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PubMed2002

Synthesis and biological characterization of L-N(6)-(1-iminoethyl)lysine 5-tetrazole-amide, a prodrug of a selective iNOS inhibitor.

The 5-tetrazole amide of L-N(6)-(1-iminoethyl)lysine (L-NIL), L-N(6)-(1-iminoethyl)lysine 5-tetrazole amide (1), has been prepared and evaluated. In contrast to L-NIL, 1 is a stable, nonhygroscopic, crystalline solid. Unlike L-NIL, 1 has minimal inhibitory activity in vitro on human inducible nitric oxide synthase (iNOS). However, it is rapidly converted in vivo to L-NIL and produces dose-dependent inhibition of iNOS in acute and chronic models of inflammation in the rodent with efficacy comparable to L-NIL. In addition, both 1 and L-NIL exhibit significant and comparable in vivo selectivity for the inhibition of iNOS vs endothelial NOS. Doses approximately 80-fold greater than those that inhibited inflammation do not elevate systemic blood pressure. In summary, both the physical properties and the pharmacological profile of 1 make it an ideal molecule for preclinical and clinical studies on the role of selective iNOS inhibitors in mediating inflammatory disease processes.

Acute Disease↗
PubMed2003

Aromatic reduced amide bond peptidomimetics as selective inhibitors of neuronal nitric oxide synthase.

Nitric oxide synthase inhibitors could act as important therapies for disorders arising from overstimulation or overexpression of individual nitric oxide synthase (NOS) isoforms. But preservation of physiologically important nitric oxide functions require the use of isoform-selective inhibitors. Recently we reported reduced amide bond pseudodipeptide analogues as potent and selective neuronal nitric oxide synthase (nNOS) inhibitors (Hah, J.-M.; Roman, L. J.; Martasek, P.; Silverman, R. B. J. Med. Chem. 2001, 44, 2667-2670). To increase the lipophilicity a series of aromatic, reduced amide bond analogues (6-25) were designed and synthesized as potential selective nNOS inhibitors. The hypothesized large increase in isoform selectivity of nNOS over inducible NOS was not obtained in this series. However, the high potency with nNOS as well as high selectivity of nNOS over endothelial NOS was retained in some of these compounds (15, 17, 21), as well as good selectivity over inducible NOS. The most potent nNOS inhibitor among these compounds is N-(4S)-[4-amino-5-[2-(2-aminoethyl)phenylamino]-pentyl]-N'-nitroguanidine (17) (K(i) = 50 nM), which also shows the highest selectivity over eNOS (greater than 2100-fold) and 70-fold selectivity over iNOS. Further modification of compound 17 should lead to even more potent and selective nNOS inhibitors.

Animals↗
PubMed2004

Identification of novel binding interactions in the development of potent, selective 2-naphthamidine inhibitors of urokinase. Synthesis, structural analysis, and SAR of N-phenyl amide 6-substitution.

The preparation and assessment of biological activity of 6-substituted 2-naphthamidine inhibitors of the serine protease urokinase plasminogen activator (uPA, or urokinase) is described. 2-Naphthamidine was chosen as a starting point based on synthetic considerations and on modeling of substituent vectors. Phenyl amides at the 6-position were found to improve binding; replacement of the amide with other two-atom linkers proved ineffective. The phenyl group itself is situated near the S1' subsite; substitutions off of the phenyl group accessed S1' and other distant binding regions. Three new points of interaction were defined and explored through ring substitution. A solvent-exposed salt bridge with the Asp60A carboxylate was formed using a 4-alkylamino group, improving affinity to K(i) = 40 nM. Inhibitors also accessed two hydrophobic regions. One interaction is characterized by a tight hydrophobic fit made with a small dimple largely defined by His57 and His99; a weaker, less specific interaction involves alkyl groups reaching into the broad prime-side protein binding region near Val41 and the Cys42-Cys58 disulfide, displacing water molecules and leading to small gains in activity. Many inhibitors accessed two of these three regions. Affinities range as low as K(i) = 6 nM, and many compounds had K(i) < 100 nM, while moderate to excellent selectivity was gained versus four of five members of a panel of relevant serine proteases. Also, some selectivity against trypsin was generated via the interaction with Asp60A. X-ray structures of many of these compounds were used to inform our inhibitor design and to increase our understanding of key interactions. In combination with our exploration of 8-substitution patterns, we have identified a number of novel binding interactions for uPA inhibitors.

