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1.
ACS Med Chem Lett ; 8(9): 947-952, 2017 Sep 14.
Article in English | MEDLINE | ID: mdl-28947942

ABSTRACT

We have discovered a novel series of isothiazole-based phenylpropanoic acids as GPR120 agonists. Extensive structure-activity relationship studies led to the discovery of a potent GPR120 agonist 4x, which displayed good EC50 values in both calcium and ß-arrestin assays. It also presented good pharmaceutical properties and a favorable PK profile. Moreover, it demonstrated in vivo antidiabetic activity in C57BL/6 DIO mice. Studies in WT and knockout DIO mice showed that it improved glucose handling during an OGTT via GPR120. Overall, 4x possessed promising antidiabetic effect and good safety profile to be a development candidate.

2.
Bioorg Med Chem Lett ; 27(15): 3272-3278, 2017 08 01.
Article in English | MEDLINE | ID: mdl-28642104
3.
Bioorg Med Chem Lett ; 24(4): 1239-42, 2014 Feb 15.
Article in English | MEDLINE | ID: mdl-23916257

ABSTRACT

SAR study of 5-aminooctahydrocyclopentapyrrole-3a-carboxamide scaffold led to identification of several CCR2 antagonists with potent activity in both binding and functional assays. Their cardiovascular safety and pharmacokinetic properties were also evaluated.


Subject(s)
Cyclopentanes/pharmacology , Drug Discovery , Pyrroles/pharmacology , Receptors, CCR2/antagonists & inhibitors , Cyclopentanes/chemical synthesis , Cyclopentanes/chemistry , Dose-Response Relationship, Drug , Humans , Molecular Conformation , Pyrroles/chemical synthesis , Pyrroles/chemistry , Structure-Activity Relationship
4.
Bioorg Med Chem Lett ; 23(1): 351-4, 2013 Jan 01.
Article in English | MEDLINE | ID: mdl-23182090

ABSTRACT

Novel CCR2 antagonists with a novel 2-aminooctahydrocyclopentalene-3a-carboxamide scaffold were designed. SAR studies led to a series of potent compounds. For example, compound 51 had a good PK profile in both dog and monkey, and exhibited excellent efficacy when dosed orally in an inflammation model in hCCR2 KI mice. In addition, an asymmetric synthesis to the core structures was developed.


Subject(s)
Amides/chemistry , Bridged Bicyclo Compounds, Heterocyclic/chemistry , Cyclopentanes/chemistry , Pyridines/chemistry , Receptors, CCR2/antagonists & inhibitors , Administration, Oral , Amides/pharmacokinetics , Amides/therapeutic use , Animals , Bridged Bicyclo Compounds, Heterocyclic/pharmacokinetics , Bridged Bicyclo Compounds, Heterocyclic/therapeutic use , Disease Models, Animal , Dogs , Half-Life , Haplorhini , Humans , Inflammation/drug therapy , Mice , Mice, Knockout , Protein Binding , Pyridines/pharmacokinetics , Pyridines/therapeutic use , Receptors, CCR2/genetics , Receptors, CCR2/metabolism , Stereoisomerism , Structure-Activity Relationship
5.
Bioorg Med Chem Lett ; 22(14): 4869-72, 2012 Jul 15.
Article in English | MEDLINE | ID: mdl-22695132

ABSTRACT

A small set of acyclic analogs 5 were prepared to explore their structure-activity relationships (SARs) relative to heterocyclic core, opioid receptor (OR) agonists 4. Compound 5l was found to have very favorable OR binding affinities at the δ and µ ORs (r K(i) δ=1.3 nM; r K(i) µ=0.9 nM; h K(i) µ=1.7 nM), with less affinity for the κ OR (gp K(i) κ=55 nM). The OR functional profile for 5l varied from the previously described dual δ/µ OR agonists 4, with 5l being a potent, mixed dual δ OR antagonist/µ OR agonist [δ IC(50)=89 nM (HVD); µ EC(50)=1 nM (GPI); κ EC(50)=1.6 µM (GPC)]. Compound 5l has progressed through a clinical Phase II Proof of Concept study on 800 patients suffering from diarrhea-predominant Irritable Bowel Syndrome (IBS-d). This Phase II study was recently completed successfully, with 5l demonstrating statistically significant efficacy over placebo.


