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1.
ACS Med Chem Lett ; 8(1): 49-54, 2017 Jan 12.
Article in English | MEDLINE | ID: mdl-28105274

ABSTRACT

Type 2 diabetes mellitus (T2DM) is an ever increasing worldwide epidemic, and the identification of safe and effective insulin sensitizers, absent of weight gain, has been a long-standing goal of diabetes research. G-protein coupled receptor 120 (GPR120) has recently emerged as a potential therapeutic target for treating T2DM. Natural occurring, and more recently, synthetic agonists have been associated with insulin sensitizing, anti-inflammatory, and fat metabolism effects. Herein we describe the design, synthesis, and evaluation of a novel spirocyclic GPR120 agonist series, which culminated in the discovery of potent and selective agonist 14. Furthermore, compound 14 was evaluated in vivo and demonstrated acute glucose lowering in an oral glucose tolerance test (oGTT), as well as improvements in homeostatic measurement assessment of insulin resistance (HOMA-IR; a surrogate marker for insulin sensitization) and an increase in glucose infusion rate (GIR) during a hyperinsulinemic euglycemic clamp in diet-induced obese (DIO) mice.

2.
ACS Med Chem Lett ; 7(2): 198-203, 2016 Feb 11.
Article in English | MEDLINE | ID: mdl-26985298

ABSTRACT

Bruton's tyrosine kinase (BTK) is a Tec family kinase with a well-defined role in the B cell receptor (BCR) pathway. It has become an attractive kinase target for selective B cell inhibition and for the treatment of B cell related diseases. We report a series of compounds based on 8-amino-imidazo[1,5-a]pyrazine that are potent reversible BTK inhibitors with excellent kinase selectivity. Selectivity is achieved through specific interactions of the ligand with the kinase hinge and driven by aminopyridine hydrogen bondings with Ser538 and Asp539, and by hydrophobic interaction of trifluoropyridine in the back pocket. These interactions are evident in the X-ray crystal structure of the lead compounds 1 and 3 in the complex with the BTK enzyme. Our lead compounds show desirable PK profiles and efficacy in the preclinical rat collagen induced arthritis model.

3.
Bioorg Med Chem Lett ; 25(7): 1592-6, 2015 Apr 01.
Article in English | MEDLINE | ID: mdl-25728416

ABSTRACT

The development of renin inhibitors with favorable oral pharmacokinetic profiles has been a longstanding challenge for the pharmaceutical industry. As part of our work to identify inhibitors of BACE1, we have previously developed iminopyrimidinones as a novel pharmacophore for aspartyl protease inhibition. In this letter we describe how we modified substitution around this pharmacophore to develop a potent, selective and orally active renin inhibitor.


Subject(s)
Enzyme Inhibitors/pharmacology , Imines/pharmacology , Pyrimidinones/pharmacology , Renin/antagonists & inhibitors , Administration, Oral , Dose-Response Relationship, Drug , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/chemistry , Imines/chemical synthesis , Imines/chemistry , Models, Molecular , Molecular Structure , Pyrimidinones/chemical synthesis , Pyrimidinones/chemistry , Renin/metabolism , Structure-Activity Relationship
4.
Bioorg Med Chem Lett ; 21(18): 5336-41, 2011 Sep 15.
Article in English | MEDLINE | ID: mdl-21840715

ABSTRACT

SAR development of indole-based palm site inhibitors of HCV NS5B polymerase exemplified by initial indole lead 1 (NS5B IC(50)=0.9 µM, replicon EC(50)>100 µM) is described. Structure-based drug design led to the incorporation of novel heterocyclic moieties at the indole C3-position which formed a bidentate interaction with the protein backbone. SAR development resulted in leads 7q (NS5B IC(50)=0.032 µM, replicon EC(50)=1.4 µM) and 7r (NS5B IC(50)=0.017 µM, replicon EC(50)=0.3 µM) with improved enzyme and replicon activity.


