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1.
J Med Chem ; 56(22): 9019-30, 2013 Nov 27.
Article in English | MEDLINE | ID: mdl-24205976

ABSTRACT

Broad-spectrum anticonvulsants are of considerable interest as antiepileptic drugs, especially because of their potential for treating refractory patients. Such "neurostabilizers" have also been used to treat other neurological disorders, including migraine, bipolar disorder, and neuropathic pain. We synthesized a series of sulfamide derivatives (4-9, 10a-i, 11a, 11b, 12) and evaluated their anticonvulsant activity. Thus, we identified promising sulfamide 4 (JNJ-26489112) and explored its pharmacological properties. Compound 4 exhibited excellent anticonvulsant activity in rodents against audiogenic, electrically induced, and chemically induced seizures. Mechanistically, 4 inhibited voltage-gated Na(+) channels and N-type Ca(2+) channels and was effective as a K(+) channel opener. The anticonvulsant profile of 4 suggests that it may be useful for treating multiple forms of epilepsy (generalized tonic-clonic, complex partial, absence seizures), including refractory (or pharmacoresistant) epilepsy, at dose levels that confer a good safety margin. On the basis of its pharmacology and other favorable characteristics, 4 was advanced into human clinical studies.


Subject(s)
Amides/chemistry , Amides/pharmacology , Anticonvulsants/chemistry , Anticonvulsants/pharmacology , Dioxanes/chemistry , Dioxanes/pharmacology , Sulfonamides/chemistry , Sulfonamides/pharmacology , Absorption , Amides/pharmacokinetics , Amides/therapeutic use , Animals , Anticonvulsants/pharmacokinetics , Anticonvulsants/therapeutic use , Dioxanes/pharmacokinetics , Dioxanes/therapeutic use , Dogs , Drug Evaluation, Preclinical , Drug Resistance , Epilepsy/drug therapy , Female , Humans , Male , Mice , Rats , Sulfonamides/pharmacokinetics , Sulfonamides/therapeutic use
2.
Bioorg Med Chem Lett ; 22(16): 5326-9, 2012 Aug 15.
Article in English | MEDLINE | ID: mdl-22795331

ABSTRACT

Inhibitors of ketohexokinase (KHK) have potential for the treatment of diabetes and obesity. We have continued studies on a pyrimidinopyrimidine series of potent KHK inhibitors by exploring the 2-position substituent (R(3)) that interacts with Asp-27B in the ATP-binding region of KHK (viz. 1, 2; Table 1). We found that increased spacing between the terminal ammonium group and the heterocyclic scaffold (viz. 16-20), such that interaction with Asp-27B is not possible, still results in potent KHK inhibition (IC(50)=15-50 nM). We propose a new interaction with Asp-194, which serves to expand the pyrimidinopyrimidine pharmacophore.


Subject(s)
Enzyme Inhibitors/chemistry , Fructokinases/antagonists & inhibitors , Ligands , Pyrimidines/chemistry , Binding Sites , Computer Simulation , Crystallography, X-Ray , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/metabolism , Fructokinases/metabolism , Hep G2 Cells , Humans , Protein Binding , Protein Structure, Tertiary , Pyrimidines/chemical synthesis , Pyrimidines/metabolism
3.
ACS Med Chem Lett ; 2(7): 538-43, 2011 Jul 14.
Article in English | MEDLINE | ID: mdl-24900346

ABSTRACT

Attenuation of fructose metabolism by the inhibition of ketohexokinase (KHK; fructokinase) should reduce body weight, free fatty acids, and triglycerides, thereby offering a novel approach to treat diabetes and obesity in response to modern diets. We have identified potent, selective inhibitors of human hepatic KHK within a series of pyrimidinopyrimidines (1). For example, 8, 38, and 47 exhibited KHK IC50 values of 12, 7, and 8 nM, respectively, and also showed potent cellular KHK inhibition (IC50 < 500 nM), which relates to their intrinsic potency vs KHK and their ability to penetrate cells. X-ray cocrystal structures of KHK complexes of 3, 8, and 47 revealed the important interactions within the enzyme's adenosine 5'-triphosphate (ATP)-binding pocket.

