxyphenoxy, 2,3-dimethylphenoxy, 5,6,7, 8-tetrahydro-l-naphthoxy, 2,3-dichlorophenoxy, 2,3-dihydro-2,2-dimethyl-7- benzofuranoxy, 2,3-dimethoxyphenoxy, 2,6-dimethylphenoxy, 2,6-diisopropylphenoxy, 2,6-di-sec-butylphenoxy, 2-tert-butyl-6-methylphenoxy, 2,6- di-tert-butylρhenoxy, 2-allyl-6-methylphenoxy, 2,6-difluorophenoxy, 2,3-difluorophenoxy, 2,6-dichlorophenoxy, 2,6-dibromophenoxy, 2-fluoro-6- methoxyphenoxy, 2,6-dimethoxyphenoxy, 3,5-dimethylphenoxy, 5-isopropyl- 3-methylphenoxy, 3,5-di-tert-butylphenoxy, 3,5-bis(trifluoromethyl)phenoxy, 3,5- difluorophenoxy, 3,5-dichlorophenoxy, 3,5-dimethoxyphenoxy, 3-chloro-5- methoxyphenoxy, 3,4-dimethylphenoxy, 5-indanoxy, 5,6,7,8-tetrahydro-2-naρhthoxy, 4-chloro-3-methylphenoxy, 2,4-dimethylphenoxy, 2,5-dimethylphenoxy, 2-isopropyl- 5-methylphenoxy, 4-isopropyl-3-methylphenoxy, 5-isopropyl-2-methylphenoxy, 2- tert-butyl-5-methylphenoxy, 2-tert-butyl-4-methylphenoxy, 2,4-di-tert-butylphenoxy, 2,4-di-tert-amylphenoxy, 4-fluoro-2-methylphenoxy, 4-fluoro-3-methylphenoxy, 2-chloro-4-methylphenoxy, 2-chloro-5-methylphenoxy, 4-chloro-2-methylphenoxy, 4- chloro-3-ethylphenoxy, 2-bromo-4-methylphenoxy, 4-iodo-2-methylphenoxy, 2-chloro-5-(trifluoromethyl)phenoxy, 2,4-difluorophenoxy, 2,5-difluorophenoxy, 3,4- difluorophenoxy, 4-chloro-2-fluorophenoxy, 3-chloro-4-fluorophenoxy, 4-chloro-3- fluorophenoxy, 2-bromo-4-fluorophenoxy, 4-bromo-2-fluorophenoxy, 2-bromo-5- fluorophenoxy, 2,4-dichlorophenoxy, 3,4-dichlorophenoxy, 2,5-dichlorophenoxy, 2- bromo-4-chlorophenoxy, 2-chloro-4-fluorophenoxy, 4-bromo-2-chlorophenoxy, 2,4-dibromophenoxy, 2-methoxy-4-methylphenoxy, 4-allyl-2-methylphenoxy, trans-2- ethoxy-5-(l-propenyl)phenoxy, 2-methoxy-4-propenylphenoxy, 3,4- dimethoxyphenoxy, 3-ethoxy-4-methoxyphenoxy, 4-allyl-2,6-dimethoxyphenoxy, 3,4- methylenedioxyphenoxy, 2,3,6-trimethylphenoxy, 2,4-dichloro-3-methylphenoxy, 2,3 ,4-trifluorophenoxy, 2,3 ,6-trifluorophenoxy, 2,3 ,5-trifluorophenoxy, 2,3,4-trichlorophenoxy, 2,3,6-trichlorophenoxy, 2,3,5-trimethylphenoxy, 3,4,5- trimethylphenoxy, 4-chloro-3,5-dimethylphenoxy, 4-bromo-3,5-dimethylphenoxy, 2,4,6-trimethylphenoxy, 2,6-bis(hydroxymethyl)-4-methylphenoxy, 2,6-di-tert-butyl- 4-methylphenoxy, 2,6-di-tert-butyl-4-methoxyphenoxy, 2,4,5- trifluorophenoxy, 2- chloro-3,5-difluorophenoxy, 2,4,6-trichlorophenoxy, 3,4,5-trimethoxyphenoxy, 2,3,5- trichlorophenoxy, 4-bromo-2,6-dimethylphenoxy, 4-bromo-6-chloro-2- methylphenoxy, 2,6-dibromo-4-methylphenoxy, 2,6-dichloro-4-fluorophenoxy, 2,6- dibromo-4-fluorophenoxy, 2,4,6-tribromophenoxy, 2,4,6-triiodophenoxy, 2-chloro- 4,5-dimethylphenoxy, 4-chloro-2-isopropyl-5-methylphenoxy, 2-bromo-4,5- difluorophenoxy, 2,4,5-trichlorophenoxy, 2,3,5,6-tetrafluorophenoxy and the like. The term "C₇ to C₁₈ substituted phenylalkoxy" denotes a C₇ to C₁₈ phenylalkoxy group bonded to the rest of the molecule through the oxygen atom, wherein the phenylalkyl portion is substituted with one or more, and preferably one or two, groups selected from halogen, hydroxy, protected hydroxy, oxo, protected oxo, amino, protected amino, (monosubstituted) amino, protected (monosubstituted)amino, (disubstituted)amino, guanidino, heterocyclic ring, substituted heterocyclic ring, C₁ to C₁₂ alkoxy, C₁ to C₁₂ acyl, C₁ to C₁₂ acyloxy, nitro, carboxy, protected carboxy, carbamoyl, carboxamide, protected carboxamide, N-(C₁ to C₁₂ alkyl)carboxamide, protected N-(C₁ to C₁₂ alkyl)carboxamide, N, N-(C₁ to C₁₂ dialkyl)carboxamide, cyano, N-(C₁ to C₁₂ alkylsulfonyl)amino, thiol, C₁ to C₁₀ alkylthio, C₁ to C₁₀ alkylsulfonyl groups; and/or the phenyl group can be substituted with one or more, and preferably one or two, substituents chosen from halogen, hydroxy, protected hydroxy, cyano, nitro, C₁ to C₁₂ alkyl, C₁ to C₁₂ alkoxy, C₁ to C₁₂ acyl, C₁ to C₁₂ acyloxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, amino, protected amino, (monosubstituted)amino, protected (monosubstituted)amino, (disubstituted)amino, carboxamide, protected carboxamide, N-(C₁ to C₁₂ alkyl) carboxamide, protected N- (C₁ to C₁₂ alkyl) carboxamide, N, N-CIi(C₁ to C₁₂ alkyl)carboxamide, trifluoromethyl, N-((Q to C₁₂ alkyl)sulfonyl)amino, N-(phenylsulfonyl)amino or a phenyl group, substituted or unsubstituted, for a resulting biphenyl group. The substituted alkyl or phenyl groups may be substituted with one or more, and preferably one or two, substituents which can be the same or different. Examples of the term "C₇ to C₁₈ substituted phenylalkoxy" include groups such as 2-(4-hydroxyphenyl)ethoxy, 4-(4-methoxyphenyl)butoxy, (2R)-3-phenyl-2- amino-propoxy, (2S)-3-phenyl-2-amino-propoxy, 2-indanoxy, 6-phenyl-l-hexanoxy, cinnamyloxy, (+/-)-2-phenyl-l-propoxy, 2,2-dimethyl-3-phenyl-l-propoxy and the like. The term "phthalimide" means a cyclic imide which is made from phthalic acid, also called 1,2-benzenedicarboxylic acid. The term "substituted phthalimide" specifies a phthalimide group substituted with one or more, and preferably one or two, moieties chosen from the groups consisting of halogen, hydroxy, protected hydroxy, cyano, nitro, C₁ to C₁₂ alkyl, C₁ to C₁₂ alkoxy, C₁ to C₁₂ substituted alkoxy, C₁ to C₁₂ acyl, C₁ to C₁₂ acyloxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, amino, protected amino, (monosubstituted)amino, protected (nionosubstituted)amino, (disubstituted)amino, carboxamide, protected carboxamide, N-(C₁ to C₁₂ alkyl)carboxamide, protected N- (C₁ to C₁₂ alkyl)carboxamide, N, N-CIi(C₁ to C₁₂ alkyl)carboxamide, trifluoromethyl, N-^C₁ to C₁₂ alkyl)sulfonyl)amino and N-(phenylsulfonyl)amino. Examples of substituted phthalimides include 4,5-dichlorophthalimido, 3- fluorophthalimido, 4-methoxyphthalimido, 3-methylphthalimido, 4-carboxyphthalimido and the like. The term "substituted naphthyl" specifies a naphthyl group substituted with one or more, and preferably one or two, moieties either on the same ring or on different rings chosen from the groups consisting of halogen, hydroxy, protected hydroxy, cyano, nitro, C₁ to C₆ alkyl, C₁ to C₇ alkoxy, C₁ to C₇ acyl, C₁ to C₇ acyloxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, amino, protected amino, (monosubstituted)amino, protected (monosubstituted)amino, (disubstituted)amino, carboxamide, protected carboxamide, N-(C₁ to C₁₂ alkyl)carboxamide, protected N- (C₁ to C₁₂ alkyl)carboxamide, N, N-CIi(C₁ to C₁₂ alkyl)carboxamide, trifluoromethyl, N-((Q to C₁₂ alkyl)sulfonyl)amino or N-(phenylsulfonyl)amino. Examples of the term "substituted naphthyl" includes a mono or di(halo)naphthyl group such as 1, 2, 3, 4, 5, 6, 7 or 8-chloronaphthyl, 2, 6- dichloronaphthyl, 2, 5-dichloronaphthyl, 3, 4-dichloronaphthyl, 1, 2, 3, 4, 5, 6, 7 or 8- bromonaphthyl, 3, 4-dibromonaphthyl, 3-chloro-4-fluoronaphthyl, 1, 2, 3, 4, 5, 6, 7 or 8-fluoronaphthyl and the like; a mono or di(hydroxy)naphthyl group such as 1, 2, 3, 4, 5, 6, 7 or 8-hydroxynaphthyl, 2, 4-dihydroxynaphthyl, the protected-hydroxy derivatives thereof and the like; a nitronaphthyl group such as 3- or 4-nitronaphthyl; a cyanonaphthyl group, for example, 1, 2, 3, 4, 5, 6, 7 or 8-cyanonaphthyl; a mono- or di(alkyl)naphthyl group such as 2, 3, 4, 5, 6, 7 or 8-methylnaphthyl, 1, 2, 4-dimethylnaphthyl, 1, 2, 3, 4, 5, 6, 7 or 8-(isopropyl)naphthyl, 1, 2, 3, 4, 5, 6, 7 or 8-ethylnaphthyl, 1, 2, 3, 4, 5, 6, 7 or 8-(n-propyl)naphthyl and the like; a mono or di (alkoxy )naphthyl group, for example, 2, 6-dimethoxynaphthyl, 1, 2, 3, 4, 5, 6, 7 or 8-methoxynaphthyl, 1, 2, 3, 4, 5, 6, 7 or 8-ethoxynaphthyl, 1, 2, 3, 4, 5, 6, 7 or 8-(isopropoxy)naphthyl, 1, 2, 3, 4, 5, 6, 7 or 8-(t-butoxy)naphthyl, 3-ethoxy-4- methoxynaphthyl and the like; 1, 2, 3, 4, 5, 6, 7 or 8-trifluoromethylnaphthyl; a mono- or dicarboxynaphthyl or (protected carboxy)naphthyl group such as 1, 2, 3, 4, 5, 6, 7 or 8-carboxynaphthyl or 2, 4-di(-protected carboxy )naphthyl; a mono-or di(hydroxymethyl)naphthyl or (protected hydroxymethyl)naphthyl such as 1, 2, 3, 4, 5, 6, 7 or 8-(protected hydroxymethyl)naphthyl or 3, 4-di(hydroxymethyl)naphthyl; a mono- or di(amino)naphthyl or (protected amino)naphthyl such as 1, 2, 3, 4, 5, 6, 7 or 8-(amino)naphthyl or 2, 4-(protected amino)-naphthyl, a mono- or di(aminomethyl)naphthyl or (protected aminomethyl)naphthyl such as 2, 3, or 4-(aminomethyl)naphthyl or 2, 4-(protected aminomethyl)-naphthyl; or a mono- or di- (N-methylsulfonylamino) naphthyl such as 1, 2, 3, 4, 5, 6, 7 or 8-(N-methylsulfonylamino)naphthyl. Also, the term "substituted naphthyl" represents disubstituted naphthyl groups wherein the substituents are different, for example, 3- methyl-4-hydroxynaphth-l-yl, 3-chloro-4-hydroxynaphth-2-yl, 2-methoxy-4- bromonaphth-1-yl, 4-ethyl-2-hydroxynaphth-l-yl, 3-hydroxy-4-nitronaphth-2-yl, 2- hydroxy-4-chloronaphth-l-yl, 2-methoxy-7-bromonaphth-l-yl, 4-ethyl-5- hydroxynaphth-2-yl, 3-hydroxy-8-nitronaphth-2-yl, 2-hydroxy-5-chloronaphth-l-yl and the like. The term "naphthylene" means a naphthyl radical bonded at two positions connecting together two separate additional groups. Similarly, the term "substituted napthylene" means a naphthylene group that is further substituted by halogen, hydroxy, protected hydroxy, C₁ to C₁₀ alkylthio, C₁ to C₁₀ alkylsulfoxide, C₁ to C₁₀ alkylsulfonyl, C₁ to C₁₀ substituted alkylthio, C₁ to C₁₀ substituted alkylsulfoxide, C₁ to C₁₀ substituted alkylsulfonyl, C₁ to C₁₂ alkyl, C₁ to C₁₂ alkoxy, C₁ to C₁₂ substituted alkyl, C₁ to C₁₂ alkoxy, oxo, protected oxo, (monosubstituted)amino, (disubstituted)amino, trifluoromethyl, carboxy, protected carboxy, phenyl, substituted phenyl, phenylthio, phenylsulfoxide, phenylsulfonyl, amino, or protected amino group. The terms "halo" and "halogen" refer to the fluoro, chloro, bromo or iodo atoms. There can be one or more halogens, which are the same or different. Preferred halogens are chloro and fluoro. The term "(monosubstituted)amino" refers to an amino group with one substituent chosen from the group consisting of phenyl, substituted phenyl, C₁ to C₁₂ alkyl, C₁ to C₁₂ substituted alkyl, C₁ to C₁₂ acyl, C₁ to C₁₂ substituted acyl, C₂ to C₁₂ alkenyl, C₂ to C₁₂ substituted alkenyl, C₂ to C₁₂ alkynyl, C₂ to C₁₂ substituted alkynyl, C₇ to C₁₈ phenylalkyl, C₇ to C₁₈ substituted phenylalkyl, heterocyclic ring, substituted heterocyclic ring, C₁ to C₁₂ heterocycloalkyl and C₁ to C₁₂ substituted heterocycloalkyl. The (monosubstituted)amino can additionally have an amino- protecting group as encompassed by the term "protected (monosubstituted)amino." The term "(disubstituted)amino" refers to an amino group with two substituents chosen from the group consisting of phenyl, substituted phenyl, C₁ to C₁₂ alkyl, C₁ to C₁₂ substituted alkyl, C₁ to C₁₂ acyl, C₂ to C₁₂ alkenyl, C₂ to C₁₂ alkynyl, C₇ to C₁₈ phenylalkyl, C₇ to C₁₈ substituted phenylalkyl, C₁ to C₁₂ heterocycloalkyl and C₁ to C₁₂ substituted heterocycloalkyl. The two substituents can be the same or different. The term "amino-protecting group" as used herein refers to substituents of the amino group commonly employed to block or protect the amino functionality while reacting other functional groups of the molecule. The term "protected (monosubstituted)amino" means there is an amino-protecting group on the monosubstituted amino nitrogen atom. In addition, the term "protected carboxamide" means there is an amino-protecting group on the carboxamide nitrogen. Similarly, the term "protected N-(C₁ to C₁₂ alkyl)carboxamide" means there is an amino-protecting group on the carboxamide nitrogen. Examples of such amino-protecting groups include the formyl ("For") group, the trityl group, the phthalimido group, the trichloroacetyl group, the chloroacetyl, bromoacetyl, and iodoacetyl groups, urethane-type blocking groups, such as t- butoxycarbonyl ("Boc"), 2-(4-biphenylyl)propyl-2-oxycarbonyl ("Bpoc"), 2- phenylpropyl-2-oxycarbonyl ("Poc"), 2-(4-xenyl)isopropoxycarbonyl, 1,1- diphenylethyl- 1 -oxycarbonyl, 1 , 1 -diphenylpropyl- 1 -oxycarbonyl, 2-(3 ,5- dimethoxyphenyl)propyl-2-oxycarbonyl ("Ddz"), 2-(p-toluyl)propyl-2-oxycarbonyl, cyclopentanyloxycarbonyl, 1-methylcyclopentanyloxycarbonyl, cyclohexanyloxy- carbonyl, 1-methylcyclohexanyloxycarbonyl, 2-methylcyclohexanyloxycarbonyl, 2- (4-toluylsulfonyl)-ethoxycarbonyl, 2-(methylsulfonyl)ethoxycarbonyl, 2-(triphenylphosphino)-ethoxycarbonyl, 9-fluorenylmethoxycarbonyl ("Fmoc"), 2-(trimethylsilyl)ethoxycarbonyl, allyloxycarbonyl, l-(trimethylsilylmethyl)prop-l- enyloxycarbonyl, 5-benzisoxalylmethoxycarbonyl, 4-acetoxybenzyl-oxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-ethynyl-2-propoxycarbonyl, cyclopropylmethoxycarbonyl, isobornyloxycarbonyl, 1-piperidyloxycarbonyl, benzyloxycarbonyl ("Cbz"), 4-phenylbenzyloxycarbonyl, 2-methylbenzyloxy- carbonyl, -2,4,5,-tetramethylbenzyloxycarbonyl ("Tmz"), 4-methoxybenzyloxycarbonyl, 4-fluorobenzyloxycarbonyl, 4-chlorobenzyloxycarbonyl, 3-chlorobenzyloxycarbonyl, 2-chlorobenzyloxycarbonyl, 2,4-dichlorobenzyl-oxycarbonyl, 4-bromobenzyloxycarbonyl, 3-bromobenzyloxycarbonyl, 4-nitrobenzyloxy-carbonyl, 4-cyanobenzyloxycarbonyl, 4-(decyloxy)benzyloxycarbonyl and the like; the benzoylmethylsulfonyl group, dithiasuccinoyl ("Dts"), the 2-(nitro)phenylsulfenyl group ("Nps"), the diphenyl- phosphine oxide group and like amino-protecting groups. The species of amino- protecting group employed is not critical so long as the derivatized amino group is stable to the conditions of the subsequent reaction(s) and can be removed at the appropriate point without disrupting the remainder of the compounds. Preferred amino-protecting groups are Boc, Cbz and Fmoc. Further examples of amino- protecting groups embraced by the above term are well known in organic synthesis and the peptide art and are described by, for example, T. W. Greene and P.G.M. Wuts, "Protective Groups in Organic Synthesis," 2nd ed., John Wiley and Sons, New York, NY, 1991, Chapter 7, M. Bodanzsky, "Principles of Peptide Synthesis," 1st and 2nd revised ed., Springer- Verlag, New York, NY, 1984 and 1993, and Stewart and Young, "Solid Phase Peptide Synthesis," 