Subject(s)
Diarrhea/etiology , Irritable Bowel Syndrome/drug therapy , Receptors, Opioid, delta/antagonists & inhibitors , Receptors, Opioid, mu/agonists , Clinical Trials, Phase II as Topic , Humans , Irritable Bowel Syndrome/complications , Molecular Structure , Structure-Activity Relationship
7.
Toxicol Sci ; 117(2): 493-504, 2010 Oct.
Article in English | MEDLINE | ID: mdl-20616206

ABSTRACT

The unexpected observation of a hyperglycemic effect of some tricycle-based delta opioid receptor (DOR) agonists led to a series of studies to better understand the finding. Single administration of two novel tricyclic DOR agonists dose dependently elevated rat plasma glucose levels; 4-week toxicology studies confirmed the hyperglycemic finding and further revealed pancreatic ß-cell hypertrophy, including vacuole formation, as well as bone dysplasia and Harderian gland degeneration with regeneration. Similar diabetogenic effects were observed in dog. A review of the literature on the antiserotonergic and antihistaminergic drug cyproheptadine (CPH) and its metabolites revealed shared structural features as well as similar hyperglycemic effects to the present series of DOR agonists. To further evaluate these effects, we established an assay measuring insulin levels in the rat pancreatic ß-cell-derived RINm5F cell line, extensively used to study CPH and its metabolites. Like CPH, the initial DOR agonists studied reduced RINm5F cell insulin levels in a concentration-dependent manner. Importantly, compound DOR potency did not correlate with the insulin-reducing potency. Furthermore, the RINm5F cell insulin results correlated with the diabetogenic effect of the compounds in a 5-day mouse study. The RINm5F cell insulin assay enabled the identification of aryl-aryl-amine DOR agonists that lacked an insulin-reducing effect and did not elevate blood glucose in repeated dosing studies conducted over a suprapharmacologic dose range. Thus, not only did the RINm5F cell assay open a path for the further discovery of DOR agonists lacking diabetogenic potential but also it established a reliable, economical, and high-throughput screen for such potential, regardless of chemotype or target pharmacology. The present findings also suggest a mechanistic link between the toxicity observed here and that underlying Wolcott-Rallison Syndrome.


Subject(s)
Cyproheptadine/toxicity , Hyperglycemia/chemically induced , Insulin-Secreting Cells/drug effects , Narcotic Antagonists/toxicity , Pancreas/drug effects , Serotonin Antagonists/toxicity , Animals , Blood Glucose/analysis , Blood Glucose/drug effects , Cell Enlargement/drug effects , Cell Line, Tumor , Cyproheptadine/analogs & derivatives , Diabetes Mellitus, Type 1/metabolism , Dogs , Epiphyses/abnormalities , Epiphyses/metabolism , Female , High-Throughput Screening Assays , Hyperglycemia/metabolism , Insulin/blood , Insulin-Secreting Cells/metabolism , Insulin-Secreting Cells/pathology , Insulinoma/drug therapy , Insulinoma/metabolism , Male , Mice , Osteochondrodysplasias/metabolism , Pancreas/metabolism , Pancreas/pathology , Rats , Rats, Sprague-Dawley , Vacuoles/drug effects , Vacuoles/ultrastructure
8.
Pharmacol Biochem Behav ; 96(2): 130-5, 2010 Aug.
Article in English | MEDLINE | ID: mdl-20438745

ABSTRACT

Discovered as part of an effort to identify delta opioid (DOPr or DOR) agonist analgesics, JNJ-20788560 and JNJ-39204880 exhibited high DOR affinity, with K(i) values of 1.7 and 2.0nM, respectively, and were selective for DOR over the mu opioid receptor (MOPr or MOR), with 596- and 122-fold selectivity, respectively. Both compounds stimulated DOR but not MOR induced GTPgammaS binding and were effective antihyperalgesic agents in the complete Freund's adjuvant model of thermal hyperalgesia in the rat, with oral ED(50) values of 13.5 and 35mg/kg, corresponding to plasma levels of 1 and 9microM, respectively. Autoradiographic analysis of DOR and MOR occupancy in sections of brain (striatum) and lumbar spinal cord (L4-L6) was determined ex vivo, using radiolabeled naltrindole or DAMGO. Quantitative image analysis resulted in striatal DOR ED(50) values of 6.9 and 10.7mg/kg, for JNJ-20788560 and JNJ-39204880 respectively, and spinal cord values of 6.4 and 3.2mg/kg, respectively. Neither compound dose-dependently occupied MOR within the dose range studied. Thus, this study confirmed the DOR selectively over MOR of both compounds following their oral administration, and further demonstrated dose-dependent DOR occupancy by each compound across its antihyperalgesic dose range. Importantly, these in vitro, in vivo, and ex vivo data revealed that the greater in vitro potency of JNJ-20788560 was paralleled by its greater in vivo potency, although JNJ-39204880 achieved higher plasma levels following its oral administration. The receptor occupancy levels observed at the pharmacologic ED(50) doses of these compounds suggest the need for greater target engagement by JNJ-39204880 than by JNJ-20788560 to elicit a similar therapeutic response.


