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1.
J Med Chem ; 63(18): 10352-10379, 2020 09 24.
Article in English | MEDLINE | ID: mdl-32900194

ABSTRACT

GPR40/FFAR1 is a G-protein-coupled receptor expressed in pancreatic ß-cells and enteroendocrine cells. GPR40 activation stimulates secretions of insulin and incretin, both of which are the pivotal regulators of glycemic control. Therefore, a GPR40 agonist is an attractive target for the treatment of type 2 diabetes mellitus. Using the reported biaryl derivative 1, we shifted the hydrophobic moiety to the terminal aryl ring and replaced the central aryl ring with piperidine, generating 2-(4,4-dimethylpentyl)phenyl piperidine 4a, which had improved potency for GPR40 and high lipophilicity. We replaced the hydrophobic moiety with N-alkyl-N-aryl benzamides to lower the lipophilicity and restrict the N-alkyl moieties to the presumed lipophilic pocket using the intramolecular π-π stacking of cis-preferential N-alkyl-N-aryl benzamide. Among these, orally available (3S)-3-cyclopropyl-3-(2-((1-(2-((2,2-dimethylpropyl)(6-methylpyridin-2-yl)carbamoyl)-5-methoxyphenyl)piperidin-4-yl)methoxy)pyridin-4-yl)propanoic acid (SCO-267) effectively stimulated insulin secretion and GLP-1 release and ameliorated glucose tolerance in diabetic rats via GPR40 full agonism.


Subject(s)
Benzamides/therapeutic use , Diabetes Mellitus, Experimental/drug therapy , Hypoglycemic Agents/therapeutic use , Piperidines/therapeutic use , Receptors, G-Protein-Coupled/agonists , Animals , Benzamides/chemical synthesis , Benzamides/pharmacokinetics , CHO Cells , Cricetulus , Hypoglycemic Agents/chemical synthesis , Hypoglycemic Agents/pharmacokinetics , Male , Mice, Inbred ICR , Molecular Structure , Piperidines/chemical synthesis , Piperidines/pharmacokinetics , Rats, Sprague-Dawley , Structure-Activity Relationship
2.
ACS Med Chem Lett ; 5(7): 787-92, 2014 Jul 10.
Article in English | MEDLINE | ID: mdl-25050166

ABSTRACT

A cis-configured 3,5-disubstituted piperidine direct renin inhibitor, (syn,rac)-1, was discovered as a high-throughput screening hit from a target-family tailored library. Optimization of both the prime and the nonprime site residues flanking the central piperidine transition-state surrogate resulted in analogues with improved potency and pharmacokinetic (PK) properties, culminating in the identification of the 4-hydroxy-3,5-substituted piperidine 31. This compound showed high in vitro potency toward human renin with excellent off-target selectivity, 60% oral bioavailability in rat, and dose-dependent blood pressure lowering effects in the double-transgenic rat model.

3.
Bioorg Med Chem Lett ; 18(19): 5280-4, 2008 Oct 01.
Article in English | MEDLINE | ID: mdl-18783943

ABSTRACT

We describe here orally active and brain-penetrant cathepsin S selective inhibitors, which are virtually devoid of hERG K(+) channel affinity, yet exhibit nanomolar potency against cathepsin S and over 100-fold selectivity to cathepsin L. The new non-peptidic inhibitors are based on a 2-cyanopyrimidine scaffold bearing a spiro[3.5]non-6-yl-methyl amine at the 4-position. The brain-penetrating cathepsin S inhibitors demonstrate potential clinical utility for the treatment of multiple sclerosis and neuropathic pain.


Subject(s)
Cathepsins/antagonists & inhibitors , Ether-A-Go-Go Potassium Channels/metabolism , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , Administration, Oral , Animals , Brain/drug effects , Cathepsin L , Combinatorial Chemistry Techniques , Cysteine Endopeptidases , Humans , Male , Molecular Structure , Multiple Sclerosis/drug therapy , Pain/drug therapy , Pyrimidines/blood , Pyrimidines/pharmacokinetics , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship
4.
J Med Chem ; 51(17): 5459-62, 2008 Sep 11.
Article in English | MEDLINE | ID: mdl-18707091

ABSTRACT

On the basis of the pyrrolopyrimidine core structure that was previously discovered, cathepsin K inhibitors having a spiro amine at the P3 have been explored to enhance the target, bone marrow, tissue distribution. Several spiro structures were identified with improved distribution toward bone marrow. The representative inhibitor 7 of this series revealed in vivo reduction in C-terminal telopeptide of type I collagen in rats and monkeys.