2nd ed., Pierce Chemical Co., Rockford, IL, 1984, each of which is incorporated herein by reference. The related term "protected amino" defines an amino group substituted with an amino-protecting group discussed above. The term "protected guanidino" as used herein refers to an "amino-protecting group" on one or two of the guanidino nitrogen atoms. Examples of "protected guanidino" groups are described by TW. Greene and P.G.M. Wuts; M. Bodanzsky; and Stewart and Young, supra. The term "epimino" means -NH-. The term "substituted epimino" means -N(R)-, where R is a substitution group listed above under the definition of "(monosubstituted)amino." The term "C₁ to C₅ alkylene epimino" refers to a one to five carbon alkylene chain with an epimino at any point along the chain. The term "C₁ to C₅ substituted alkylene epimino" refers to a C₁ to C₅ alkylene epimino group that is substituted a) at the epimino position (in the same way as "substituted epimino," described above); and/or b) at one or more of the alkylene positions (in the same way as "substituted alkylene," as described above). The term "thio" refers to -SH or, if between two other groups, -S-. The term "C₁ to C₁₀ alkylene thio" refers to a one to ten carbon alkylene chain with a thio at any point along the chain. The term "C₁ to C₁₀ substituted alkylene thio" refers to a C₁ to C₁₀ alkylene thio group that is substituted at one or more of the alkylene positions (in the same way as "substituted alkylene," as described above). The term "sulfonyl" refers to -S(O)₂-. The term "C₁ to C₁₀ alkylene sulfonyl" refers to a one to ten carbon alkylene chain with a sulfonyl at any point along the chain. The term "C₁ to C₁₀ substituted alkylene sulfonyl" refers to a C₁ to C₁₀ alkylene sulfonyl group that is substituted at one or more of the alkylene positions (in the same way as "substituted alkylene," as described above). The term "sulfinyl" refers to -S(O)-. The term "C₁ to C₁₀ alkylene sulfinyl" refers to a one to ten carbon alkylene chain with a sulfinyl at any point along the chain. The term "C₁ to C₁₀ substituted alkylene sulfinyl" refers to a C₁ to C₁₀ alkylene sulfinyl group that is substituted at one or more of the alkylene positions (in the same way as "substituted alkylene," as described above). The term "oxy" refers to -O-. The terms "C₁ to C₁₀ alkylene oxy," "C₁ to C₁₀ alkylene dioxy" and "C₁ to C₁₀ alkylene trioxy" refer to a one to ten carbon alkylene chain with, respectively, one, two or three -O- at any point along the chain, provided that no two oxygen atoms are consecutive, and provided that any two oxygen atoms are separated by at least two carbons. The terms "C₁ to C₁₀ substituted alkylene oxy," "C₁ to C₁₀ substituted alkylene dioxy" and "C₁ to C₁₀ substituted alkylene trioxy" refer, respectfully to "C₁ to C₁₀ alkylene oxy," "C₁ to C₁₀ alkylene dioxy" and "C₁ to C₁₀ alkylene trioxy" that are substituted at one or more of the alkylene positions (in the same way as "substituted alkylene," as described above). The term "thiocarbonyl" refers to -C(S)H or, if between two other groups, - C(S)-. The term "thioester" refers to -C(O)SH or, if between two other groups, C(O)S-. The term "carboxy-protecting group" as used herein refers to one of the ester derivatives of the carboxylic acid group commonly employed to block or protect the carboxylic acid group while reactions are carried out on other functional groups on the compound. Examples of such carboxylic acid protecting groups include t-butyl, 4-nitrobenzyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, 2,4-dimethoxybenzyl, 2,4,6-trimethoxybenzyl, 2,4,6-trimethylbenzyl, pentamethylbenzyl, 3,4- methylenedioxybenzyl, benzhydryl, 4,4'-dimethoxytrityl, 4,4',4"-trimethoxytrityl, 2-phenylpropyl, trimethylsilyl, t-butyldimethylsilyl, phenacyl, 2,2,2-trichloroethyl, (trimethylsilyl)ethyl, (di(n-butyl)methylsilyl)ethyl, p- toluenesulfonylethyl, 4- nitrobenzylsulfonylethyl, allyl, cinnamyl, l-(trimethylsilylmethyl)propenyl and like moieties. The species of carboxy-protecting group employed is not critical so long as the derivatized carboxylic acid is stable to the conditions of subsequent reaction(s) and can be removed at the appropriate point without disrupting the remainder of the molecule. Further examples of these groups are found in E. Haslam, "Protective Groups in Organic Chemistry," J.G.W. McOmie, Ed., Plenum Press, New York, NY, 1973, Chapter 5, and T. W. Greene and P.G.M. Wuts, "Protective Groups in Organic Synthesis," 2nd ed., John Wiley and Sons, New York, NY, 1991, Chapter 5, each of which is incorporated herein by reference. A related term is "protected carboxy," which refers to a carboxy group substituted with one of the above carboxy-protecting groups. The term "hydroxy-protecting group" refers to readily cleavable groups bonded to hydroxyl groups, such as the tetrahydropyranyl, 2-methoxy propyl, 1- ethoxyethyl, methoxymethyl, 2-methoxy ethoxymethyl, methylthiomethyl, t-butyl, t- amyl, trityl, 4-methoxytrityl, 4,4'-dimethoxytrityl, 4,4',4"-trimethoxytrityl, benzyl, allyl, trimethylsilyl, (t-butyl)dimethylsilyl, 2,2,2-trichloroethoxycarbonyl groups and the like. The species of hydroxy-protecting groups is not critical so long as the derivatized hydroxyl group is stable to the conditions of subsequent reaction(s) and can be removed at the appropriate point without disrupting the remainder of the molecule. Further examples of hydroxy-protecting groups are described by CB. Reese and E. Haslam, "Protective Groups in Organic Chemistry," J.G.W. McOmie, Ed., Plenum Press, New York, NY, 1973, Chapters 3 and 4, respectively, and T. W. Greene and P.G.M. Wuts, "Protective Groups in Organic Synthesis," 2nd ed., John Wiley and Sons, New York, NY, 1991, Chapters 2 and 3. Related terms are "protected hydroxy," and "protected hydroxymethyl" which refer to a hydroxy or hydroxymethyl substituted with one of the above hydroxy-protecting groups. The term "C₁ to C₁₀ alkylthio" refers to sulfide groups such as methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, t-butylthio and like groups. The term "C₁ to C₁₀ alkylsulfoxide" indicates sulfoxide groups such as methylsulfoxide, ethylsulfoxide, n-propylsulfoxide, isopropylsulfoxide, n- butylsulfoxide, sec-butylsulfoxide and the like. The term "C₁ to C₁₀ alkylsulfonyl" encompasses groups such as methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, t-butylsulfonyl and the like, it should also be understood that the above thio, sulfoxide or sulfonyl groups can be at any point on the alkyl chain (e.g., 2-methylmercaρtoethyl). The terms "C₁ to C₁₀ substituted alkylthio," "C₁ to C₁₀ substituted alkylsulfoxide," and "C₁ to C₁₀ substituted alkylsulfonyl," denote the C₁ to C₁₀ alkyl portion of these groups may be substituted as described above in relation to "substituted alkyl." The terms "phenylthio," "phenylsulf oxide," and "phenylsulfonyl" specify a thiol, a sulfoxide, or sulfone, respectively, containing a phenyl group. The terms "substituted phenylthio," "substituted phenylsulf oxide," and "substituted phenylsulfonyl" means that the phenyl of these groups can be substituted as described above in relation to "substituted phenyl." The term "C₁ to C₁₂ alkylaminocarbonyl" means a C₁ to C₁₂ alkyl attached to a nitrogen of the aminocarbonyl group. Examples of C₁ to C₁₂ alkylaminocarbonyl include methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl and butylaminocarbonyl. The term "C₁ to C₁₂ substituted alkylaminocarbonyl" denotes a substituted alkyl bonded to a nitrogen of the aminocarbonyl group, which alkyl may be substituted as described above in relation to C₁ to C₁₂ substituted alkyl. Examples of C₁ to C₁₂ substituted alkylaminocarbonyl include, for example, methoxymethylaminocarbonyl, 2-chloroethylaminocarbonyl, 2- oxopropylaminocarbonyl and 4-phenylbutylaminocarbonyl. The term "C₁ to C₁₂ alkoxycarbonyl" means a "C₁ to C₁₂ alkoxy" group attached to a carbonyl group. The term "C₁ to C₁₂ substituted alkoxycarbonyl" denotes a substituted alkoxy bonded to the carbonyl group, which alkoxy may be substituted as described above in relation to "C₁ to C₁₂ substituted alkyl." The term "phenylaminocarbonyl" means a phenyl attached to a nitrogen of the aminocarbonyl group. The term "substituted phenylaminocarbonyl" denotes a substituted phenyl bonded to a nitrogen of the aminocarbonyl group, which phenyl may be substituted as described above in relation to substituted phenyl. Examples of substituted phenylaminocarbonyl include 2-chlorophenylaminocarbonyl, 3- chlorophenylaminocarbonyl , 2-nitorphenylaminocarbonyl, 4-biphenylaminocarbonyl, and 4-methoxyphenylaminocarbonyl. The term "C₁ to C₁₂ alkylaminothiocarbonyl" means a C₁ to C₁₂ alkyl attached to an aminothiocarbonyl group, wherein the alkyl has the same meaning as defined above. Examples of C₁ to C₁₂ alkylaminothiocarbonyl include methylaminothiocarbonyl, ethylaminothiocarbonyl, propylaminothiocarbonyl and butylaminothiocarbonyl. The term "C₁ to C₁₂ substituted alkylaminothiocarbonyl" denotes a substituted alkyl bonded to an aminothiocarbonyl group, wherein the alkyl may be substituted as described above in relation to C₁ to C₁₂ substituted alkyl. Examples of C₁ to C₁₂ substituted alkylaminothiocarbonyl include, for example, methoxymethylaminothiocarbonyl, 2-chloroethylaminothiocarbonyl, 2-oxopropylaminothiocarbonyl and 4-phenylbutylaminothiocarbonyl. The term "phenylaminothiocarbonyl" means a phenyl attached to an aminothiocarbonyl group, wherein the phenyl has the same meaning as defined above. The term "substituted phenylaminothiocarbonyl" denotes a substituted phenyl bonded to an aminothiocarbonyl group, wherein phenyl may be substituted as described above in relation to substituted phenyl. Examples of substituted phenylaminothiocarbonyls include 2-chlorophenylaminothiocarbonyl, 3-chlorophenylaminothiocarbonyl, 2-nitorphenylaminothiocarbonyl, 4- biphenylaminothiocarbonyl and 4-methoxyphenylaminothiocarbonyl. The term "phenylene" means a phenyl group where the phenyl radical is bonded at two positions connecting together two separate additional groups. Examples of "phenylene" include 1,2-phenylene, 1,3-phenylene, and 1,4-phenylene. The term "substituted phenylene" means a phenyl group where the phenyl radical is bonded at two positions connecting together two separate additional groups, wherein the phenyl is substituted as described above in relation to "substituted phenyl." The term "substituted C_j to C₁₂ alkylene" means a C₁ to C₁₂ alkyl group where the alkyl radical is bonded at two positions connecting together two separate additional groups and further bearing an additional substituent. Examples of "substituted C₁ to C₁₂ alkylene" includes aminomethylene, l-(amino)-l,2-ethyl, 2- (amino)-l,2-ethyl, l-(acetamido)-l,2-ethyl, 2-(acetamido)-l,2-ethyl, 2-hydroxy-l,l- ethyl, l-(amino)-l,3-propyl. The terms "cyclic C₂ to C₇ alkylene," "substituted cyclic C₂ to C₇ alkylene," "cyclic C₂ to C₇ heteroalkylene," and "substituted cyclic C₂ to C₇ heteroalkylene," defines such a cyclic group bonded ("fused") to the phenyl radical resulting in a bicyclic ring system. The cyclic group may be saturated or contain one or two double bonds. Furthermore, the cyclic group may have one or two methylene or methine groups replaced by one or two oxygen, nitrogen or sulfur atoms which are the cyclic C₂ to C₇ heteroalkylene. The cyclic alkylene or heteroalkylene group may be substituted once or twice by the same or different substituents which, if appropriate, can be connected to another part of the compound (e.g., alkylene) selected from the group consisting of the following moieties: hydroxy, protected hydroxy, carboxy, protected carboxy, oxo, protected oxo, C₁ to C₄ acyloxy, formyl, C₁ to C₁₂ acyl, C₁ to C₁₂ alkyl, C₁ to C₇ alkoxy, C₁ to C₁₀ alkylthio, C₁ to C₁₀ alkylsulfoxide, C₁ to C₁₀ alkylsulfonyl, halo, amino, protected amino, (monosubstituted)amino, protected (monosubstituted)amino, (disubstituted)amino, hydroxymethyl or a protected hydroxymethyl. The cyclic alkylene or heteroalkylene group fused onto the benzene radical can contain two to ten ring members, but it preferably contains three to six members. Examples of such saturated cyclic groups are when the resultant bicyclic ring system is 2,3-dihydro-indanyl and a tetralin ring. When the cyclic groups are unsaturated, examples occur when the resultant bicyclic ring system is a naphthyl ring or indolyl. Examples of fused cyclic groups which each contain one nitrogen atom and one or more double bond, preferably one or two double bonds, are when the benzene radical is fused to a pyridino, pyrano, pyrrolo, pyridinyl, dihydropyrrolo, or dihydropyridinyl ring. Examples of fused cyclic groups which each contain one oxygen atom and one or two double bonds are when the benzene radical ring is fused to a furo, pyrano, dihydrofurano, or dihydropyrano ring. Examples of fused cyclic groups which each have one sulfur atom and contain one or two double bonds are when the benzene radical is fused to a thieno, thiopyrano, dihydrothieno or dihydrothiopyrano ring. Examples of cyclic groups which contain two heteroatoms selected from sulfur and nitrogen and one or two double bonds are when the benzene radical ring is fused to a thiazolo, isothiazolo, dihydrothiazolo or dihydroisothiazolo ring. Examples of cyclic groups which contain two heteroatoms selected from oxygen and nitrogen and one or two double bonds are when the benzene ring is fused to an oxazolo, isoxazolo, dihydrooxazolo or dihydroisoxazolo ring. Examples of cyclic groups which contain two nitrogen heteroatoms and one or two double bonds occur when the benzene ring is fused to a pyrazolo, imidazolo, dihydropyrazolo or dihydroimidazolo ring or pyrazinyl. The term "carbamoyl" means an -NC(O)- group where the radical is bonded at two positions connecting two separate additional groups. One or more of the compounds of the invention, even within a given library, may