Subject(s)
Drug Discovery , Enzyme Inhibitors/pharmacology , Heterocyclic Compounds/pharmacology , Indoles/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Carboxylic Acids , Catalytic Domain/drug effects , Crystallography, X-Ray , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Heterocyclic Compounds/chemical synthesis , Heterocyclic Compounds/chemistry , Indoles/chemical synthesis , Indoles/chemistry , Models, Molecular , Molecular Structure , Stereoisomerism , Structure-Activity Relationship , Viral Nonstructural Proteins/metabolism
5.
Bioorg Med Chem Lett ; 21(11): 3290-6, 2011 Jun 01.
Article in English | MEDLINE | ID: mdl-21536438

ABSTRACT

The lead optimization studies of a series of GPR119 agonists incorporating a nortropanol scaffold are described. Extensive structure-activity relationship (SAR) studies of the lead compound 20f led to the identification of compound 36j as a potent, single digit nanomolar GPR119 agonist with high agonist activity. Compound 36j was orally active in lowering blood glucose levels in a mouse oral glucose tolerance test and increased plasma insulin levels in a rat hyperglycemic model. It showed good to excellent pharmacokinetic properties in rats and monkeys and no untoward activities in counter-screen assays. Compound 36j demonstrated an attractive in vitro and in vivo profile for further development.


Subject(s)
Diabetes Mellitus, Type 2/drug therapy , Drug Discovery , Hyperglycemia/drug therapy , Nortropanes/chemical synthesis , Receptors, G-Protein-Coupled/agonists , Administration, Oral , Animals , Disease Models, Animal , Glucose Tolerance Test , Inhibitory Concentration 50 , Mice , Nortropanes/chemistry , Nortropanes/therapeutic use , Rats
6.
Bioorg Med Chem Lett ; 21(2): 861-4, 2011 Jan 15.
Article in English | MEDLINE | ID: mdl-21186123

ABSTRACT

A series of 2-piperidinopiperidine-5-arylthiadiazoles was synthesized and subjected to a structure-activity relationship (SAR) investigation. The potency of this series was improved to the single digit nanomolar range. The key analogs were shown to be free of P450 issues, and they also maintained good ex vivo activity and brain penetration.


Subject(s)
Histamine Antagonists/chemistry , Histamine Antagonists/pharmacology , Receptors, Histamine H3/metabolism , Thiadiazoles/chemistry , Thiadiazoles/pharmacology , Animals , Brain/metabolism , Histamine Antagonists/pharmacokinetics , Humans , Mice , Rats , Structure-Activity Relationship , Thiadiazoles/pharmacokinetics
8.
Bioorg Med Chem Lett ; 20(3): 1189-93, 2010 Feb 01.
Article in English | MEDLINE | ID: mdl-20022498

ABSTRACT

A novel series of TNF-alpha convertase (TACE) inhibitors which are non-hydroxamate have been discovered. These compounds are bis-amides of L-tartaric acid (tartrate) and coordinate to the active site zinc in a tridentate manner. They are selective for TACE over other MMP's. We report the first X-ray crystal structure for a tartrate-based TACE inhibitor.


Subject(s)
ADAM Proteins/antagonists & inhibitors , ADAM Proteins/metabolism , Drug Discovery , Protease Inhibitors/chemistry , Tartrates/chemistry , Tumor Necrosis Factor-alpha/metabolism , ADAM17 Protein , Binding Sites , Combinatorial Chemistry Techniques , Crystallography, X-Ray , Drug Discovery/methods , Humans , Protease Inhibitors/metabolism , Protease Inhibitors/pharmacology , Tartrates/metabolism , Tartrates/pharmacology
9.
Bioorg Med Chem Lett ; 19(21): 6018-22, 2009 Nov 01.
Article in English | MEDLINE | ID: mdl-19800231

ABSTRACT

Vasopressin 1b (V1b) antagonists have been postulated as possible treatments for depression and anxiety. A novel series of potent and selective V1b antagonists has been identified starting from an in-house screen hit. The incorporation of a sulfonamide linker between a tetrahydroisoquinoline core and amino piperidine lead to the identification of a V1b antagonist with similar affinity for human and rat receptors. Further optimization of the right hand portion afforded potent V1b antagonists that possessed moderate to high selectivity over other receptors.