Amidines↗
PubMed2004

Tetramethylcyclopropyl analogue of a leading antiepileptic drug, valproic acid. Synthesis and evaluation of anticonvulsant activity of its amide derivatives.

Although valproic acid (VPA) is an extensively used antiepileptic drug for treatment of various kinds of epilepsies, it has been proven to possess two life-threatening side effects: hepatotoxicity and teratogenicity. Amide and urea derivatives of 2,2,3,3-tetramethylcyclopropanecarboxylic acid (TMCA) were prepared to discover lead compounds with clinical potential. In the amide and alkylamide series of TMCA derivatives, N-methoxy-2,2,3,3-tetramethylcyclopropanecarboxamide (21) was one of the most active compounds, having the subcutaneous metrazol test (scMet) ED50 values of 35 mg/kg in rats and 74 mg/kg in mice. In the maximal electroshock-induced seizure test (MES), this compound had ED50 values of 108 mg/kg in rats and 115 mg/kg in mice. Compound 21 was 18.5 and 4.5 times more potent than VPA in the corresponding rat tests. The most active compound in the series of urea derivatives was 2,2,3,3-tetramethylcyclopropanecarbonylurea (25), possessing MES ED50 values of 29 mg/kg in rats and 90 mg/kg in mice. In the scMet test this compound had ED50 values of 92 mg/kg in rats and 125 mg/kg in mice. The median toxic dose (TD50) in rats was 538 mg/kg, providing compound 25 with a wide safety margin and a protective index (TD50/ED50) of 18.5 in the MES test, which is about 12 times greater than that of VPA. Compounds 21 and 25 have the potential for development as novel potent and safe central nervous system active drugs with a broad spectrum of antiepileptic activity.

Animals↗
PubMed1996

Esters and amides of 6-(chloromethyl)-2-oxo-2H-1-benzopyran-3-carboxylic acid as inhibitors of alpha-chymotrypsin: significance of the "aromatic" nature of the novel ester-type coumarin for strong inhibitory activity.

A series of esters and amides of 6-(chloromethyl)-2-oxo-2H-1-benzopyran-3-carboxylic acid were synthesized and evaluated in vitro for their inhibitory activity toward bovine alpha-chymotrypsin and human leukocyte elastase. Both series behaved as time-dependent inhibitors of alpha-chymotrypsin, but ester-type coumarins were clearly more efficient than the corresponding amides in inactivating the serine proteinase. The best inactivations were observed with "aromatic" esters, in particular with meta-substituted phenyl esters such as m-chlorophenyl 6-(chloromethyl)-2-oxo-2H-1-benzopyran-3-carboxylate, which appears to be one of the most powerful inactivators of alpha-chymotrypsin yet reported (kinact/KI = 760,000 M-1 S-1 at pH 7.5 and 25 degrees C). Usually, the coumarin derivatives failed to inhibit significantly human leukocyte elastase. As a result, the reported series of aromatic coumarinic esters behaves as a new chemical family of selective alpha-chymotrypsin inhibitors.

Animals↗
PubMed1996

Inactivation of S-adenosyl-L-homocysteine hydrolase by amide and ester derivatives of adenosine-5'-carboxylic acid.