be present as a salt. The term "salt" encompasses those salts that form with the carboxylate anions and amine nitrogens and include salts formed with the organic and inorganic anions and cations discussed below. Furthermore, the term includes salts that form by standard acid-base reactions with basic groups (such as amino groups) and organic or inorganic acids. Such acids include hydrochloric, hydrofluoric, trifluoroacetic, sulfuric, phosphoric, acetic, succinic, citric, lactic, maleic, fumaric, palmitic, cholic, pamoic, mucic, D-glutamic, D-camphoric, glutaric, phthalic, tartaric, lauric, stearic, salicyclic, methanesulfonic, benzenesulfonic, sorbic, picric, benzoic, cinnamic, and like acids. The term "organic or inorganic cation" refers to counter-ions for the carboxylate anion of a carboxylate salt. The counter-ions are chosen from the alkali and alkaline earth metals, (such as lithium, sodium, potassium, barium, aluminum and calcium); ammonium and mono-, di- and tri-alkyl amines such as trimethylamine, cyclohexylamine; and the organic cations, such as dibenzylammonium, benzylammonium, 2-hydroxyethylammonium, bis(2-hydroxyethyl)ammonium, phenylethylbenzylammonium, dibenzylethylenediammonium, and like cations. See, for example, "Pharmaceutical Salts," Berge et al., J. Pharm. Sci., 66: 1-19 (1977), which is incorporated herein by reference. Other cations encompassed by the above term include the protonated form of procaine, quinine and N-methylglucosamine, and the protonated forms of basic amino acids such as glycine, ornithine, histidine, phenylglycine, lysine and arginine. Furthermore, any zwitterionic form of the instant compounds formed by a carboxylic acid and an amino group is referred to by this term. For example, a cation for a carboxylate anion will exist when a position is substituted with a (quaternary ammonium)methyl group. A preferred cation for the carboxylate anion is the sodium cation. The compounds of the invention can also exist as solvates and hydrates. Thus, these compounds may crystallize with, for example, waters of hydration, or one, a number of, or any fraction thereof of molecules of the mother liquor solvent. The solvates and hydrates of such compounds are included within the scope of this invention. One or more compounds of the invention can be in the biologically active ester form, such as the non-toxic, metabolically-labile ester-form. Such ester forms induce increased blood levels and prolong the efficacy of the corresponding non- esterified forms of the compounds. Ester groups which can be used include the lower alkoxymethyl groups, for example, methoxymethyl, ethoxymethyl, isopropoxymethyl and the like; the -(C₁ to C₁₂) alkoxyethyl groups, for example methoxyethyl, ethoxyethyl, propoxyethyl, isopropoxyethyl and the like; the 2-oxo-l,3-diooxlen-4- ylmethyl groups, such as 5-methyl-2-oxo-l,3-dioxolen-4-ylmethyl, 5-ρhenyl-2-oxo- l,3-dioxolen-4-ylmethyl and the like; the C₁ to C₁₀ alkylthiomethyl groups, for example methylthiomethyl, ethylthiomethyl, iso-propylthiomethyl and the like; the acyloxymethyl groups, for example pivaloyloxymethyl, pivaloyloxyethyl, - acetoxymethyl and the like; the ethoxycarbonyl-1-methyl group; the -acetoxy ethyl; the 1-(C₁ to C₁₂ alkyloxycarbonyloxy)ethyl groups such as the 1- (ethoxycarbonyloxy)ethyl group; and the 1-(C₁ to C₁₂ alkylaminocarbonyloxy)ethyl groups such as the l-(methylaminocarbonyloxy)ethyl group. The term "amino acid" includes any one of the twenty naturally-occurring amino acids or the D-form of any one of the naturally-occurring amino acids. In addition, the term "amino acid" also includes other non-naturally occurring amino acids besides the D-amino acids, which are functional equivalents of the naturally- occurring amino acids. Such non-naturally-occurring amino acids include, for example, norleucine ("NIe"), norvaline ("Nva"), L- or D- naphthalanine, ornithine ("Orn"), homoarginine (homoArg) and others well known in the peptide art, such as those described in M. Bodanzsky, "Principles of Peptide Synthesis," 1st and 2nd revised ed., Springer- Verlag, New York, NY, 1984 and 1993, and Stewart and Young, "Solid Phase Peptide Synthesis," 2nd ed., Pierce Chemical Co., Rockford, IL, 1984, both of which are incorporated herein by reference. Amino acids and amino acid analogs can be purchased commercially (Sigma Chemical Co.; Advanced Chemtech) or synthesized using methods known in the art. It should be understood that any position of the claimed invention has up to three serial "substitutions." For example, a "substituted alkyl" that is substituted with a "substituted phenyl" that is, in turn, substituted with a "substituted alkyl" can, in turn, be susbstitued by one more group and no longer further substituted. However, it should also be understood that the invention contemplates, if appropriate, more than three parallel substitutions. For example, if appropriate, more than three hydrogens on an alkyl moiety may be substituted with any one or more of a variety of groups, including halo and hydroxy. As used herein, "small interfering RNAs" (siRNA) are short double-stranded RNA fragments that elicit a process known as "RNA interference" (RNAi), a form of sequence-specific gene silencing. Zamore, Phillip et al., Cell 101:25-33(2000); Elbashir, Sayda M., et al.. Nature 411:494-497 (2001). SiRNAs are assembled into a multi-component complex known as the RNA-induced silencing complex (RISC). The siRNAs guide RISC to homologous mRNAs, thus targeting them for destruction. Hammond et al., Nature Genetics Reviews 2: 110-119(2000). RNAi has been observed in a variety of organisms including plants, insects and mammals. An "siRNA" is a double-stranded RNA that is preferably between 16 and 25, more preferably 17 and 23 and most preferably between 18 and 21 base pairs long, each strand of which has a 3' overhang of 2 or more nucleotides. Functionally, the characteristic distinguishing an siRNA over other forms of dsRNA is that the siRNA comprises a sequence capable of specifically inhibiting genetic expression of a gene or closely related family of genes by a process termed RNA interference. siRNAs for use in the present invention can be produced from a MNR encoding nucleic acid sequence. For example, short complementary DNA strands are first prepared that represent portions of both the "sense" and "antisense" strands of the MNR coding region. This is typically accomplished using solid phase nucleic acid synthesis techniques, as known in the art. The short duplex DNA thus formed is ligated into a suitable vector that is then used to transfect a suitable cell line. Other methods for producing siRNA molecules are known in the art. (See, e.g., Elbashir, S.M., Harborth, J., Lendeckel, W., Yalcin, A., Weber, K., and Tuschl, T. (2001) Duplexes of 21 -nucleotide RNAs mediate RNA interference in cultured mammalian cells. Nature 411:494-498). Libraries of siRNAs specific for MNR can be constructed by, for example, mechanically shearing MNR cDNA, ligating the resulting fragments into suitable vector constructs and transfecting a suitable host cell with the vectors. For a review of RNAi and siRNA expression, see Hammond, Scott M. et al, Nature Genetics Reviews, 2:110-119; Fire, Andrew (1999) TIG, 15(9):358- 363; Bass, Brenda L. (2000) Cell, 101:235-238. The targeting of antisense oligonucleotides to mRNA is another mechanism of decreasing protein synthesis, and, consequently, represents a powerful and targeted approach to diminishing MNR expression. For example, the synthesis of polygalactauronase and the muscarine type 2 acetylcholine receptor are inhibited by antisense oligonucleotides directed to their respective mRNA sequences (U.S. Pat. Nos. 5,739,119 and 5,759,829, each specifically incorporated herein by reference in its entirety). Further, examples of antisense inhibition have been demonstrated with the nuclear protein cyclin, the multiple drug resistance gene (MDGl), ICAM-I, E- selectin, STK-I, striatal GABA.sub.A receptor and human EGF (Jaskulski et al., 1988; Vasanthakumar and Ahmed, 1989; Peris et al, 1998; U.S. Pat. Nos. 5,801,154; 5,789,573; 5,718,709 and 5,610,288, each specifically incorporated herein by reference in its entirety). Antisense constructs have also been described that inhibit and can be used to treat a variety of abnormal cellular proliferations, e.g. cancer (U.S. Pat. Nos. 5,747,470; 5,591,317 and 5,783,683, each specifically incorporated herein by reference in its entirety). The invention provides therefore oligonucleotide sequences that comprise all, or a portion of, any sequence that is capable of specifically binding to a polynucleotide sequence described herein, or a complement thereof. In one embodiment, the antisense oligonucleotides comprise DNA or derivatives thereof. In another embodiment, the oligonucleotides comprise RNA or derivatives thereof. In a third embodiment, the oligonucleotides are modified DNAs comprising a phosphorothioated modified backbone. In a fourth embodiment, the oligonucleotide sequences comprise peptide nucleic acids or derivatives thereof. Selection of antisense compositions specific for a given gene sequence is based upon analysis of the chosen target sequence and determination of secondary structure, binding energy, relative stability, and antisense compositions were selected based upon their relative inability to form dimers, hairpins, or other secondary structures that would reduce or prohibit specific binding to the target mRNA in a host cell. When treating Type II diabetes or hyperglycemia, generally satisfactory results are obtained when the compounds of the present invention are administered at a daily dosage of from 0.01 milligrams to about 100 milligrams per kilogram of subject body weight, preferably given in a single dose or in divided doses two to six times a day, or in sustained release form. In the case of a 70kg adult human, the total daily dose will generally be from about 0.7 milligrams to about 3500 milligrams. This dosage regimen may be adjusted to provide the optimal therapeutic response and preferably given in a single dose or in divided doses two to six times a day, or in sustained release form. To make the compounds of the present invention more selective for targeting the liver, they can be conjugated with a bile acid, for example, cholate. Such conjugates can achieve the desired results while minimizing undesirable peripheral effects. Such conjugates can also provide a sustained release delivery mechanism due to their ability to be reabsorbed. Methods of such conjugation are disclosed in WO 00/58337 (PCT No. EP00/02429); and Kramer et al., Biol. Chem.. 267:18598-604 (1992). Methods of testing compounds, such as those of the present invention, for conditions such as Type II diabetes or hyperglycemia, are disclosed for example in WO 98/27986 (PCT US 97/24237). Such methods include testing in animal models such as mice. The following examples are intended to illustrate but not limit the present invention. EXAMPLES Example 1 This example describes the G6Pase/luciferase assay utilized for the discovery and validation of the role of MNR in the regulation of glucose in the liver, in accordance with the present invention. G6Pase catalyzes the hydrolysis of glucose-6-phosphate to glucose, which is the final step of both hepatic gluconeogenesis and of glycogen breakdown in the liver. G6Pase is induced in starved and diabetic animals when glucagon levels are increased and insulin levels decrease. In vitro models have shown that both glucocorticoids and cAMP induce G6Pase expression at the transcriptional level. This effect is opposed by insulin, which reduces the basal expression of the G6Pase gene thereby lowering blood sugar. In light of these facts, a cell-based reporter assay was developed based upon a modified G6Pase promoter driving expression of the luciferase gene. A 300bp region of the G6Pase promoter was cloned upstream of the luciferase gene that included insulin receptor responsive elements, glucocorticoid responsive elements and cAMP responsive elements. The construct was then transfected into hepatoma cells, and the activity of the GόPase promoter was assayed by means of a luciferase activity assay. Treatment of the cells with agents that promote GόPase transcription in physiological conditions, such as glucocorticoids (e.g., dexamethasone) or activation of the glucagon receptor (e.g., dibutyril-cAMP) resulted in increased luciferase expression. Treatment of the cells with agents that inhibit G6Pase transcription in physiological conditions, such as insulin, resulted in decreased luciferase expression. Experimental results validating the utility of this assay are shown in Figure 1. The 300bp GβPase construct was transfected into HepG2 cells using Lipofectamine 2000™, with a Renilla Luciferase reporter co-transfected for normalization. Sixteen hours after transfection, the cells were shocked with glycerol for two minutes and then treated for 16 hours with dexamethasone ("DEX"), or with dibutyril-cAMP ("db"), or with insulin ("ins"), or with a combination of dexamethasone and dibutyril- c AMP, or with a combination of dexamethasone and dibutyril-cAMP and insulin. Luciferase was measured (white bars) using the Promega Corporation (Madison, WI) Dual-Luciferase® Reporter Assay System, with values normalized based on Renilla Luciferase activity (N=3). RNA samples of GόPase from sub-confluent cultures were prepared in parallel by standard procedures, and real-time PCR (RT-PCR) was performed on the samples. GόPase mRNA level was normalized to the internal ribosomal 18S RNA control level (in Figure 1, relative mRNA levels are depicted as arbitrary units). Figure 2 shows the results of the identical experiment using HuH7 cells. These results lead to the conclusion that the glucocorticoid receptor is either poorly expressed or inactive in HuH7 cells and that the cell line is not responsive to insulin in this assay.