4.
J Med Chem ; 52(23): 7528-36, 2009 Dec 10.
Article in English | MEDLINE | ID: mdl-19388676

ABSTRACT

In seeking broad-spectrum anticonvulsants to treat epilepsy and other neurological disorders, we synthesized and tested a group of sulfamide derivatives (4a-k, 5), which led to the clinical development of 4a (JNJ-26990990). This compound exhibited excellent anticonvulsant activity in rodents against audiogenic, electrically induced, and chemically induced seizures, with very weak inhibition of human carbonic anhydrase-II (IC(50) = 110 microM). The pharmacological profile for 4a supports its potential in the treatment of multiple forms of epilepsy, including pharmacoresistant variants. Mechanistically, 4a inhibited voltage-gated Na(+) channels and N-type Ca(2+) channels but was not effective as a K(+) channel opener. The pharmacokinetics and metabolic properties of 4a are discussed.


Subject(s)
Amides/chemistry , Amides/pharmacology , Anticonvulsants/chemistry , Anticonvulsants/pharmacology , Sulfonamides/chemistry , Sulfonamides/pharmacology , Thiophenes/chemistry , Thiophenes/pharmacology , Amides/metabolism , Amides/pharmacokinetics , Animals , Anticonvulsants/metabolism , Anticonvulsants/pharmacokinetics , Carbonic Anhydrase II/antagonists & inhibitors , Cell Line , Clinical Trials as Topic , Drug Evaluation, Preclinical , Female , Humans , Male , Mice , Rats , Sulfonamides/metabolism , Sulfonamides/pharmacokinetics , Thiophenes/metabolism , Thiophenes/pharmacokinetics
5.
J Med Chem ; 51(8): 2518-21, 2008 Apr 24.
Article in English | MEDLINE | ID: mdl-18363349

ABSTRACT

The marketed drug topiramate ( 1) is a moderate inhibitor of carbonic anhydrase-II (CA-II) ( K i or K d = 0.3-0.6 microM), whereas sulfamide cognate 2 is a comparatively weak inhibitor ( K i or K d = 25-650 microM). From an X-ray cocrystal structure of 2.CA-II, Winum et al. ( J. Med. Chem. 2006, 49, 7024) proposed that an adverse steric interaction between the C8 methyl group in 2 and Ala-65 of CA-II is responsible for the diminished CA-II inhibitory potency of 2. We performed a straightforward test of this Ala-65 effect by synthesizing and examining ligand 3, which lacks the offending (pro- S or C8) methyl substituent in 2. We also prepared and evaluated related sulfamides 5, 7, and 9. In a CA-II inhibition assay (4-nitrophenyl acetate), the K i for 3 was approximately 300 microM, indicating very weak inhibition, close to that for 2 (4NPA, K i = 340 microM). In a CA-II binding assay (ThermoFluor), the K d for 3 was >57 microM, indicating very weak binding, lower than the affinity of 2 ( K d = 25 microM). Our results draw into question the proposed steric interaction between the C8 methyl of 2 and Ala-65 of CA-II.


Subject(s)
Carbonic Anhydrase II/antagonists & inhibitors , Carbonic Anhydrase Inhibitors/pharmacology , Fructose/analogs & derivatives , Carbonic Anhydrase Inhibitors/chemistry , Crystallography, X-Ray , Fructose/chemistry , Fructose/pharmacology , Kinetics , Magnetic Resonance Spectroscopy , Topiramate
6.
J Org Chem ; 73(6): 2302-10, 2008 Mar 21.
Article in English | MEDLINE | ID: mdl-18278942

ABSTRACT

An improved scale-up synthesis was required for the alpha(V)beta(3)/alpha(V)beta(5) integrin antagonist 1, which had demonstrated oral efficacy in eye disease models of angiogenesis and vascular permeability. A stereodefined, quinoline-substituted, unsaturated ester was conveniently prepared by a Suzuki-Miyaura coupling to facilitate exploration of multiple methods of asymmetric reduction. The catalytic chiral hydrogenation of the corresponding unsaturated acid (Z-5b) with a ruthenium-based metal precursor and the (R)-XylPhanePhos ligand proved particularly efficient and economical. The resulting (3S)-quinoline-containing intermediate was reduced to an equal mixture of tetrahydroquinoline diastereomers. The undesired diastereomer could be recycled to the desired one by an oxidation/reduction protocol. The absolute stereochemistry of 1 was established as 3S,3'S by a combination of X-ray diffraction and chemical means.


