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1.
ACS Med Chem Lett ; 7(7): 666-70, 2016 Jul 14.
Article in English | MEDLINE | ID: mdl-27437074

ABSTRACT

Two 1-(4-aryl-5-alkyl-pyridin-2-yl)-3-methylurea glucokinase activators were identified with robust in vivo efficacy. These two compounds possessed higher solubilities than the previously identified triaryl compounds (i.e., AM-2394). Structure-activity relationship studies are presented along with relevant pharmacokinetic and in vivo data.

2.
ACS Med Chem Lett ; 7(7): 714-8, 2016 Jul 14.
Article in English | MEDLINE | ID: mdl-27437083

ABSTRACT

Glucokinase (GK) catalyzes the phosphorylation of glucose to glucose-6-phosphate. We present the structure-activity relationships leading to the discovery of AM-2394, a structurally distinct GKA. AM-2394 activates GK with an EC50 of 60 nM, increases the affinity of GK for glucose by approximately 10-fold, exhibits moderate clearance and good oral bioavailability in multiple animal models, and lowers glucose excursion following an oral glucose tolerance test in an ob/ob mouse model of diabetes.

3.
Bioorg Med Chem Lett ; 26(1): 15-20, 2016 Jan 01.
Article in English | MEDLINE | ID: mdl-26620255

ABSTRACT

As a follow-up to the GPR40 agonist AMG 837, which was evaluated in clinical trials for the treatment of type II diabetes, further optimization led to the discovery of AM-3189 (13k). AM-3189 is representative of a new class of compounds with minimal CNS penetration, superior pharmacokinetic properties and in vivo efficacy comparable to AMG 837.


Subject(s)
Drug Discovery , Imidazoles/chemistry , Imidazoles/pharmacology , Receptors, G-Protein-Coupled/agonists , Animals , Dogs , Dose-Response Relationship, Drug , Humans , Imidazoles/chemical synthesis , Macaca fascicularis , Mice , Molecular Structure , Rats , Structure-Activity Relationship
4.
ACS Med Chem Lett ; 5(12): 1284-9, 2014 Dec 11.
Article in English | MEDLINE | ID: mdl-25516785

ABSTRACT

Glucokinase (GK) activators represent a class of type 2 diabetes therapeutics actively pursued due to the central role that GK plays in regulating glucose homeostasis. Herein we report a novel C5-alkyl-2-methylurea-substituted pyridine series of GK activators derived from our previously reported thiazolylamino pyridine series. Our efforts in optimizing potency, enzyme kinetic properties, and metabolic stability led to the identification of compound 26 (AM-9514). This analogue showed a favorable combination of in vitro potency, enzyme kinetic properties, acceptable pharmacokinetic profiles in preclinical species, and robust efficacy in a rodent PD model.

5.
ACS Med Chem Lett ; 5(4): 384-9, 2014 Apr 10.
Article in English | MEDLINE | ID: mdl-24900845

ABSTRACT

We recently reported the discovery of a potent GPR40 full agonist AM-1638 (1). Herein, we describe our efforts in improving the drug-like properties of the full agonists through the systematic introduction of polar groups in the C-, D-, and A-rings. This led to the discovery of new GPR40 full agonists with significantly improved pharmacokinetic propeties. Compound 8 and 20 also showed potent in vivo efficacy in oral glucose tolerance tests in mice in addition to the improvement in properties.

6.
J Med Chem ; 55(17): 7667-85, 2012 Sep 13.
Article in English | MEDLINE | ID: mdl-22876881

ABSTRACT

Structure-based rational design led to the synthesis of a novel series of potent PI3K inhibitors. The optimized pyrrolopyridine analogue 63 was a potent and selective PI3Kß/δ dual inhibitor that displayed suitable physicochemical properties and pharmacokinetic profile for animal studies. Analogue 63 was found to be efficacious in animal models of inflammation including a keyhole limpet hemocyanin (KLH) study and a collagen-induced arthritis (CIA) disease model of rheumatoid arthritis. These studies highlight the potential therapeutic value of inhibiting both the PI3Kß and δ isoforms in the treatment of a number of inflammatory diseases.


Subject(s)
Drug Discovery , Drug Evaluation, Preclinical , Phosphoinositide-3 Kinase Inhibitors , Protein Kinase Inhibitors/pharmacology , Models, Molecular
7.
Bioorg Med Chem Lett ; 18(3): 1037-41, 2008 Feb 01.
Article in English | MEDLINE | ID: mdl-18178086

ABSTRACT

The LPA(2) protein is overexpressed in many tumor cells. We report the optimization of a series of LPA(2) antagonists using calcium mobilization assay (aequorin assay) that led to the discovery of the first reported inhibitors selective for LPA(2). Key compounds were evaluated in vitro for inhibition of LPA(2) mediated Erk activation and proliferation of HCT-116 cells. These compounds could be used to evaluate the benefits of LPA(2) inhibition both in vitro and in vivo.


Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Combinatorial Chemistry Techniques , Extracellular Signal-Regulated MAP Kinases/metabolism , Receptors, Lysophosphatidic Acid/antagonists & inhibitors , Antineoplastic Agents/chemistry , Dose-Response Relationship, Drug , Drug Design , Humans , Molecular Structure , Tumor Cells, Cultured
8.
Bioorg Med Chem Lett ; 16(9): 2347-51, 2006 May 01.
Article in English | MEDLINE | ID: mdl-16298130

ABSTRACT

A series of 1-aryloxy-3-piperidinylpropan-2-ols possessing potent dual 5-HT1A receptor antagonism and serotonin reuptake inhibition was discovered. 1-(1H-Indol-4-yloxy)-3-(4-benzo[b]thiophen-2-ylpiperidinyl)propan-2-ols exhibited selective and high affinities at the 5-HT1A receptor and serotonin reuptake site in vitro. In vivo evaluation of this series of compounds demonstrated elevated extracellular serotonin levels from the basal and quick recovery of neuron firing that was presumably suppressed by the initial acute activation of 5-HT1A somatodendritic autoreceptors.


Subject(s)
Antidepressive Agents/pharmacology , Piperidines/pharmacology , Propanols/pharmacology , Selective Serotonin Reuptake Inhibitors/pharmacology , Serotonin 5-HT1 Receptor Antagonists , Animals , Antidepressive Agents/administration & dosage , Antidepressive Agents/chemistry , Brain/drug effects , Drug Evaluation, Preclinical , In Vitro Techniques , Male , Molecular Conformation , Piperidines/administration & dosage , Piperidines/chemistry , Propanols/administration & dosage , Propanols/chemistry , Rats , Rats, Sprague-Dawley , Selective Serotonin Reuptake Inhibitors/administration & dosage , Selective Serotonin Reuptake Inhibitors/chemistry , Stereoisomerism , Structure-Activity Relationship
10.
Bioorg Med Chem Lett ; 14(1): 245-50, 2004 Jan 05.
Article in English | MEDLINE | ID: mdl-14684336

ABSTRACT

With the aim of reducing molecular weight and adjusting log D value of BACE inhibitors to more favorable range for BBB penetration and better bioavailability, we synthesized and evaluated several series of P3 cap modified BACE inhibitors obtained via replacement of the P3NHBoc moiety as seen in 3 with other polar functional groups such as amino, hydroxyl and fluorine. Several promising inhibitors emerging from this P3 cap SAR study (e.g., 15 and 19) demonstrated good enzyme inhibitory potencies (BACE-1 IC(50) <50 nM) and whole cell activities (IC(50) approximately 1 microM).


Subject(s)
Dipeptides/chemistry , Dipeptides/pharmacology , Endopeptidases/metabolism , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , Amyloid Precursor Protein Secretases , Aspartic Acid Endopeptidases , Cell Line , Humans
13.
Bioorg Med Chem Lett ; 13(11): 1903-5, 2003 Jun 02.
Article in English | MEDLINE | ID: mdl-12749894

ABSTRACT

A series of 1-aryloxy-3-piperidinylpropan-2-ols possessing potent dual 5-HT(1A) receptor antagonism and serotonin reuptake inhibition was discovered. 1-(1H-Indol-4-yloxy)-3-(4-benzo[b]thiophen-2-ylpiperidinyl)propan-2-ols exhibited selective and high affinity at the 5-HT(1A) receptor and serotonin reuptake inhibition at nanomolar concentrations for dual activities.


Subject(s)
Antidepressive Agents, Second-Generation/chemistry , Antidepressive Agents, Second-Generation/pharmacology , Propanols/chemistry , Propanols/pharmacology , Selective Serotonin Reuptake Inhibitors/pharmacology , Serotonin 5-HT1 Receptor Antagonists , Antidepressive Agents, Second-Generation/chemical synthesis , Guanosine 5'-O-(3-Thiotriphosphate)/metabolism , Indoles/chemistry , Indoles/pharmacology , Paroxetine/pharmacology , Propanols/chemical synthesis , Receptor, Serotonin, 5-HT1A/metabolism , Selective Serotonin Reuptake Inhibitors/chemical synthesis , Selective Serotonin Reuptake Inhibitors/chemistry , Structure-Activity Relationship
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