Example 2 This example shows that the MNR is expressed in liver cells. RNA samples from sub-confluent cultures of liver, heart and kidney tissues were prepared by standard procedures, and real-time PCR (RT-PCR) was performed on these samples. The relative levels of MNR mRNA in liver, heart and kidney are shown in Figure 3. "Ct" (y axis) is the average cycle of threshold, the cycle at which the fluorescence signal from the probe dye rises above the baseline signal of the dye mRNA levels. Under this experimental setup, genes expressed at very high level (such as ribosomal RNA) have Ct<19; high level mRNA transcripts have 19>Ct<24; medium level have 24>Ct<28; low level have 28>Ct<30; and very low level have Ct<30. The expression of MNR mRNA in HeLa, HuH7 and HepG2 cells, and in primary human hepatocytes, was also measured. RNA samples from sub-confluent cultures were prepared by standard procedures and real-time PCR (RT-PCR) was performed on these samples. The results are shown in Figure 4. Western Blot analysis of the expression of MNR protein in HepG2 cells and in primary human hepatocytes (HPP) was also carried out. Protein extracted from HepG2 cells and HPP were run in a 6% SDS-PAGE gel and blotted onto a nitrocellulose membrane. MNR antibody (H-300) from Santa Cruz Biotechnology was used at 1:200 dilution, with rabbit IgG antibody used as a negative control. Figure 5 provides photographs of the gels, showing the positions of molecular weight markers; arrows indicate the MNR band.