Subject(s)
Integrin alphaVbeta3/antagonists & inhibitors , Integrins/antagonists & inhibitors , Naphthyridines/chemical synthesis , Quinolines/chemical synthesis , Receptors, Vitronectin/antagonists & inhibitors , Naphthyridines/chemistry , Naphthyridines/pharmacology , Quinolines/chemistry , Quinolines/pharmacology , Stereoisomerism , X-Ray Diffraction
7.
J Med Chem ; 51(2): 282-97, 2008 Jan 24.
Article in English | MEDLINE | ID: mdl-18159923

ABSTRACT

We have developed a novel series of potent and selective factor Xa inhibitors that employ a key 7-fluoroindazolyl moiety. The 7-fluoro group on the indazole scaffold replaces the carbonyl group of an amide that is found in previously reported factor Xa inhibitors. The structure of a factor Xa cocrystal containing 7-fluoroindazole 51a showed the 7-fluoro atom hydrogen-bonding with the N-H of Gly216 (2.9 A) in the peptide backbone. Thus, the 7-fluoroindazolyl moiety not only occupied the same space as the carbonyl group of an amide found in prior factor Xa inhibitors but also maintained a hydrogen bond interaction with the protein's beta-sheet domain. The structure-activity relationship for this series was consistent with this finding, as the factor Xa inhibitory potencies were about 60-fold greater (DeltaDelta G approximately 2.4 kcal/mol) for the 7-fluoroindazoles 25a and 25c versus the corresponding indazoles 25b and 25d. Highly convergent synthesis of these factor Xa inhibitors is also described.


Subject(s)
Factor Xa Inhibitors , Indazoles/chemical synthesis , Serine Proteinase Inhibitors/chemical synthesis , Caco-2 Cells , Cell Membrane Permeability , Crystallography, X-Ray , Factor Xa/chemistry , Humans , Hydrogen Bonding , In Vitro Techniques , Indazoles/chemistry , Indazoles/pharmacology , Microsomes, Liver/enzymology , Models, Molecular , Protein Conformation , Serine Proteinase Inhibitors/chemistry , Serine Proteinase Inhibitors/pharmacology , Structure-Activity Relationship , Thermodynamics
8.
Bioorg Med Chem Lett ; 17(23): 6623-8, 2007 Dec 01.
Article in English | MEDLINE | ID: mdl-17942308

ABSTRACT

We have continued to explore spirobenzazepines as vasopressin receptor antagonists to follow up on RWJ-339489 (2), which had advanced into preclinical development. Further structural modifications were pursued to find a suitable backup compound for human clinical studies. Thus, we identified carboxylic acid derivative 3 (RWJ-676070; JNJ-17158063) as a potent, balanced vasopressin V(1a)/V(2) receptor antagonist with favorable properties for clinical development. Compound 3 is currently undergoing human clinical investigation.


Subject(s)
Antidiuretic Hormone Receptor Antagonists , Benzazepines/chemistry , Spiro Compounds/chemistry , Animals , Antihypertensive Agents/administration & dosage , Antihypertensive Agents/chemistry , Antihypertensive Agents/metabolism , Antihypertensive Agents/pharmacokinetics , Benzazepines/administration & dosage , Benzazepines/pharmacokinetics , Benzazepines/pharmacology , Drug Evaluation, Preclinical , Female , Humans , Male , Rats , Rats, Long-Evans , Receptors, Vasopressin/metabolism , Receptors, Vasopressin/physiology , Spiro Compounds/administration & dosage , Spiro Compounds/metabolism , Spiro Compounds/pharmacokinetics , Spiro Compounds/pharmacology , Vasopressins/metabolism
9.
Chem Biol Drug Des ; 68(2): 113-9, 2006 Aug.
Article in English | MEDLINE | ID: mdl-16999776