S-Adenosyl-L-homocysteine (AdoHcy) hydrolase has been shown to have (5'/6') hydrolytic activity with vinyl (5') or homovinyl (6') halides derived from adenosine (Ado). This hydrolytic activity is independent of its 3'-oxidative activity. The vinyl (or homovinyl) halides are converted into 5'(or 6')-carboxaldehydes by the hydrolytic activity of the enzyme, and inactivation occurs via the oxidative activity. Amide and ester derivatives of Ado-5'-carboxylic acid were prepared to further probe the hydrolytic capability of AdoHcy hydrolase. The oxidative activity (but not the hydrolytic activity) is involved in the mechanism of inhibition of the enzyme by the ester and amide derivatives of Ado-5'-carboxylic acid, in contrast to the inactivation of this enzyme by adenosine-derived vinyl or homovinyl halide analogues during which both activities are manifested.

Adenosine↗
PubMed1996

Heterocyclic amides: inhibitors of acyl-CoA:cholesterol O-acyl transferase with hypocholesterolemic activity in several species and antiatherosclerotic activity in the rabbit.

A series of heterocyclic amides were synthesized and evaluated as inhibitors of acyl-CoA: cholesterol O-acyltransferase (ACAT) in vitro and for cholesterol lowering in cholesterol-fed rats. Compounds were evaluated for cell-based macrophage ACAT inhibition, bioactivity, and adrenal toxicity. Candidates were selected for evaluation in cholesterol-fed dogs and, ultimately, the injured cholesterol-fed rabbit model of atherosclerosis. The heterocyclic amides potently inhibited rabbit liver ACAT (IC50's = 0.014-0.11 microM), and the majority of compounds significantly lowered plasma cholesterol (42-68%) in an acute cholesterol-fed rat model at 3 mg/kg. The most efficacious compounds in the rat were evaluated for bioactivity in vivo and arterial ACAT inhibition in a cell-based macrophage ACAT assay. Two highly bioactive analogs, (+/-)-2-(3-dodecylisoxazol-5-yl)-2-phenyl-N-(2,4,6-trimethoxypheny l) acetamide (13a) and (+/-)-2-(5-dodecylisoxazol-3-yl)-2-phenyl-N-(2,4,6-trimethoxypheny l) acetamide (16a), were selected for further study and were found to be nontoxic in a guinea pig model of adrenal toxicity. Compounds 13a and 16a lowered total cholesterol in the cholesterol-fed rat, rabbit, and dog models of pre-established hypercholesterolemia. Compound 13a in the injured cholesterol-fed rabbit model of atherosclerosis was effective in slowing the development of cholesteryl ester-rich thoracic aortic lesions, reducing lesion coverage by 53% at a dose of 1 mg/kg.

Acetamides↗
PubMed1997

Address and message sequences for the nociceptin receptor: a structure-activity study of nociceptin-(1-13)-peptide amide.

Nociceptin (NC) and some of its fragments as well as nociceptin-(1-13)-peptide amide [NC- (1-13)-NH2] and a series of its analogues were prepared and tested in the mouse vas deferens in an attempt to identify the sequences involved in the activation (message) and in the binding (address) of nociceptin to its receptor. The NC receptor that inhibits the electrically evoked twitches of the mouse vas deferens was demonstrated to be distinct from the delta opioid receptor, since naloxone and Dmt-Tic-OH (a selective delta opioid receptor antagonist) block the delta opioid receptor but have no effect on the nociceptin receptor. Results from structure-activity experiments suggest that (a) the entire sequence of NC may not be required for full biological activities, since NC(1-13)-NH2 is as active as NC; (b) fragments of NC have however to be amidated as in NC(1-13)-NH2 in order to be protected from degradation by proteases; (c) cationic residues (as Arg8,12, Lys9,13) appear to play a functional role, since their replacement with Ala in the sequence of NC(1-13)-NH2 leads to inactivity; (d) the N-terminal tetrapeptide Phe-Gly-Gly-Phe is essential for activity: its full length and flexibility appear to be required for NC receptor activation and/or occupation; (e) Phe4 and not Phe1 appears to be the residue involved in receptor activation, since the replacement of Phe1 with Leu has no effect, while that of Phe4 leads to inactivity. Results summarized in this paper indicate that the structural requirements of NC for occupation and activation of its receptor are different from that of opioids, particularly delta agonists.