Example 3 This example shows that knock-down of the MNR gene reduces expression of GόPase. Five different siRNAs against MNR were constructed, having the following sequences:

Vectors expressing these five siRNAs, as well as two scrambled control siRNAs (PSD224 and PSD277) and a luciferase positive control siRNA (PSD105) were transiently transfected into HepG2 cells (plated in 96-well plates) along with the GόPase/Luciferase reporter plasmids, using Lipofectamine 2000™. The vectors were constructed as described in WO 2004/009794. After 16 hours, the cells were induced to express the reporter with a glycerol shock and dexamethasone and dbcAMP. Luciferase was measured on the following day, as described above. Figure 6 presents the results (averages and SEM) of three separate experiments, each having six independent wells. They show that all five siRNAs targeting MNR caused a reduction in the expression of the GόPase reporter, while the scrambled control siRNAs did not affect GόPase activity. In a separate experiment, the siRNA labeled MNR294 (SEQ ID NO:2) was stably transduced into HepG2 cells (plated in 96-well plates) as a "hairpin" siRNA in accordance with the teachings of WO 2004/009796, utilizing the ρBSK+ plasmid (Stratagene). The full sequence of this siRNA construct was: 5'-AATCTAAGGAACTTTCAGCAACTTCTCTTGAAAGTTGCTGAAAGTT CCTTAGATT-3' (SEQ ID NO:6; sequence of the sense strand marked in bold). Figure 7 shows the average and standard deviation for six independent wells. As can be seen, the silencing of MNR by this siRNA transfected in this manner was also effective in down-regulating expression of GόPase, as measured by the Luciferase reporter. To further confirm the correlation between siRNA silencing of MNR and inhibition of GόPase expression, the five siRNAs described above were also transfected into HeLa cells, utilizing the same procedure as described above. HeLa cells were chosen both because they express MNR (see Figure 4) and because they are capable of being transfected with high efficiency (which is required to assess knock-down effectively). RNA samples from sub-confluent cultures were prepared using standard procedures, and real-time (RT-PCR) was performed on these samples. The results are shown in Figure 8 (MNR mRNA normalized to the internal ribosomal 18S RNA control level; relative mRNA levels depicted as arbitrary units and normalized to transfection efficiency (70%)). As shown in Figure 8, four of the five siRNAs caused marked reduction in MNR mRNA. Further confirmation was obtained based upon Taqman® analysis of a HepG2 cell line which had been stably transduced with the hairpin siRNA (SEQ ID NO: 6) described above. As shown in Figures 9 A and 9B, a significant knock-down of both MNR mRNA (Figure 9A) and GόPase mRNA (Figure 9B) was observed. Example 4 This example shows that treatment of liver cells with a small-molecule antagonist of MNR, a molecule of the present invention, causes a marked reduction in GόPase activity. HepG2 cells were plated in 96-well plates and transfected the following day with the GόPase reporter construct. After 16 hours, the cells were induced to express the reporter with a glycerol shock and dexamethasone (lμM) and dbcAMP (500μM), in the presence or absence of 50μM and lOOμM concentrations of spironolactone dissolved in ethyl alcohol. GόPase expression was assayed the following day, as described above. Figure 10 shows the results (averages and SEM) of three independent experiments. As can be seen, both concentrations of this known MNR antagonist were effective in reducing the level of GόPase expression. Note that dexamethasone also acts as a MNR agonist and that a 50-fold excess of antagonist (spironolactone) over the agonist (dexamethasone) was required to lower GόPase expression. Based upon this, it is predicted that in vivo the level of MNR antagonist in blood serum that will be needed will be in the nanomolar range. The mRNA level of the endogenous GόPase gene in these cells after treatment with spironolactone was also measured. RNA samples from sub-confluent cultures were prepared by standard procedures, and real-time PCR (RT-PCR) was performed on these samples. The results are depicted in Figure 11, with the MNR mRNA level normalized to the internal ribosomal 18S RNA control level (relative mRNA levels depicted as arbitrary units). As can be seen, these results correlated well with the results of the GόPase/luciferase assay. A similar experiment was conducted using HuH7 cells which we have shown to be insensitive to insulin. Three different concentrations of the MNR antagonist spironolactone were used ~ lμM, 50μM and 100μM. The results (averages and SEM of six independent wells) are shown in Figure 12. As shown in Figure 12, even the lowest concentration of this MNR antagonist was effective in reducing expression of GόPase as compared to insulin. The effect of several additional MNR antagonists (RU28318 and R305847) on GόPase expression in HepG2 cells was also tested, with the results shown in Figure 13. HepG2 cells were seeded in 96-well plates, and transfected the following day with the GόPase reporter construct. After 16 hours, the cells were induced to express the reporter with glycerol shock and dexamethasone and dbcAMP in the presence of 50μM of each of the following MNR antagonists: spironolactone, RU28318 and R305847. A glucocorticoid anatagonist, RU486, was used as a positive control. Luciferase was measured on the following day, as described above. Figure 13 shows the averages and SEM for three independent experiments for each of the reagents. As shown in Figure 13, each of the MNR antagonists caused a marked reduction in the expression of GόPase.

