Abstract: Renal-selective prodrugs are described which are preferentially converted in the kidney to compounds capable of inhibiting synthesis of catecholamine-type neurotransmitters involved in renal sympathetic nerve activity. The prodrugs described herein are derived from inhibitor compounds capable of inhibiting one or more of the enzymes involved in catecholamine synthesis, such compounds being classifiable as tyrosine hydroxylase inhibitors, or as dopa-decarboxylase inhibitors, or as dopamine-&bgr;-hydroxylase inhibitors. These inhibitor compounds are linked to a chemical moiety, such as a glutamic acid derivative, by a cleavable bond which is recognized selectively by enzymes located predominantly in the kidney. The liberated inhibitor compound is then available in the kidney to inhibit one or more of the enzymes involved in catecholamine synthesis. Inhibition of renal catecholamine synthesis can suppress heightened renal nerve activity associated with sodium-retention related disorders such as hypertension.
Type:
Application
Filed:
October 20, 2003
Publication date:
May 27, 2004
Applicant:
G.D. Searle & Co.
Inventors:
David B. Reitz, John P. Koepke, Edward H. Blaine, Joseph R. Schuh, Robert E. Manning, Glenn J. Smits
Abstract: A combination therapy comprising a therapeutically-effective amount of an epoxy-free spirolactone-type aldosterone receptor antagonist and a therapeutically-effective amount of an angiotensin II receptor antagonist is described for treatment of circulatory disorders, including cardiovascular disorders such as hypertension, congestive heart failure, cirrhosis and ascites. Preferred angiotensin II receptor antagonists are those compounds having high potency and bioavailability and which are characterized in having an imidazole or triazole moiety attached to a biphenylmethyl or pyridinyl/phenylmethyl moiety. A preferred epoxy-free spirolactone-type aldosterone receptor antagonist is spironolactone. A preferred combination therapy includes the angiotensin II receptor antagonist 5-[2-[5-[(3,5-dibutyl-1H-1,2,4-triazol-1-yl)methyl]-2-pyridinyl]phenyl-1H-tetrazole and the aldosterone receptor antagonist spironolactone.
Abstract: Use of low dosages of an aldosterone receptor antagonist, such as spironolactone, is described for use in treatment of circulatory disorders. This therapy would be particularly useful to treat congestive heart failure while avoiding or reducing aldosterone-antagonist-induced side effects, such as hyperkalemia.
Abstract: An aromatic sulfonyl alpha-cycloamino hydroxamic acid compound that inter alia inhibits matrix metalloprotease activity is disclosed as are a treatment process that comprises administering a contemplated aromatic sulfonyl alpha-cycloamino hydroxamic acid compound in a MMP enzyme-inhibiting effective amount to a host having a condition associated with pathological matrix metalloprotease activity.
Type:
Application
Filed:
October 27, 2003
Publication date:
May 20, 2004
Applicant:
G.D. Searle & Co.
Inventors:
Hui Li, Daniel P. Becker, Clara I. Villamil, Terri L. Boehm, Daniel P. Getman, Joseph J. McDonald, Gary A. DeCrescenzo
Abstract: Compounds characterized generally as imidazolyl/benzimidazolyl-terminated alkylamino ethynyl alanine amino diol derivatives are useful as renin inhibitors for the treatment of hypertension.
Abstract: Selected amino acid hydroxyethylamino sulfonamide compounds are effective as retroviral protease inhibitors, and in particular as inhibitors of HIV protease. The present invention relates to such retroviral protease inhibitors and, more particularly, relates to selected novel compounds, composition and method for inhibiting retroviral proteases, such as human immunodeficiency virus (HIV) protease, prophylactically preventing retroviral infection or the spread of a retrovirus, and treatment of a retroviral infection.
Type:
Grant
Filed:
July 23, 2002
Date of Patent:
May 4, 2004
Assignee:
G. D. Searle & Co.
Inventors:
Daniel P Getman, Gary A. DeCrescenzo, John N. Freskos, Michael L. Vazquez, James A. Sikorski, Balekudru Devadas, Srinivasan Nagarajan, David L. Brown, Joseph J. McDonald
Abstract: Succinoylamino hydroxyethylamino sulfonamide compounds are effective as retroviral protease inhibitors, and in particular as inhibitors of HIV protease.
Type:
Grant
Filed:
September 9, 2002
Date of Patent:
April 27, 2004
Assignee:
G.D. Searle & Co.