Subject(s)
Analgesics, Opioid/pharmacology , Autoradiography/methods , Azabicyclo Compounds/pharmacology , Pyrimidines/pharmacology , Pyrrolidines/pharmacology , Receptors, Opioid, delta/agonists , Xanthenes/pharmacology , Analgesics, Opioid/blood , Animals , Azabicyclo Compounds/blood , Corpus Striatum/diagnostic imaging , Corpus Striatum/metabolism , Dose-Response Relationship, Drug , Enkephalin, Ala(2)-MePhe(4)-Gly(5)-/analysis , Guanosine 5'-O-(3-Thiotriphosphate)/metabolism , Lumbar Vertebrae/diagnostic imaging , Male , Naltrexone/analogs & derivatives , Naltrexone/analysis , Pain Measurement/drug effects , Pyrimidines/blood , Pyrrolidines/blood , Radiography , Radioligand Assay/methods , Rats , Rats, Sprague-Dawley , Rats, Wistar , Receptors, Opioid, delta/metabolism , Receptors, Opioid, mu/drug effects , Receptors, Opioid, mu/metabolism , Spinal Cord/diagnostic imaging , Spinal Cord/metabolism , Xanthenes/blood
9.
Chem Commun (Camb) ; 46(8): 1347-9, 2010 Feb 28.
Article in English | MEDLINE | ID: mdl-20449299

ABSTRACT

The first chemoselective direct dehydrative cross-coupling of tautomerizable heterocycles with alkynes has been achieved via C-H/C-OH bond activations with direct C(sp(2))-C(sp) bond formation, which is in line with ideal synthesis using readily available materials.


Subject(s)
Alkynes/chemistry , Heterocyclic Compounds/chemistry , Organophosphorus Compounds/chemistry , Catalysis , Copper/chemistry , Palladium/chemistry
10.
Bioorg Med Chem Lett ; 16(9): 2505-8, 2006 May 01.
Article in English | MEDLINE | ID: mdl-16483774

ABSTRACT

Using previously reported opioid receptor (OR) agonist analogs 4a-c as starting points, the structure-activity relationship (SAR) for their related series has been further refined. This SAR study has led to the identification of 2,6-di-Me-Tyr (DMT) analogs 4h and 4j as the most potent OR agonist within the series. In addition, it was discovered that 4-(aminocarbonyl)-2,6-dimethyl-Phe is a reasonable bioisostere surrogate for the DMT moiety, as supported by the OR activities of compounds 4x and 4y.


Subject(s)
Imidazoles/pharmacology , Receptors, Opioid/agonists , Imidazoles/chemical synthesis , Imidazoles/chemistry , Molecular Structure , Stereoisomerism , Structure-Activity Relationship
11.
J Am Chem Soc ; 127(43): 15296-303, 2005 Nov 02.
Article in English | MEDLINE | ID: mdl-16248672

ABSTRACT

This paper describes a systematic study of addition reactions between the chiral Ni(II) complex of the Schiff base of glycine with (S)-o-[N-(N-benzylprolyl)amino]benzophenone and (S)- or (R)-3-[(E)-enoyl]-4-phenyl-1,3-oxazolidin-2-ones as a general and synthetically efficient approach to beta-substituted pyroglutamic acids and relevant compounds. These reactions were shown to occur at room temperature in the presence of nonchelating organic bases and, most notably, with very high (>98% diastereomeric excess (de)) stereoselectivity at both newly formed stereogenic centers. The stereochemical outcome of the reactions was found to be overwhelmingly controlled by the stereochemical preferences of the Michael acceptors, and the chirality of the glycine complex influenced only the reaction rate. Thus, in the reactions of both the (S)-configured Ni(II) complex and the Michael acceptors, the reaction rates were exceptionally high, allowing preparation of the corresponding products with virtually quantitative (>98%) chemical and stereochemical yields. In contrast, reactions of the (S)-configured Ni(II) complex and (R)-configured Michael acceptors proceeded at noticeably lower rates, but the addition products were obtained in high diastereo- and enantiomeric purity. To rationalize the remarkably high and robust stereoselectivity observed in these reactions, we consider an enzyme-substrate-like mode of interaction involving a topographical match or mismatch of two geometric figures. Excellent chemical and stereochemical yields, combined with the simplicity and operational convenience of the experimental procedures, render the present method of immediate use for preparing various beta-substituted pyroglutamic acids and related compounds.