Example 5 This example shows that RNAi-mediated silencing of MNR modulates the expression of several different genes involved in hepatic glucose output. The ability of the MNR to affect the expression of two additional gluconeogenic genes (phosphoenolpyruvate carboxykinase ("PEPCK") and 1, 6 fructose biphosphatase ("FBPl")) was tested in two independently established HepG2 polyclonal cell lines and in HuH7 cells stably transduced with a hairpin siRNA (shRNA) targeting the MNR. HepG2 and HuH7 cells were stably transduced with a lentiviral vector that expresses siRNA MNR294 or a control shRNA. mRNA from the cell lines was then extracted using standard procedures. The PEPCK and FBPl transcripts levels were quantified using real-time PCR, with 18S levels used for normalization. The results are shown in Figure 14. mRNA levels are depicted relative to the expression of the transcript in the cell line stably-transfected with the control shRNA. These results suggest a broad involvement of the MNR in hepatic glucose output.

Claims

1. Use of an antagonist of the mineralcorticoid receptor in the manufacture of a medicament for the treatment of a disease condition characterized by hyperglycemia.

2. The use of claim 1 wherein the disease condition is Type II diabetes milletus.

3. The use of claim 1 wherein the antagonist comprises an siRNA.

4. The use of claim 1 wherein the antagonist is a small organic molecule.

5. The use of claim 1 wherein the antagonist is a steroidal derivative.

6. The use of claim 1, wherein the antagonist has the core formula (I):

wherein:

the dotted lines denote optional double bonds; X is a carbon atom; R₁ is selected from the group consisting of hydrogen, -C(O)-Y, -C(O)-O-Y, C₁ to C₆ alkyl, C₁ to C₆ substituted alkyl, nitro and amino, and Y is selected from the group consisting of hydrogen, C₁ to C₆ alkyl and C₁ to C₆ substituted alkyl; R₂ is selected from the group consisting of hydrogen and halo; R₃ is selected from the group consisting of hydrogen and hydroxyl; or R₂ and R₃ combine to form -O- (epoxy) or -CH₂- (methylene); R₄ is selected from the group consisting of hydrogen, hydroxyl, C₁ to C₆ alkyl and C₁ to C₆ substituted alkyl; or R₃ and R₄ combine to form -0-CH₂-; R₅ and R₆ are, independently, selected from the group consisting of hydrogen, hydroxyl, -C(O)-Y, -C(O)-O-Y, C₁Io C₆ alkyl and C₁ to C₆ substituted alkyl, and Y is selected from the group consisting of hydrogen, Cj to C₆ alkyl and C₁ to C₆ substituted alkyl; or R₅ and R₆ and X of the core formula combine to form

where R₁₃ and R₁₄ are, independently, selected from the group consisting of hydrogen, hydroxyl, oxo, -C(O)-Y, -C(O)-O-Y, C₁ to C₆ alkyl and C₁ to C₆ substituted alkyl, and Y is selected from the group consisting of hydrogen, C₁ to C₆ alkyl and C₁ to C₆ substituted alkyl; Z is selected from the group consisting of hydrogen, hydroxyl and oxo; R₇ is selected from the group consisting of hydrogen, hydroxyl and oxo; R₈ is selected from the group consisting of hydrogen, hydroxyl and halo; R₉ is selected from the group consisting of hydrogen, hydroxyl, -C(O)-Y, - C(O)-O-Y, -S-C(O)-Y, -S-C(O)-O-Y, -S-Y, C₁ to C₆ alkyl and C₁ to C₆ substituted alkyl, and Y is selected from the group consisting of hydrogen, C₁ to C₆ alkyl and C₁ to C₆ substituted alkyl; R₁₀ is selected from the group consisting of hydrogen, hydroxyl and oxo; or R₉ and R₁₀ combine to from methylene or epoxy; R₁₁ is absent or is selected from the group consisting of hydrogen, cyano, C₁ to C₆ alkyl, C₁Io C₆ substituted alkyl, phenyl, substituted phenyl, heteroaryl and substituted heteroaryl; R₁₀ and R₁₂ and the attached ring depicted form a moiety selected from the group consisting of cyclopropyl, cyclobutyl or cyclopentyl, said moiety optionally substituted by oxo; or R₁₂ is selected from the group consisting of hydrogen, hydroxyl and oxo; or a pharmaceutically acceptable salt of a compound thereof.

7. The use of claim 6, wherein the antagonist has the core formula (I), where: the dotted lines denote optional double bonds; Z is hydrogen; R₁ is selected from the group consisting of hydrogen, methyl, hydroxymethyl and -CHO; R₂ is selected from the group consisting of hydrogen and fluoro; R₃ is hydrogen; or R₂ and R₃ combine to from -O- (epoxy) or -CH₂- (methylene); R₄ is methyl; or R₃ and R₄ combine to form -0-CH₂-; R₅ and R₆ are, independently, selected from the group consisting of hydrogen, hydroxyl, propionate and acetyl, or R₅ and R₆ and X of the core formula combine to form

R₇ is selected from the group consisting of hydrogen and oxo; R₈ is selected from the group consisting of hydrogen and hydroxyl; R₉ is selected from the group consisting of hydrogen, propyl, hydroxyl, -C(O)- O-methyl and -S-C(O)-methyl; R₁₀ is hydrogen; or R₉ and R₁₀ combine to form methylene; R₁₁ is absent or is selected from the group consisting of hydrogen and cyano; or R₁₀ and R₁₂ and the attached ring depicted form cyclobutyl, optionally substituted with oxo; or R₁₂ is hydrogen.

8. The use of claim 7, wherein the antagonist has the core formula (I), where: there is a double bond between the ring carbons that are attached to R₁₁ and R₁₂; R₁ is methyl; R₂ is hydrogen; R₃ is hydrogen; R₄ is methyl; R₅ and R₆ and X of the core formula combine to form

Z and R₇ are each hydrogen; R₈ is hydrogen; R₉ is -S-C(O)-methyl; R₁₀ is hydrogen; R₁₁ is hydrogen; and R₁₂ is hydrogen.

9. The use of claim 7, wherein the antagonist has the core formula (I), where: there is a double bond between the ring carbons that are attached to R₁₁ and R₁₂ and R₉ and R₁₀, respectively; R₁ is methyl; R₂ is hydrogen; R₃ is hydrogen; R₄ is methyl; one of R₅ and R₆ is hydroxyl and the other is propionate; Z and R₇ are each hydrogen; R₈ is hydrogen; R₉ is hydrogen; R₁₀ is hydrogen; R₁₁ is hydrogen; and R₁₂ is hydrogen.

10. The used of claim 7, wherein the antagonist has the core formula (I), where: there is a double bond between the ring carbons that are attached to R₁₁ and R₁₂; R₁ is methyl; R₂ is hydrogen; R₃ is hydrogen; R₄ is methyl; one of R₅ and R₆ is hydroxyl and the other is propionate; Z and R₇ are each hydrogen; R₈ is hydrogen; R₉ is propyl; R₁₀ is hydrogen; R₁₁ is hydrogen; and R₁₂ is hydrogen; or the potassium salt thereof.

11. The use of claim 7, wherein the antagonist has the core formula (I), where: there is a double bond between the ring carbons that are attached to R₁₁ and R₁₂; R₁ is methyl; R₂ is hydrogen; R₃ is hydrogen; R₄ is methyl; one of R₅ and R₆ is hydroxyl and the other is propionate; Z and R₇ are each hydrogen; R₈ is hydrogen; R₉ and R₁₀ combine to form methylene; R₁₁ is hydrogen; and R₁₂ is hydrogen.

12. The use of claim 7, wherein the antagonist has the core formula (I), where: there is a double bond between the ring carbons that are attached to R₁₁ and R₁₂; R₁ is methyl; R₂ is hydrogen; R₃ is hydroxyl; R₄ is methyl; R₅ and R₆ and X of the core formula combine to form

Z and R₇ are each hydrogen; R₈ is hydrogen; R₉ is -C(O)-O~methyl; R₁₀ is hydrogen; R₁₁ is hydrogen; and R₁₂ is hydrogen.

13. The use of claim 7, wherein the antagonist has the core formula (I), where: there is a double bond between the ring carbons that are attached to R_n and R₁₂; R₁ is methyl; R₂ and R₃ combine to from epoxy; R₄ is methyl; R₅ and R₆ and X of the core formula combine to form

Z and R₇ are each hydrogen; R₈ is hydrogen; R₉ is -C(O)-O-methyl; R₁₀ is hydrogen R_n is hydrogen; and R₁₂ is hydrogen.