ABSTRACT

Enzyme inhibition assays often require deviations from physiological conditions. For carbonic anhydrases, procedures involving native CO(2) and non-native substrates have been used. We compared a native and a non-native substrate in the context of inhibition of human carbonic anhydrases I and II by examining various sulfamate and sulfamide compounds in two kinetic assays: hydration of CO(2) and hydrolysis of 4-nitrophenylacetate. For carbonic anhydrase II, the two assays consistently generated similar K(i) values, with the relative difference between the assays never exceeding 2.5-fold. However, for carbonic anhydrase I there was more variability between the two assays, with K(i) values for three compounds differing by more than 2.5-fold, up to eightfold. In the CO(2) hydration assay, some sulfamates and sulfamides exhibited mixed kinetics or partial inhibition. Our results indicate that K(i) or K(d) values from carbonic anhydrase assays involving non-native substrates should be confirmed by assays that use CO(2) (or HCO), to establish pharmacological relevance. From structure-activity comparisons, the sulfamate is more effective than the sulfamide in inhibiting carbonic anhydrase I and II, but the sulfamate does not confer selectivity. In contrast, the sulfonamide confers selectivity for carbonic anhydrase I (10- to 30-fold). Selectivity for carbonic anhydrase II occurred with the substituted fructose moiety, especially the d-enantiomer (>100-fold).


Subject(s)
Carbonic Anhydrase II/antagonists & inhibitors , Carbonic Anhydrase I/antagonists & inhibitors , Carbonic Anhydrase Inhibitors/chemistry , Carbonic Anhydrase Inhibitors/pharmacology , Sulfonic Acids/chemistry , Sulfonic Acids/pharmacology , Kinetics , Structure-Activity Relationship
10.
Chem Biol Drug Des ; 68(1): 29-36, 2006 Jul.
Article in English | MEDLINE | ID: mdl-16923023

ABSTRACT

Compound 2 (RWJ-445167; 3DP-10017), a dual inhibitor of thrombin and factor Xa, was advanced into human clinical studies. However, its oral bioavailability in humans proved to be below acceptable limits. To address this issue, we explored a prodrug approach involving numerous guanidine derivatives. Prodrug candidates of classes A (carbamate derivatives), B (imidate derivatives), and C (alkyl and acyl derivatives), compounds 3-6, were synthesized and evaluated for anticoagulant activity at 2 h after oral administration to rats. In comparison to the parent drug (2), little worthwhile improvement was observed for the prodrug candidates.


Subject(s)
Anticoagulants/pharmacology , Factor Xa Inhibitors , Guanidines/pharmacology , Prodrugs/pharmacology , Sulfonamides/pharmacology , Thrombin/antagonists & inhibitors , Administration, Oral , Animals , Anticoagulants/chemical synthesis , Anticoagulants/pharmacokinetics , Biological Availability , Carbamates/chemical synthesis , Dogs , Guanidine/analogs & derivatives , Guanidine/chemistry , Guanidines/chemical synthesis , Guanidines/pharmacokinetics , Imidoesters/chemical synthesis , Male , Prodrugs/chemical synthesis , Prodrugs/pharmacokinetics , Rats , Rats, Sprague-Dawley , Sulfonamides/chemical synthesis , Sulfonamides/pharmacokinetics , Time Factors
11.
J Med Chem ; 49(12): 3496-500, 2006 Jun 15.
Article in English | MEDLINE | ID: mdl-16759092

ABSTRACT

This paper examines the relative effectiveness of bioisosteric sulfamate and sulfamide derivatives for inhibition of human carbonic anhydrase-II (CA-II) by using a direct binding assay based on the ThermoFluor method (Matulis et al. Biochemistry 2005, 44, 5258). Compounds 1-10, which represent five cognate sulfamate/sulfamide pairs, were studied by ThermoFluor to obtain binding affinities (K(a) values). The corresponding dissociation constants, K(d), provide an independent measure of CA-II activity relative to commonly used K(i) values from enzyme kinetics studies. There was a sizable difference in potency between the sulfamates and sulfamides, with the sulfamides being much less potent, by factors ranging from 25 (7/8) to 1,200 (3/4). These results are consistent with our recent report that sulfamides tend to be much weaker inhibitors of CA-II than their corresponding sulfamates (Maryanoff et al. J. Med. Chem. 2005, 48, 1941). Additionally, for arylsulfamides 10-12 the K(d) values determined by ThermoFluor and the K(i) values determined from enzyme kinetics are consistent. It appears that the sulfamide group is less suitable than the sulfamate group for obtaining potent inhibition of CA-II.