Inventors:
Michael L. Vazquez, Richard A. Mueller, John J. Talley, Daniel Getman, Gary A. DeCrescenzo, John N. Freskos
Abstract: Combinations of an ACE inhibitor and an epoxy-steroidal aldosterone receptor antagonist are described for use in treatment of circulatory disorders. Of particular interest are therapies using epoxy-steroidal-type aldosterone receptor antagonist compounds, such as eplerenone, in combination with an angiotensin converting enzyme inhibitor. This co-therapy would be particularly useful to treat congestive heart failure while avoiding or reducing aldosterone-antagonist-induced side effects such as hyperkalemia.
Type:
Application
Filed:
May 19, 2003
Publication date:
April 22, 2004
Applicant:
G.D. Searle & Co.
Inventors:
John C. Alexander, Barbara Roniker, Subhash Desai
Abstract: A therapeutic method is described for treating cardiofibrosis or cardiac hypertrophy using a combination therapy comprising a therapeutically-effective amount of an epoxy-free spirolactone-type aldosterone receptor antagonist and a therapeutically-effective amount of an angiotensin II receptor antagonist. Preferred angiotensin II receptor antagonists are those compounds having high potency and bioavailability and which are characterized in having an imidazole or triazole moiety attached to a biphenylmethyl or pyridinyl/phenylmethyl moiety. A preferred epoxy-free spirolactone-type aldosterone receptor antagonist is spironolactone. A preferred combination therapy includes the angiotensin II receptor antagonist 5-[2-[5-[(3,5-dibutyl-1H-1,2,4-triazol-1-yl)methyl]-2-pyridinyl]phenyl-1H-tetrazole and the aldosterone receptor antagonist spironolactone.
Type:
Application
Filed:
May 5, 2003
Publication date:
April 8, 2004
Applicant:
G.D. Searle & Co.
Inventors:
Ellen G. McMahon, Gillian M. Olins, Joseph R. Schuh
Abstract: The present invention provides methods of treating, inhibiting or preventing pathogenic change resulting from vascular injury in a subject, particularly restenosis resulting substantially from angioplasty. The methods comprise administering a therapeutically-effective amount of an aldosterone antagonist, particularly eplerenone, in a mammalian subject susceptible to or suffering from said pathogenic change.
Type:
Application
Filed:
August 26, 2003
Publication date:
April 8, 2004
Applicant:
G.D. Searle & Co.,
Inventors:
John A. Delyani, Kenton N. Fedde, John W. Funder, Michael R. Ward, Peter Kanellakis, Alex Bobik
Abstract: A class of pyrazolyl benzenesulfonamide compounds is descrbed for use in treating inflammation and inflammation-related disorders.
Type:
Grant
Filed:
March 4, 2003
Date of Patent:
April 6, 2004
Assignee:
G. D. Searle & Co.
Inventors:
John J Talley, Thomas D Penning, Paul W Collins, Donald J Rogier, Jr., James W Malecha, Julie M Miyashiro, Stephen R Bertenshaw, Ish K Khanna, Matthew J Graneto, Roland S Rogers, Jeffery S Carter, Stephen H. Doctor, Stella S Yu
Abstract: Bis-sulfonamido hydroxyethylamino compounds are effective as retroviral protease inhibitors, and in particular as inhibitors of HIV protease.
Type:
Application
Filed:
April 17, 2003
Publication date:
April 1, 2004
Applicant:
G.D. Searle & Co.
Inventors:
John N. Freskos, Daniel P. Getman, John J. Talley, James A. Sikorski
Abstract: A therapeutic method is described for treating cardiofibrosis or cardiac hypertrophy using a combination therapy comprising a therapeutically-effective amount of an epoxy-steroidal aldosterone receptor antagonist and a therapeutically-effective amount of an angiotensin II receptor antagonist. Preferred angiotensin II receptor antagonists are those compounds having high potency and bioavailability and which are characterized in having an imidazole or triazole moiety attached to a biphenylmethyl or pyridinyl/phenylmethyl moiety. Preferred epoxy-steroidal aldosterone receptor antagonists are 20-spiroxane steroidal compounds characterized by the presence of a 9&agr;, 11&agr;-substituted epoxy moiety. A preferred combination therapy includes the angiotensin II receptor antagonist 5-[2-[5-[(3,5-dibutyl-1H-1,2,4-triazol-1-yl)methyl]-2-pyridinyl]phenyl-1H-tetrazole and the aldosterone receptor antagonist epoxymexrenone.