14. The use of claim 4, wherein said small organic molecule has the core formula (H):

wherein: R₁ is selected from the group consisting of C₁ to C₁₂ alkyl, C₂ to C₆ alkenyl, C₂ to C₆ alkynyl, C₁ to C₁₂ substituted alkyl, C₂ to C₆ substituted alkenyl, C₂ to C₆ substituted alkynyl, C₃ to C₇ cycloalkyl, C₃ to C₇ substituted cycloalkyl, C₅ to C₇ cycloalkenyl, C₅ to C₇ substituted cycloalkenyl, heterocycle, substituted heterocycle, heteroaryl, substituted heteroaryl, C₇ to C₁₈ phenylalkyl, C₇ to C₁₈ substituted phenylalkyl, phenyl, substituted phenyl, naphthyl, substituted naphthyl, cyclic C₂ to C₇ alkylene, substituted cyclic C₂ to C₇ alkylene, cyclic C₂ to C₇ heteroalkylene, substituted cyclic C₂ to C₇ heteroalkylene and -CH₂COR₇; R₂ is selected from the group consisting of C₁ to C₁₂ alkyl, C₁ to C₁₂ substituted alkyl, C₃ to C₇ cycloalkyl, C₃ to C₇ substituted cycloalkyl, and -(CH₂)_n-phenyl, wherein n is 0, 1 or 2, and said phenyl is optionally substituted one, two or three times with a moiety selected from the group consisting of hydroxyl, C₁ to C₄ alkyl, C₁ to C₄ alkoxy, halo, nitro, amino, -NH(C₁Io C₆)alkylamine, N₅N-(C₁Io C₄)dialkylamine, -NH-(C₁ to C₄)alkylsulfonyl and -NH-acyl, or said phenyl has a fused heterocyclic ring attached to it; R₃ is phenyl, which is optionally substituted one, two or three times with a moiety selected from the group consisting of hydroxyl, C₁ to C₄ alkyl, C₁ to C₄ alkoxy, halo, nitro, amino, -NH(C₁ to C₆)alkylamine and N₅N-(C₁ to C₄)dialkylamine; R₄ and R₅ are, independently, selected from the group consisting of hydrogen, halo, hydroxyl, C₁ to C₄ alkyl, C₁ to C₄ alkoxy, C₃ to C₅ cycloalkyl, CF₃, OCF₃, CHF₂, OCHF₂, CF₂CF₃, cyano, nitro, amino, -NH(C₁ to C₆)alkylamine and N,N- (C₁ to C₆)dialkylamine; and R₇ is selected from the group consisting of C₁ to C₆ alkyl, C₃ to C₇ cycloalkyl, - NH-(C₃ to C₇ cycloalkyl), C₁ to C₄ alkoxy, phenyl, substituted phenyl, heterocycle and substituted heterocycle; or a pharmaceutically acceptable salt thereof.

15. The use of claim 14, wherein said small organic molecule has the core formula (II) where: R₁ is selected from the group consisting of substituted phenyl, substituted heterocycle and C₁ to C₄ alkyl-substituted phenyl.

16. The use of claim 15, wherein said small organic molecule has the core formula (II) where: R₁ is selected from the group consisting of 4-methoxybenzyl, 3- methoxybenzyl, 4-hydroxybenzyl, 4-fluorobenzyl, 2-fluorobenzyl, 4- bromobenzyl, 2,6-difluorobenzyl, 2-bromobenzyl, 3-bromobenzyl, 2,4- difluorobenzyl, 2,3-difluorobenzyl, 2-chlorobenzyl, 3-chlorobenzyl, 3,4- dichlorobenzyl, 2,6-dichlorobenzyl, 2-chloro-6-fluorobenzyl, 4-bromo-2- fluorobenzyl, 4-chloro-2-fluorobenzyl, 2-methylbenzyl, 2,6-dimethylbenzyl, 2- cyanobenzyl, 4-methoxycarbonylbenzyl, 3-methoxycarbonylbenzyl, A- methanesulfonylbenzyl, 4-tert-butylbenzyl, 2-difluoromethoxybenzyl, 2- trifluormethylbenzyl, 3-trifluoimethoxybenzyl, 3-trifluoromethylbenzyl, A- tiifluorormethylbenzyl, 4-trifluoromethoxybenzyl, 2,4-Bis- trifluoromethylbenzyl, 3,5-Bis-trifluorometb.ylbenzyl, 2-fluoro-3-methylbenzyl, 2, fluoro-5-trifluoromethylbenzyl, 4-nitrobenzyl, 2-nitrobenzyl, 3-nitrobenzyl, 2-aminobenzyl, 3-aminobenzyl, 4-aminobenzyl, 4-benzoylbenzyl, A- benzyloxybenzyl, l-biphenyl-2-ylmethyl and 4-[l,2,3]thiadiazol-4-yl-benzyl.

17. The use of claim 15, wherein said small organic molecule has the core formula (II) where, in R₂, n is 0.

18. The use of claim 17, where the phenyl ring in R₂ is unsubstituted or substituted with a moiety selected from the group consisting of hydroxyl, C₁ to C₄ alkyl, halo, nitro, amino -NH-COCH₃ and -NH-SO₂CH₃.

19. The use of claim 18, wherein R₂ is selected from the group consisting of A- hydroxy-3,5-dimethylphenyl, 4-hydroxy-3-ethylphenyl, 4-hydroxy-3- methylphenyl, 4-hydroxyphenyl, 4-hydroxy-3,5-dichlorophenyl, 4-amino-3,5- dimethylphenyl, 4-aminophenyl, 4-nitrophenyl, 2-hydroxy-3,4-dimethylphenyl, 2-hydroxy-3 ,5-dimethylphenyl, 2-hydroxy-4,5-dimethylphenyl, 2-hydroxy-5- methylphenyl, 3,4-dihydroxy-5-methylphenyl, 4-hydroxy-3-methyl-5- propylphenyl, 3,4-dimethylphenyl, 3,4,5-trimethylphenyl, 4~amino-3-chloro-5- methylphenyl, 4-amino-3-methylphenyl, 2,4-dihydroxyphenyl, 2,4-dihydroxy- 3-methylphenyl, 2-hydroxy-3-ethylphenyl, 2-hydroxyphenyl, 4-NH(SO₂)CH₃- phenyl and 4-NH(CO)CH₃-phenyl.

20. The use of claim 14, where R₃ is selected from the group consisting of A- hydroxy-3,5-dimethylphenyl, 4-hydroxy-3-ethylphenyl, 4-hydroxy-3- methylphenyl, 4-hydroxy-3,5-dichlorophenyl, 3,5-dimethylphenyl and 3,4,5- trimethylphenyl.

21. The use of claim 14, where R₄ and R₅, independently, are selected from the group consisting of hydrogen, halo, hydroxyl, C₁ to C₄ alkyl, C₁ to C₄ alkoxy, CF₃, OCF₃, CHF₂, OCHF₂, CF₂CF₃, cyano, nitro and amino.

22. The use of claim 14, where R₄ and R₅, independently, are selected from the group consisting of hydrogen, bromo, chloro, methyl, ethyl and methoxy.

23. A method of treating a disease condition in a mammal characterized by hyperglycemia comprising administering to the mammal a therapeutically effective amount of an antagonist of the mineralcorticoid receptor.

24. The method of claim 23 wherein the disease is Type II diabetes mellitus.

25. The method of claim 23 wherein the antagonist comprises an siRNA.

26. The method of claim 23, wherein the antagonist is a small organic molecule.

27. The method of claim 23, wherein the antagonist has the core formula (I):

wherein: the dotted lines denote optional double bonds; X is a carbon atom; R₁ is selected from the group consisting of hydrogen, -C(O)-Y, -C(O)-O-Y, C₁ to C₆ alkyl, C₁ to C₆ substituted alkyl, nitro and amino, and Y is selected from the group consisting of hydrogen, C₁ to C₆ alkyl and C₁ to C₆ substituted alkyl; R₂ is selected from the group consisting of hydrogen and halo; R₃ is selected from the group consisting of hydrogen and hydroxyl; or R₂ and R₃ combine to form -O- (epoxy) or -CH₂- (methylene); R₄ is selected from the group consisting of hydrogen, hydroxyl, C₁ to C₆ alkyl and C₁ to C₆ substituted alkyl; or R₃ and R₄ combine to form -0-CH₂-; R₅ and R₆ are, independently, selected from the group consisting of hydrogen, hydroxyl, -C(O)-Y, -C(O)-O-Y, C₁ to C₆ alkyl and C₁ to C₆ substituted alkyl, and Y is selected from the group consisting of hydrogen, C₁ to C₆ alkyl and C₁ to C₆ substituted alkyl; or R₅ and R₆ and X of the core formula combine to form

where R₁₃ and R₁₄ are, independently, selected from the group consisting of hydrogen, hydroxyl, oxo, -C(O)-Y, -C(O)-O-Y, C₁ to C₆ alkyl and C₁ to C₆ substituted alkyl, and Y is selected from the group consisting of hydrogen, C₁ to C₆ alkyl and C₁ to C₆ substituted alkyl; Z is selected from the group consisting of hydrogen, hydroxyl and oxo; R₇ is selected from the group consisting of hydrogen, hydroxyl and oxo; R₈ is selected from the group consisting of hydrogen, hydroxyl and halo; R₉ is selected from the group consisting of hydrogen, hydroxyl, -C(O)-Y, - C(O)-O-Y, -S-C(O)-Y, -S-C(O)-O-Y, -S-Y, C₁ to C₆ alkyl and C₁ to C₆ substituted alkyl, and Y is selected from the group consisting of hydrogen, C₁ to C₆ alkyl and C₁ to C₆ substituted alkyl; R₁₀ is selected from the group consisting of hydrogen, hydroxyl and oxo; or R₉ and R₁₀ combine to from methylene or epoxy; R₁₁ is absent or is selected from the group consisting of hydrogen, cyano, C₁ to C₆alkyl, C₁ to C₆ substituted alkyl, phenyl, substituted phenyl, heteroaryl and substituted heteroaryl; R₁₀ and R₁₂ and the attached ring depicted form a moiety selected from the group consisting of c^'yclopropyl, cyclobutyl or cyclopentyl, said moiety optionally substituted by oxo; or R₁₂ is selected from the group consisting of hydrogen, hydroxyl and oxo; or a pharmaceutically acceptable salt of a compound thereof.