Amino Acid Sequence↗
PubMed1998

Discovery and development of the novel potent orally active thrombin inhibitor N-(9-hydroxy-9-fluorenecarboxy)prolyl trans-4-aminocyclohexylmethyl amide (L-372,460): coapplication of structure-based design and rapid multiple analogue synthesis on solid support.

Early studies in these laboratories of peptidomimetic structures containing a basic P1 moiety led to the highly potent and selective thrombin inhibitors 2 (Ki = 5.0 nM) and 3 (Ki = 0.1 nM). However, neither attains significant blood levels upon oral administration to rats and dogs. With the aim of improving pharmacokinetic properties via a more diverse database, we devised a resin-based route for the synthesis of analogues of these structures in which the P3 residue is replaced with a range of lipophilic carboxylic amides. Assembly proceeds from the common P2-P1 template 7 linked via an acid-labile carbamate to a polystyrene support. Application of the methodology in a repetitive fashion afforded several interesting analogues out of a collection of some 200 compounds. Among the most potent of the group, N-(9-hydroxy-9-fluorenecarboxy)-prolyl trans-4-aminocyclohexylmethyl amide (L-372,460 8, Ki = 1.5 nM), in addition to being fully efficacious in a rat model of arterial thrombosis at an infusion rate of 10 micrograms/kg/min, exhibits oral bioavailability of 74% in dogs, and oral bioavailability of 39% in monkeys with a serum half-life of just under 4 h. On the basis of its favorable biological properties, inhibitor 8 has been subject to further evaluation as a possible treatment for thrombogenic disorders.

Animals↗
PubMed2000

Recognition of amides by new rigid Calix

The synthesis of new hosts specifically designed for the recognition of amides, characterized by two binding regions: a rigid calix[4]arene cavity and a sidearm, inserted at its rim, able to form strong hydrogen bonds, is described. The binding abilities of the new receptors toward amides of general structure R(1)CONR(2)R(3) have been investigated in CDCl(3) solution by (1)H NMR spectroscopy. When the additional binding site is the N-phenylureido group spaced by a methylene unit from the apolar cavity, binding constants up to 756 M(-)(1) were measured. Neither the two separate potential binding sites, nor the model host, where the calix[4]arene skeleton is flexible show detectable binding ability toward the series of guests examined. The rigidity of the calix[4]arene apolar cavity is the key control element in determining the efficiency of these molecular recognition processes. The presence of NH groups in the guest controls the efficiency and selectivity of binding.

Journal Article↗
PubMed2001

Improved catalysts for the palladium-catalyzed synthesis of oxindoles by amide alpha-arylation. Rate acceleration, use of aryl chloride substrates, and a new carbene ligand for asymmetric transformations.

Catalysts comprised Pd(OAc)(2) and either PCy(3) or sterically hindered N-heterocyclic carbene ligands provide fast rates for a palladium-catalyzed synthesis of oxindoles by amide alpha-arylation. This catalyst system allowed for room-temperature reactions in some cases and reactions of aryl chlorides at 70 degrees C. Most important, reactions occurred in high yields under mild conditions to form the quaternary carbon in alpha,alpha-disubstituted oxindoles. The combined inter- and intramolecular reaction afforded an efficient synthetic method for formation of alpha-aryloxindole derivatives. Surprisingly, catalysts containing tert-butylphosphine ligands, which have been most reactive for ketone arylations, were less active than those containing PCy(3). Use of new, optically active heterocyclic carbene ligands gave substantial enantioselectivity in formation of an alpha,alpha-disubstituted oxindole. In contrast, a variety of optically active phosphine ligands that were tested gave poor enantioselectivity. Mechanistic studies showed that the reaction involves rate-limiting oxidative addition of aryl halide. Base-induced formation of and reductive elimination from an arylpalladium enolate intermediate were both faster than oxidative addition. Deprotonation of the tethered amide appeared to be faster than reductive elimination of the resulting palladium enolate to form the oxindole product.