Type:
Application
Filed:
February 21, 2003
Publication date:
March 18, 2004
Applicant:
G.D. Searle & Co.
Inventors:
James J. Egan, Ellen G. McMahon, Gillian M. Olins, Joseph R. Schuh
Abstract: Oral pharmaceutical formulation which improves the bioavailability of pharmaceuticals which are substantially water and oil insoluble is disclosed. In addition to the pharmaceutical, the formulation includes an emulsifier, an oil and an solubilizer. Alternatively, the formulation includes an aqueous solution of solubilizer.
Type:
Application
Filed:
April 29, 2003
Publication date:
March 11, 2004
Applicant:
G.D. Searle & Co.
Inventors:
Rajeev Gokhale, Martin J. Griffin, James E. Truelove, James C. Stolzenbach, Aziz Karim, Ajit K. Roy
Abstract: The invention relates to substituted aryl and heteroaryl (R)-Chiral Halogenated 1-Substitutedamino-(n+1)-Alkanol compounds useful as inhibitors of cholesteryl ester transfer protein (CETP; plasma lipid transfer protein-I) and compounds, compositions and methods for treating atherosclerosis and other coronary artery diseases. Novel high yield, stereoselective processes for the preparation of the chiral substituted alkanol compounds from chiral and achiral intermediates are described. Preferred (R)-Chiral 1-Substitutedamino-(n+1)-Alkanol compounds are substituted (R)-Chiral fused heterocyclic amino compounds.
Type:
Application
Filed:
February 4, 2003
Publication date:
March 4, 2004
Applicant:
G.D. Searle & Co.
Inventors:
James A. Sikorski, Richard C. Durley, Margaret L. Grapperhaus, Mark A. Massa, Emily J. Reinhard, Yvette M. Fobian, Michael B. Tollefson, Lijuan Wang, Brian S. Hickory, Monica B. Norton, William F. Vernier, Deborah A. Mischke, Michele A. Promo, Ashton T. Hamme, Dale P. Spangler, Melvin L. Rueppel
Abstract: &agr;- and &bgr;-amino acid hydroxyethylamino sulfonamide compounds are effective as retroviral protease inhibitors, and in particular as inhibitors of HIV protease.
Type:
Application
Filed:
July 22, 2002
Publication date:
March 4, 2004
Applicant:
G.D. Searle & Co.
Inventors:
Michael J. Vazquez, Richard A. Mueller, John J. Talley, Daniel P. Getman, Gary A. DeCrescenzo, John N. Freskos, Robert M. Heintz, Deborah E. Bertenshaw
Abstract: A class of benzopyrans, benzothiopyrans, dihydroquinolines, dihydronaphthalenes, and analogs thereof, is described for use in treating cyclooxygenase-2 mediated disorders.
Type:
Application
Filed:
November 22, 2002
Publication date:
February 26, 2004
Applicant:
G.D. Searle & Co.
Inventors:
Jeffery S. Carter, Mark G. Obukowicz, Balekudru Devadas, John J. Talley, David L. Brown, Matthew J. Graneto, Stephen R. Bertenshaw, Donald J. Rogier, Srinivasan Raj Nagarajan, Cathleen E. Hanau, Susan J. Hartmann, Cindy L. Ludwig, Suzanne Metz, Donald E. Korte
Abstract: A combination drug therapy is disclosed for the treatment of a patient affected with Gaucher's disease or other such glycolipid storage diseases. The method comprises administering to said patient a therapeutically effective amount of both a N-alkyl derivative of deoxynojirimycin (DNJ) and a glucocerebrosidase enzyme to alleviate or inhibit the glycolipid storage disease. The alkyl group has from about two to about 20 carbon atoms and preferably is butyl, nonyl or decyl.
Abstract: The present invention provides combinations of cardiovascular therapeutic compounds for the prophylaxis or treatment of cardiovascular disease including hypercholesterolemia, atherosclerosis, or hyperlipidemia. Combinations disclosed include an ileal bile acid transport inhibitor combined with a bile acid sequestrant.
Type:
Application
Filed:
February 26, 2003
Publication date:
February 12, 2004
Applicant:
G.D. Searle & Co.
Inventors:
Bradley T. Keller, Kevin C. Glenn, Joseph R. Schuh