28. The method of claim 27, wherein the antagonist has the core formula (I), where: the dotted lines denote optional double bonds; Z is hydrogen; R₁ is selected from the group consisting of hydrogen, methyl, hydroxymethyl and -CHO; R₂ is selected from the group consisting of hydrogen and fluoro; R₃ is hydrogen; or R₂ and R₃ combine to from -O- (epoxy) or -CH₂- (methylene); R₄ is methyl; or R₃ and R₄ combine to form -0-CH₂-; R₅ and R₆ are, independently, selected from the group consisting of hydrogen, hydroxyl, propionate and acetyl, or R₅ and R₆ and X of the core formula combine to form

29. The method of claim 27, wherein the antagonist has the core formula (I), where: there is a double bond between the ring carbons that are attached to R₁₁ and R₁₂; R₁ is methyl; R₂ is hydrogen; R₃ is hydrogen; R₄ is methyl; R₅ and R₆ and X of the core formula combine to form

30. The method of claim 27, wherein the antagonist has the core formula (I), where: there is a double bond between the ring carbons that are attached to R₁₁ and R₁₂ and R₉ and R₁₀, respectively; R₁ is methyl; R₂ is hydrogen; R₃ is hydrogen; R₄ is methyl; one of R₅ and R₆ is hydroxyl and the other is propionate; Z and R₇ are each hydrogen; R₈ is hydrogen; R₉ is hydrogen; R₁₀ is hydrogen; R₁₁ is hydrogen; and R₁₂ is hydrogen.

31. The method of claim 27, wherein the antagonist has the core formula (I), where: there is a double bond between the ring carbons that are attached to R₁₁ and R₁₂; R₁ is methyl; R₂ is hydrogen; R₃ is hydrogen; R₄ is methyl; one of R₅ and R₆ is hydroxyl and the other is propionate; Z and R₇ are each hydrogen; R₈ is hydrogen; R₉ is propyl; R₁₀ is hydrogen; R₁₁ is hydrogen; and R₁₂ is hydrogen; or the potassium salt thereof.

32. The method of claim 27, wherein the antagonist has the core formula (I), where: there is a double bond between the ring carbons that are attached to R₁₁ and R₁₂; R₁ is methyl; R₂ is hydrogen; R₃ is hydrogen; R₄ is methyl; one of R₅ and R₆ is hydroxyl and the other is propionate; Z and R₇ are each hydrogen; R₈ is hydrogen; R₉ and R₁₀ combine to form methylene; R₁₁ is hydrogen; and R₁₂ is hydrogen.

33. The method of claim 27, wherein the antagonist has the core formula (I), where: There is a double bond between the ring carbons that are attached to R₁₁ and R₁₂; R₁ is methyl; R₂ is hydrogen; R₃ is hydroxyl; R₄ is methyl; R₅ and R₆ and X of the core formula combine to form

Z and R₇ are each hydrogen; R₈ is hydrogen; R₉ is -C(O)-O-methyl; R₁₀ is hydrogen; R₁₁ is hydrogen; and R₁₂ is hydrogen.

34. The method of claim 27, wherein the antagonist has the core formula (I), where: there is a double bond between the ring carbons that are attached to R₁₁ and R₁₂; R₁ is methyl; R₂ and R₃ combine to from epoxy; R₄ is methyl; R₅ and R₆ and X of the core formula combine to form

Z and R₇ are each hydrogen; R₈ is hydrogen; R₉ is -C(O)-O-methyl; R₁₀ is hydrogen R₁₁ is hydrogen; and R₁₂ is hydrogen.

35. The method of claim 26, wherein said small organic molecule has the core formula (II):

wherein: R₁ is selected from the group consisting of C₁ to C₁₂ alkyl, C₂ to C₆ alkenyl, C₂ to C₆ alkynyl, C₁ to C₁₂ substituted alkyl, C₂ to C₆ substituted alkenyl, C₂ to C₆ substituted alkynyl, C₃ to C₇ cycloalkyl, C₃ to C₇ substituted cycloalkyl, C₅ to C₇ cycloalkenyl, C₅ to C₇ substituted cycloalkenyl, heterocycle, substituted heterocycle, heteroaryl, substituted heteroaryl, C₇ to C₁₈ phenylalkyl, C₇ to C₁₈ substituted phenylalkyl, phenyl, substituted phenyl, naphthyl, substituted naphthyl, cyclic C₂ to C₇ alkylene, substituted cyclic C₂ to C₇ alkylene, cyclic C₂ to C₇ heteroalkylene, substituted cyclic C₂ to C₇ heteroalkylene and -CH₂COR₇; R₂ is selected from the group consisting of C₁ to C₁₂ alkyl, C₁ to C₁₂ substituted alkyl, C₃ to C₇ cycloalkyl, C₃ to C₇ substituted cycloalkyl, and -(CH₂)_n-phenyl, wherein n is 0, 1 or 2, and said phenyl is optionally substituted one, two or three times with a moiety selected from the group consisting of hydroxyl, C₁ to C₄ alkyl, C₁ to C₄ alkoxy, halo, nitro, amino, -NH(C₁ to C₆)alkylamine, N₅N-(C₁ to C₄)dialkylamine, -NH-(C₁ to C₄)alkylsulfonyl and -NH-acyl, or said phenyl has a fused heterocyclic ring attached to it; R₃ is phenyl, which is optionally substituted one, two or three times with a moiety selected from the group consisting of hydroxyl, C₁ to C₄ alkyl, C₁ to C₄ alkoxy, halo, nitro, amino, -NH(C₁ to C₆)alkylamine and N₁N-(C₁ to C₄)dialkylamine; R₄ and R₅ are, independently, selected from the group consisting of hydrogen, halo, hydroxyl, C₁ to C₄ alkyl, C₁ to C₄ alkoxy, C₃ to C₅ cycloalkyl, CF₃, OCF₃, CHF₂, OCHF₂, CF₂CF₃, cyano, nitro, amino, -NH(C₁ to C₆)alkylamine and NJNf- (C₁ to C₆)dialkylamine; and R₇ is selected from the group consisting of C₁ to C₆ alkyl, C₃ to C₇ cycloalkyl, - NH-(C₃ to C₇ cycloalkyl), C₁ to C₄ alkoxy, phenyl, substituted phenyl, heterocycle and substituted heterocycle; or a pharmaceutically acceptable salt thereof.

36. The method of claim 35, wherein said small organic molecule has the core formula (II) where: R₁ is selected from the group consisting of substituted phenyl, substituted heterocycle and C₁ to C₄ alkyl-substituted phenyl.

37. The method of claim 36, wherein said small organic molecule has the core formula (II) where: R₁ is selected from the group consisting of 4- methoxybenzyl, 3-methoxybenzyl, 4-hydroxybenzyl, 4-fluorobenzyl, 2- fluorobenzyl, 4-bromobenzyl, 2,6-difluorobenzyl, 2-bromobenzyl, 3- bromobenzyl, 2,4-difluorobenzyl, 2,3-difluorobenzyl, 2-chlorobenzyl, 3- chlorobenzyl, 3,4-dichlorobenzyl, 2,6-dichlorobenzyl, 2-chloro-6-fluorobenzyl, 4-bromo-2-fluorobenzyl, 4-chloro-2-fluorobenzyl, 2-methylbenzyl, 2,6- dimethylbenzyl, 2-cyanobenzyl, 4-methoxycarbonylbenzyl, 3- methoxycarbonylbenzyl, 4-methanesulfonylbenzyl, 4-tert-butylbenzyl, 2- difluoromethoxybenzyl, 2-trifluormethylbenzyl, 3-trifluormethoxybenzyl, 3- trifluoromethylbenzyl, 4-trifluorormethylbenzyl, 4-trifluoromethoxybenzyl, 2,4- Bis-trifluoromethylbenzyl, 3,5-Bis-trifluoromethylbenzyl, 2-fluoro-3- methylbenzyl, 2, fluoro-5-trifluoromethylbenzyl, 4-nitrobenzyl, 2-nitrobenzyl, 3-nitrobenzyl, 2-aminobenzyl, 3-aminobenzyl, 4-aminobenzyl, A- benzoylbenzyl, 4-benzyloxybenzyl, l-biphenyl-2-ylmethyl and A- [1 ,2,3]thiadiazol-4-yl-benzyl.

38. The method of claim 36, wherein said small organic molecule has the core formula (II) where, in R₂, n is 0.

39. The method of claim 38, where the phenyl ring in R₂ is unsubstituted or substituted with a moiety selected from the group consisting of hydroxyl, C₁ to C₄ alkyl, halo, nitro, amino -NH-COCH₃ and -NH-SO₂CH₃.

40. The method of claim 39 R₂ is selected from the group consisting of 4-hydroxy- 3,5-dimethylphenyl, 4-hydroxy-3-ethylphenyl, 4-hydroxy-3-methylphenyl, A- hydroxyphenyl, 4-hydroxy-3,5-dichlorophenyl, 4-amino-3,5-dimethylphenyl, 4- aminophenyl, 4-nitrophenyl, 2-hydroxy-3,4-dimethylphenyl, 2-hydroxy-3,5- dimethylphenyl, 2-hydroxy-4,5-dimethylphenyl, 2-hydroxy-5-methylphenyl, 3,4-dihydroxy-5-methylphenyl, 4-hydroxy-3-methyl-5-propylphenyl, 3,4- dimethylphenyl, 3,4,5-trimethylphenyl, 4-amino-3-chloro-5-methylphenyl, A- amino-3-methylphenyl, 2,4-dihydroxyphenyl, 2,4-dihydroxy-3-methylphenyl, 2-hydroxy-3-ethylphenyl, 2-hydroxyphenyl, 4-NH(SO₂)CH₃-phenyl and 4- NH(CO)CH₃-phenyl.

41. The method of claim 28, where R₃ is selected from the group consisting of 4- hydroxy-3,5-dimethylphenyl, 4-hydroxy-3-ethylphenyl, 4-hydroxy-3- methylphenyl, 4-hydroxy-3,5-dichlorophenyl, 3,5-dimethylphenyl and 3,4,5- trimethylphenyl.

42. The method of claim 28, where R₄ and R₅, independently, are selected from the group consisting of hydrogen, halo, hydroxyl, C₁ to C₄ alkyl, C₁ to C₄ alkoxy, CF₃, OCF₃, CHF₂, OCHF₂, CF₂CF₃, cyano, nitro and amino.

43. The method of claim 28, where R₄ and R₅, independently, are selected from the group consisting of hydrogen, bromo, chloro, methyl, ethyl and methoxy.

44. A method for identifying a compound useful for treating hyperglycemia, the method comprising treating primary hepatocytes with the compound and determining that the compound is an MNR antagonist.

45. The method of claim 44 wherein the step of determining comprises assaying the level of expression of an enzyme selected from the group comprising glucose-6- phosphatase, phosphoenolpyruvate carboxykinase, and 1, 6 fructose biphosphatase.