Subject(s)
Carbonic Anhydrase II/antagonists & inhibitors , Carbonic Anhydrase II/chemistry , Carbonic Anhydrase Inhibitors/chemistry , Sulfonamides/chemistry , Sulfonic Acids/chemistry , Dioxolanes/chemistry , Humans , Kinetics , Protein Binding , Structure-Activity Relationship , Thermodynamics
12.
J Med Chem ; 48(6): 1941-7, 2005 Mar 24.
Article in English | MEDLINE | ID: mdl-15771438

ABSTRACT

This paper examines the relative effectiveness of sulfamate and sulfamide groups for the inhibition of carbonic anhydrase-II (CA-II). Topiramate (1) and its sulfamide analogue 4, and 4,5-cyclic sulfate 6 and its sulfamide analogue 5, were compared for inhibition of human CA-II. A colorimetric assay, based on the pH shift that accompanies hydration of carbon dioxide, and an esterase assay were used. For these bioisosteric pairs, 1/4 and 6/5, the sulfamate compound was markedly more potent than its sulfamide counterpart. A similar, large difference in potency was also observed for the sulfamate/sulfamide pairs 14/15 and 16/17. These results indicate that the sulfamide moiety is not particularly suitable for obtaining potent carbonic anhydrase inhibition. A discussion of this structure-activity relationship with respect to the interactions of 1 and 6 with CA-II from published X-ray data is presented. A metabolic acidosis study was performed in rats with 1, 4, 6, and 2, and the results are discussed with respect to the degree of inhibition of CA-II in vivo.


Subject(s)
Anticonvulsants/chemical synthesis , Carbonic Anhydrase II/metabolism , Carbonic Anhydrase Inhibitors/chemical synthesis , Fructose/analogs & derivatives , Fructose/chemical synthesis , Sulfonamides/chemical synthesis , Sulfonic Acids/chemistry , Acidosis/chemically induced , Animals , Anticonvulsants/chemistry , Anticonvulsants/pharmacology , Carbonic Anhydrase II/chemistry , Carbonic Anhydrase Inhibitors/chemistry , Carbonic Anhydrase Inhibitors/pharmacology , Fructose/chemistry , Fructose/pharmacology , Humans , Male , Models, Molecular , Molecular Structure , Protein Binding , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Sulfonamides/chemistry , Sulfonamides/pharmacology , Topiramate
13.
J Med Chem ; 48(6): 1725-8, 2005 Mar 24.
Article in English | MEDLINE | ID: mdl-15771419

ABSTRACT

Novel indolylindazolylmaleimides were synthesized and examined for kinase inhibition. We identified low-nanomolar inhibitors of PKC-beta with good to excellent selectivity vs other PKC isozymes and GSK-3beta. In a cell-based functional assay, 8f and 8i effectively blocked IL-8 release induced by PKC-betaII (IC(50) = 20-25 nM). In cardiovascular safety assessment, representative lead compounds bound to the hERG channel with high affinity, potently inhibited ion current in a patch-clamp experiment, and caused a dose-dependent increase of QT(c) in guinea pigs.


Subject(s)
Indazoles/chemical synthesis , Indoles/chemical synthesis , Maleimides/chemical synthesis , Protein Kinase C/antagonists & inhibitors , Animals , Cell Line , ERG1 Potassium Channel , Ether-A-Go-Go Potassium Channels , Glycogen Synthase Kinase 3/antagonists & inhibitors , Glycogen Synthase Kinase 3/chemistry , Glycogen Synthase Kinase 3 beta , Guinea Pigs , Humans , Indazoles/pharmacology , Indazoles/toxicity , Indoles/pharmacology , Indoles/toxicity , Interleukin-8/metabolism , Isoenzymes/antagonists & inhibitors , Isoenzymes/chemistry , Long QT Syndrome/chemically induced , Maleimides/pharmacology , Maleimides/toxicity , Models, Molecular , Patch-Clamp Techniques , Potassium Channel Blockers/chemical synthesis , Potassium Channel Blockers/chemistry , Potassium Channel Blockers/pharmacology , Potassium Channels, Voltage-Gated/drug effects , Potassium Channels, Voltage-Gated/metabolism , Protein Kinase C/chemistry , Protein Kinase C beta , Structure-Activity Relationship
14.
Bioorg Med Chem Lett ; 13(18): 3049-53, 2003 Sep 15.
Article in English | MEDLINE | ID: mdl-12941331