Subject(s)
Bone Resorption/drug therapy , Cathepsins/antagonists & inhibitors , Cysteine Proteinase Inhibitors/chemistry , Cysteine Proteinase Inhibitors/pharmacokinetics , Animals , Bone Marrow/metabolism , Cathepsin K , Collagen Type I/metabolism , Haplorhini , Pyrimidines/chemistry , Pyrimidines/pharmacology , Pyrroles/chemistry , Pyrroles/pharmacology , Rats , Spiro Compounds , Tissue Distribution
6.
Bioorg Med Chem Lett ; 18(16): 4642-6, 2008 Aug 15.
Article in English | MEDLINE | ID: mdl-18662880

ABSTRACT

We describe here a novel 4-amino-2-cyanopyrimidine scaffold for nonpeptidomimetic cathepsin S selective inhibitors. Some of the synthesized compounds have sub-nanomolar potency and high selectivity toward cathepsin S along with promising pharmacokinetic and physicochemical properties. The key structural features of the inhibitors consist of a combination of a spiro[2.5]oct-6-ylmethylamine P2 group at the 4-position, a small or polar P3 group at the 5-position and/or a polar group at the 6-position of the pyrimidine.


Subject(s)
Cathepsins/antagonists & inhibitors , Chemistry, Pharmaceutical/methods , Cysteine Proteinase Inhibitors/chemical synthesis , Nitriles/chemical synthesis , Peptides/chemistry , Pyrimidines/chemistry , Pyrimidines/chemical synthesis , Animals , Cysteine Proteinase Inhibitors/pharmacology , Drug Design , Humans , Inhibitory Concentration 50 , Male , Molecular Conformation , Nitriles/pharmacology , Pyrimidines/pharmacology , Rats , Rats, Sprague-Dawley , Recombinant Proteins/chemistry , Structure-Activity Relationship
7.
Bioorg Med Chem Lett ; 18(14): 3959-62, 2008 Jul 15.
Article in English | MEDLINE | ID: mdl-18572405

ABSTRACT

Nonpeptidic, selective, and potent cathepsin S inhibitors were derived from an in-house pyrrolopyrimidine cathepsin K inhibitor by modification of the P2 and P3 moieties. The pyrrolopyrimidine-based inhibitors show nanomolar inhibition of cathepsin S with over 100-fold selectivity against other cysteine proteases, including cathepsin K and L. Some of the inhibitors showed cellular activities in mouse splenocytes as well as oral bioavailabilities in rats.


Subject(s)
Cathepsins/antagonists & inhibitors , Cysteine Endopeptidases/chemical synthesis , Cysteine Proteinase Inhibitors/chemical synthesis , Biological Availability , Cathepsin K , Cathepsin L , Cathepsins/chemistry , Chemistry, Pharmaceutical , Cysteine Endopeptidases/chemistry , Cysteine Proteinase Inhibitors/pharmacology , Drug Design , Humans , Inhibitory Concentration 50 , Models, Chemical , Molecular Conformation , Molecular Structure , Pyridines/chemistry , Structure-Activity Relationship
9.
Chemistry ; 12(22): 5868-77, 2006 Jul 24.
Article in English | MEDLINE | ID: mdl-16718730

ABSTRACT

An efficient divergent synthesis of L-sugars and L-iminosugars from D-sugars is described. The important intermediate, delta-hydroxyalkoxamate, prepared from D-glucono-/galactono-1,5-lactone, was cyclized under Mitsunobu conditions to give the O-cyclized oxime compound and the N-cyclized lactam compound as mixtures. A more detailed investigation revealed that the appropriate protecting groups and solvents controlled the specificity for the O-/N-cyclization of the delta-hydroxyalkoxamate. Suitable protection at the 6-position of delta-hydroxyalkoxamate, derived from D-glucono-1,5-lactone, afforded the corresponding O-alkylation product alone. Thus we succeeded in applying this to the total synthesis of L-iduronic acid. In contrast, with both TBDMS as the protecting group and RCN as the solvent the efficient conversion of D-glucono/galactono-1,5-lactone into the corresponding L-iminosugars (L-idonolactam and L-altronolactam) was achieved.


Subject(s)
Carbohydrates/chemical synthesis , Iduronic Acid/chemical synthesis , Imino Sugars/chemical synthesis , Carbohydrate Conformation , Carbohydrates/chemistry , Cyclization , Lactones/chemistry , Siloxanes/chemistry , Styrenes/chemistry
10.
Org Lett ; 4(14): 2401-3, 2002 Jul 11.
Article in English | MEDLINE | ID: mdl-12098257

ABSTRACT

[reaction: see text] D-Mannono-1,4-lactone was efficiently converted into L-ribose in eight steps. A key step of this synthesis is the cyclization of a gamma-hydroxyalkoxamate under Mitsunobu conditions. It is noteworthy that the O-alkylation product was obtained in 94% yield and that none of the N-alkylation product was detected in this cyclization.


Subject(s)
4-Butyrolactone/analogs & derivatives , 4-Butyrolactone/chemistry , Ribose/chemical synthesis , Alkylation , Cyclization , Indicators and Reagents
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