Subject(s)
Antidiuretic Agents/chemistry , Antidiuretic Hormone Receptor Antagonists , Quinolines/chemistry , Sulfonamides/chemistry , Animals , Antidiuretic Agents/chemical synthesis , Antidiuretic Agents/pharmacology , Humans , Quinolines/chemical synthesis , Quinolines/pharmacology , Rats , Receptors, Oxytocin/antagonists & inhibitors , Receptors, Oxytocin/metabolism , Receptors, Vasopressin/metabolism , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/pharmacology
10.
Bioorg Med Chem Lett ; 18(18): 5032-6, 2008 Sep 15.
Article in English | MEDLINE | ID: mdl-18752952

ABSTRACT

A series of non-imidazole histamine H(3) receptor antagonists based on the (3-phenoxypropyl)amine motif, which is a common pharmacophore for H(3) antagonists, has been identified. A preliminary SAR study around the amine moiety has identified 8a as a potent H(3) antagonist possessing a good pharmacokinetic profile in the rat.


Subject(s)
Amines/chemical synthesis , Amines/pharmacology , Benzimidazoles/chemical synthesis , Benzimidazoles/pharmacology , Receptors, Histamine H3/drug effects , Amines/chemistry , Animals , Benzimidazoles/chemistry , Combinatorial Chemistry Techniques , Molecular Structure , Rats , Structure-Activity Relationship
11.
J Comb Chem ; 10(1): 56-62, 2008.
Article in English | MEDLINE | ID: mdl-17988101

ABSTRACT

A novel methodology for parallel liquid-phase synthesis of carbamates suitable for the preparation of sterically hindered molecules is disclosed. The alcohols are converted to 4-nitrophenylcarbonates, followed by the reaction with amines. Side product 4-nitrophenol and the unreacted excess amines are scavenged by appropriately chosen cleanup resins, selected among Amberlyst A26 (hydroxide form) and macroporous sulfonic acid (MP-TsOH) or polystyrene isocyanate (PS-NCO) and polystyrene benzaldehyde (PS-PhCHO) resins. As a part of a medicinal chemistry program directed toward finding gamma-secretase inhibitors as prospective drug candidates for Alzheimer's disease, a 6 x 24 library of carbamates was prepared. Out of 144 library members, 133 had a purity for the targeted compound of 80% or better. The prepared compounds were assessed in the gamma-secretase inhibition assay and demonstrated activity with IC 50 values in the range from 1 microM to 5 nM, with the activity of 7 compounds being better than 10 nM.


Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Carbamates , Combinatorial Chemistry Techniques , Enzyme Inhibitors , Small Molecule Libraries , Amyloid beta-Protein Precursor/biosynthesis , Amyloid beta-Protein Precursor/genetics , Carbamates/chemical synthesis , Carbamates/chemistry , Carbamates/pharmacology , Cell Line , Cell Membrane/drug effects , Cell Membrane/enzymology , Cell Membrane/metabolism , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Humans , Molecular Structure , Mutation , Phase Transition , Small Molecule Libraries/chemical synthesis , Small Molecule Libraries/chemistry , Small Molecule Libraries/pharmacology , Solutions , Structure-Activity Relationship
12.
Bioorg Med Chem Lett ; 17(1): 57-62, 2007 Jan 01.
Article in English | MEDLINE | ID: mdl-17055268

ABSTRACT

A novel piperidine series of gamma-secretase inhibitors, potentially useful for the treatment of Alzheimer's disease, is disclosed. SAR investigation revealed the requirement for cis-stereochemistry of the substituents attached to the core, which resulted in the chair-like diaxial conformation of the piperidine ring. The series was optimized to provide inhibitors with IC(50)'s in the single-digit nanomolar range. Absolute stereochemistry of the active enantiomer was assigned.


Subject(s)
Alzheimer Disease/drug therapy , Amyloid Precursor Protein Secretases/antagonists & inhibitors , Piperidines/chemistry , Protease Inhibitors/chemistry , Inhibitory Concentration 50 , Piperidines/chemical synthesis , Protease Inhibitors/chemical synthesis , Stereoisomerism , Structure-Activity Relationship
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