ABSTRACT

Efficient methods were developed to synthesize a novel series of macrocyclic bisindolylmaleimides containing linkers with multiple heteroatoms. Potent inhibitors (single digit nanomolar IC(50)) for PKC-beta and GSK-3beta were identified, and compounds showed good selectivity over PKC-alpha, -gamma, -delta, -epsilon, and -zeta. Representative compound 5a also had high selectivity in a screening panel of 10 other protein kinases. In cell-based functional assays, several compounds effectively blocked interleukin-8 release induced by PKC-betaII and increased glycogen synthase activity by inhibiting GSK-3beta.


Subject(s)
Indoles/chemical synthesis , Maleimides/chemical synthesis , Protein Kinase C/antagonists & inhibitors , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Cell Line , Cyclization , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Glycogen Synthase Kinase 3/antagonists & inhibitors , Glycogen Synthase Kinase 3 beta , Humans , Indoles/pharmacology , Inhibitory Concentration 50 , Isoenzymes/chemical synthesis , Isoenzymes/pharmacology , Maleimides/pharmacology , Protein Kinase C beta , Structure-Activity Relationship
15.
Bioorg Med Chem Lett ; 13(13): 2199-203, 2003 Jul 07.
Article in English | MEDLINE | ID: mdl-12798334

ABSTRACT

A new generation of indole-based peptide mimetics, bearing a basic amine at the C-terminus, was developed by the agency of two complementary, multistep, trityl resin-based approaches. Thus, we obtained several high-affinity thrombin receptor (PAR-1) ligands, such as 32 and 34. Compounds 32 and 34 were found to bind to PAR-1 with excellent affinity (IC(50)=25 and 35 nM, respectively) and to effectively block platelet aggregation induced by SFLLRN-NH(2) (TRAP-6) and alpha-thrombin.


Subject(s)
Indoles/chemical synthesis , Indoles/pharmacology , Receptors, Thrombin/drug effects , Urea/analogs & derivatives , Amines/chemistry , Hemostatics/antagonists & inhibitors , Hemostatics/pharmacology , Humans , In Vitro Techniques , Indazoles/chemistry , Ligands , Molecular Mimicry , Peptide Fragments/antagonists & inhibitors , Peptide Fragments/pharmacology , Platelet Aggregation/drug effects , Structure-Activity Relationship , Thrombin/antagonists & inhibitors , Thrombin/pharmacology , Urea/chemistry
16.
Bioorg Med Chem ; 11(11): 2463-70, 2003 May 29.
Article in English | MEDLINE | ID: mdl-12735993

ABSTRACT

McN-5652-X, (+)-1, is a potent, selective inhibitor of serotonin reuptake in mammalian brain. When radiolabeled with (11)C, it has served as a positron-emission tomography (PET) radiotracer for in vivo imaging of central serotonin transporters. We have determined the solid-state structures of (+)-1.HClO(4) and (+)-1.(+)-(2R,3R)-tartrate by single-crystal X-ray diffraction, thereby confirming the trans relative configuration (Chemical Abstracts Service rules of nomenclature) and the 6S,10bR absolute configuration for (+)-1. Results from a vibrational circular dichroism (VCD) study on (+)-1 in CDCl(3) are consistent with the 6S,10bR absolute configuration.


Subject(s)
Isoquinolines/chemistry , Membrane Transport Proteins , Nerve Tissue Proteins , Selective Serotonin Reuptake Inhibitors/chemistry , Carrier Proteins/metabolism , Circular Dichroism , Crystallography, X-Ray , Isoquinolines/metabolism , Kinetics , Membrane Glycoproteins/metabolism , Models, Molecular , Serotonin Plasma Membrane Transport Proteins , Selective Serotonin Reuptake Inhibitors/metabolism , Stereoisomerism
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