Subject(s)
Glycine/chemistry , Nickel/chemistry , Oxazolidinones/chemistry , Pyrrolidonecarboxylic Acid/chemistry , Catalysis , Kinetics , Models, Chemical , Molecular Structure , Schiff Bases/chemistry , Spectrometry, Mass, Fast Atom Bombardment , Stereoisomerism
12.
J Org Chem ; 69(15): 4984-90, 2004 Jul 23.
Article in English | MEDLINE | ID: mdl-15255725

ABSTRACT

This study demonstrates a new strategy for controlling the stereochemical outcome of the Michael addition reactions between nucleophilic glycine equivalents and alpha,beta-unsaturated carboxylic acid derivatives: The addition reactions between achiral Ni(II)-complex of the Schiff base of glycine with o-[N-alpha-pycolylamino]acetophenone and (S)- or (R)-3-(E-enoyl)-4-phenyl-1,3-oxazolidin-2-ones were shown to occur at room temperature in the presence of nonchelating organic bases and, most notably, with very high stereoselectivity at both newly formed stereogenic centers. Thus, the chiral 4-phenyl-1,3-oxazolidin-2-one moiety was found to control efficiently both face diastereoselectivities of the glycine derived enolate and the C,C double bond of the Michael acceptor. The new strategy developed in this work is methodologically superior to previous methods, most notably in terms of generality and synthetic efficiency. Excellent chemical yields and diastereoselectivities, combined with the simplicity of the experimental procedures, render the present method of immediate use for preparing various 3-substituted pyroglutamic acids and related amino acids (glutamic acids, glutamines, prolines, etc.) available via conventional transformations of the former.


Subject(s)
Glycine/chemistry , Proline/chemical synthesis , Pyrrolidonecarboxylic Acid/chemical synthesis , Molecular Structure , Proline/chemistry , Pyrrolidonecarboxylic Acid/chemistry , Stereoisomerism
13.
J Org Chem ; 67(18): 6353-60, 2002 Sep 06.
Article in English | MEDLINE | ID: mdl-12201753

ABSTRACT

A stereoselective method has been developed for the synthesis of 7- and 8-substituted dipeptide beta-turn mimetic azabicyclo[4.3.0]nonane amino acid esters. The allyl groups were introduced in high diastereoselectivity, controlled by 3-phenyl or 4-benzyl groups in pyroglutamic acid derivatives 3 or 9, respectively. The precursors, dehydroamino acids 7 and 13 derived from 5 or 11, underwent asymmetric hydrogenations with Burk's DuPHOS Rh(I)-based catalysts to furnish alpha-amino acid derivatives in high stereoselectivity. The resulting amino acids 8 and 14 were converted to the beta-turn mimetics 6,5-bicyclic lactams 1a-d in high yields.


Subject(s)
Amino Acids/chemistry , Aza Compounds/chemical synthesis , Bridged Bicyclo Compounds/chemical synthesis , Combinatorial Chemistry Techniques , Peptides/chemical synthesis , Catalysis , Cyclization , Esters , Indicators and Reagents , Molecular Mimicry , Molecular Structure , Protein Conformation , Stereoisomerism , Structure-Activity Relationship
14.
J Org Chem ; 67(4): 1399-402, 2002 Feb 22.
Article in English | MEDLINE | ID: mdl-11846696

ABSTRACT

The asymmetric synthesis of beta-phenyl-substituted cysteine, tryptophan, and serine derivatives was successfully developed. In this approach, the key intermediate, enantiomerically pure 3-phenylaziridine-2-carboxylic ester 7, was prepared from alpha,beta-unsaturated ester 1 by employing the Sharpless asymmetric dihydroxylation. The aziridine 7 was treated with 4-methoxybenzylthiol, indole, and acetic acid to give beta-phenyl-substituted cysteine, tryptophan, and serine, respectively, in a clean S(N)2 type ring opening at the C3 position. This general approach can be used to synthesize a variety of beta-substituted novel amino acids.


Subject(s)
Aziridines/chemical synthesis , Cysteine/analogs & derivatives , Cysteine/chemical synthesis , Serine/analogs & derivatives , Serine/chemical synthesis , Tryptophan/analogs & derivatives , Tryptophan/chemical synthesis , Amino Acids/chemical synthesis , Aziridines/chemistry , Benzene Derivatives/chemical synthesis , Benzene Derivatives/chemistry , Catalysis , Chromatography, Thin Layer , Cyclization , Cysteine/chemistry , Magnetic Resonance Spectroscopy , Mass Spectrometry , Molecular Structure , Phenylalanine/analogs & derivatives , Phenylalanine/chemical synthesis , Serine/chemistry , Stereoisomerism , Tryptophan/chemistry
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