Anilides↗
PubMed2001

Can we predict the conformational preference of amides?

To what extent, if any, is the conformation of secondary amides revealed by theory? This question has now been addressed by computational methods using calculations at the B3LYP/6-31G level of theory and (1)H NMR spectroscopy. Both gas-phase and solvent studies predict a Z-anti conformation to be the lowest in energy for an evaluated series of acetamides. Moreover, Z-anti conformations may also be inferred from the chemical shifts of the N-CH alpha protons determined by NMR spectroscopy. Thus, a proton situated anti to the N-H proton consistently appears approximately 0.8 ppm further downfield than a proton situated gauche to the N-H proton. This finding, which could only be derived by using the DFT calculations of conformational preference as a guide to interpret the NMR data, might prove to be useful as a simple and convenient methodology for establishing amide conformation experimentally.

Journal Article↗
PubMed2001

Synthesis of primary aromatic amides by aminocarbonylation of aryl halides using formamide as an ammonia synthon.

Primary aromatic amides were prepared by a palladium-catalyzed aminocarbonylation reaction of aryl halides in high yields (70-90%) using formamide as the amine source. The reactions require a palladium catalyst in combination with a nucleophilic Lewis base such as imidazole or 4-(dimethylamino)pyridine (DMAP). Aryl, heteroaryl, and vinyl bromides and chlorides were converted to the primary amides under mild conditions (5 bar, 120 degrees C) using 1 mol % of a palladium-phosphine complex. Best results were obtained in dioxane using triphenylphosphine as the ligand and DMAP as the base. For activated aryl bromides, a phosphine-to-palladium ratio of 2:1 was sufficient, but less reactive aryl bromides or aryl chlorides required ligand-to-palladium ratios up to 8:1 in order to stabilize the catalyst and achieve full conversion. The influence of catalyst, base, solvent, pressure, and temperature was studied in detail. The mechanism of the reaction could be clarified by isolating and identifying the reaction intermediates. In addition, methylamides and dimethylamides were prepared by the same method using N-methylformamide and N,N-dimethylformamide as the amine source.

Journal Article↗
PubMed2002

Z-selective synthesis of alpha,beta-unsaturated amides with triphenylsilylacetamides.

With the purpose of developing a method of preparing Z-alpha,beta-unsaturated amides, the Peterson reaction of the (triphenylsilyl)acetamide Ph(3)SiCH(2)COX (1, X = NBn(2); 3, X = NMe(2)) with various aldehydes was examined. The reaction of aromatic aldehydes gave selectivities up to >97:3. It was found that the selectivity was a function of the electronic nature of the aromatic ring and higher Z selectivity was attained with electron-rich aldehydes. With aliphatic aldehydes selectivities up to 92:8 were achieved, and unlike with analogous phosphorus reagents, less sterically hindered aldehydes gave higher Z selectivity. Also, 3, which has a smaller amide group than 1, tended to give rise to higher selectivity. A comparison with the reaction of trimethylsilyl analogues revealed the significance of the phenyl substituents on the silyl group.

Journal Article↗
PubMed2002

Incorporation of Ahc into model dipeptides as an inducer of a beta-turn with a distorted amide bond. Conformational analysis.

The proline residue of dipeptides Ser-Pro and Pro-Ser has been replaced by 7-azabicyclo[2.2.1]heptane-1-carboxylic acid (Ahc), a conformationally restricted analogue of proline that is capable of mimicking distorted amides. The conformational analysis of the new peptides in the solid state revealed that the Ahc-Ser sequence displays a type I beta-turn, which includes a distorted amide bond. In contrast, the Ser-Ahc sequence exists in a nonfolded structure.

Bridged Bicyclo Compounds, Heterocyclic↗