(1S)-1-(aminomethyl)-2-(arylacetyl)-1,2,3,4-tetrahydroisoquinoline and heterocycle-condensed tetrahydropyridine derivatives: members of a novel class of very potent kappa opioid analgesics.

The synthesis and structure-activity relationship (SAR) of a novel class of kappa opioid analgesics, 1-(aminomethyl)-2-(arylacetyl)-1,2,3,4- tetrahydroisoquinolines and (aminomethyl)-N-(arylacetyl)-4,5,6,7-tetrahydrothienopyridines+ ++, are described. These compounds, formally derived by the condensation of a benzene or thiophene ring on the piperidine nucleus of the recently described compounds 1, are from 3 to 7 times more potent as antinociceptive agents and with a longer duration of action than the original lead compounds. A similar N2-C1-C9-N10 pharmacophore torsional angle of approximately 60 degrees was also found for this class of compounds by using X-ray and 1H NMR analyses. The same absolute configuration (S) at the chiral center of the active (-) enantiomers was determined by X-ray crystallographic analysis. A varied degree of kappa receptor selectivity was a feature of this novel class of antinociceptive agents (mu/kappa ratio from 44 to 950 according to the nature of the basic moiety). SAR analysis indicated that the presence of electron-withdrawing and lipophilic substituents in para and/or meta positions in the arylacetic moiety and the pyrrolidino or dimethylamino basic groups are required to optimize biological activity. The lead compounds 28, 30, and 48 are among the most potent antinociceptive agents (ED50 ca. 0.020 microM/kg sc) and kappa ligands (Ki(kappa) ca. 0.20 nM) identified so far.     

Substituted 1-(aminomethyl)-2-(arylacetyl)-1,2,3,4-tetrahydroisoquinolines: a novel class of very potent antinociceptive agents with varying degrees of selectivity for kappa and mu opioid receptors.

This study describes the synthesis of a series of novel substituted 1-(aminomethyl)-2-(arylacetyl)-1,2,3,4-tetrahydroisoquinolines, and discusses their structure-activity relationships (SARs) using binding affinity for opioid receptors and antinociceptive potency as the indices of biological activity. The introduction of a hydroxy substituent in position 5 of the isoquinoline nucleus generated a compound, 40, which is 2 times more potent than the previously disclosed unsubstituted analogue 39 in mouse models of antinociception. A QSAR analysis of the 5-substitution clearly demonstrates that antinociceptive activity is inversely associated with the lipophilicity of the substituents. The substituted compounds described herein are less selective for the kappa opioid receptors than the unsubstituted isoquinoline 39. For example, the 5-hydroxy-substituted compound 59 shows high affinity for kappa opioid receptors (Ki kappa = 0.09 nM) and a Ki mu/Ki kappa ratio of only 5. However, a multiple linear regression analysis demonstrates a lack of correlation between antinociceptive activity and affinity for the mu opioid receptor. On the other hand, the correlation between binding affinity to kappa opioid receptor and antinociceptive activity was statistically significant.     

Identification of the first trans-(3R,4R)- dimethyl-4-(3-hydroxyphenyl)piperidine derivative to possess highly potent and selective opioid kappa receptor antagonist activity

A structurally novel opioid kappa receptor selective ligand has been identified. This compound, (3R)-7-hydroxy-N-((1S)-1-[[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl]-2-methylpropyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxamide (JDTic, 10) demonstrated high affinity for the kappa receptor in the binding assay (kappa K(i) = 0.3 nM) and highly potent and selective kappa antagonism in the [(35)S]GTP-gamma-S assay using cloned opioid receptors (kappa K(i) = 0.006 nM, mu/kappa ratio = 570, delta/kappa ratio > 16600).     

Discovery of (1S,2R,3R)-2,3-dimethyl-2-phenyl-1-sulfamidocyclopropanecarboxylates: novel and highly selective aggrecanase inhibitors

Aggrecanases, particularly aggrecanase-1 (ADAMTS-4) and aggrecanase-2 (ADAMTS-5), are believed to be key enzymes involved in the articular cartilage breakdown that leads to osteoarthritis. Thus, aggrecanases are considered to be viable drug targets for the treatment of this debilitating disease. A series of (1S,2R,3R)-2,3-dimethyl-2-phenyl-1-sulfamidocyclopropanecarboxylates was discovered to be potent, highly selective, and orally bioavailable aggrecanase inhibitors. These compounds have unique P1' groups comprising novel piperidine- or piperazine-based heterocycles that are connected to a cyclopropane amino acid scaffold via a sulfamido linkage. These P1' groups are quite effective in imparting selectivity over other MMPs, and this selectivity was further increased by incorporation of a methyl substituent in the 2-position of the cyclopropane ring. In contrast to classical hydroxamate-based inhibitors that tend to lack metabolic stability, our aggrecanase inhibitors bear a carboxylate zinc-binding group and have good oral bioavailability. Lead compound 13b, characterized by the novel P1' portion of 1,2,3,4-tetrahydropyrido[3',4':4,5]imidazo[1,2-a]pyridine ring, is a potent and selective aggrecanse inhibitor with excellent pharmacokinetic profiles.     

Novel piperidine derivatives. Synthesis and anti-acetylcholinesterase activity of 1-benzyl-4-[2-(N-benzoylamino)ethyl]piperidine derivatives

A series of 1-benzyl-4-[2-(N-benzoylamino)ethyl]piperidine derivatives was synthesized and evaluated for anti-acetylcholinesterase (anti-AChE) activity. Substituting the benzamide with a bulky moiety in the para position led to a substantial increase in activity. Introduction of an akyl or phenyl group at the nitrogen atom of benzamide dramatically enhanced the activity. The basic quality of the nitrogen atom of piperidine appears to play an important role in the increased activity, since the N-benzoylpiperidine derivative was almost inactive. We found that 1-benzyl-4-[2-(N-[4'-(benzylsulfonyl) benzoyl]-N-methylamino]ethyl]piperidine hydrochloride (21) (IC50 = 0.56 nM) is one of the most potent inhibitors of acetylcholinesterase. Compound 21 showed an affinity 18,000 times greater for AChE than for BuChE. At a dose of 3 mg/kg, 21 produced a marked and significant increase in acetylcholine (ACh) content in the cerebral vortex and hippocampus of rats. Compound 21 was chosen for advanced development as an antidementia agent.     

Highly selective kappa opioid analgesics. 4. Synthesis of some conformationally restricted naphthalene derivatives with high receptor affinity and selectivity.

This paper describes the synthesis and kappa and mu opioid receptor binding affinity of some conformationally restrained derivatives of the arylacetamide group in the selective kappa opioid receptor agonist (+/-)-trans-N-methyl-N-[2-(1-pyrrolidinyl) cyclohexyl]benzo [b]thiophene-4-acetamide monohydrochloride (1,PD117302), which is an analogue of U-50, 488. The methyl-substituted derivatives (+/-)-trans-N, alpha-dimethyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzo-[b] thiophene-4-acetamide monohydrochloride (6a,b) possess significantly weaker affinity than 1 for the kappa opioid receptor (Ki = 172 and 3.7 nM, respectively). It is proposed that this is due to the conformational restriction imposed by the methyl group of 6. In order to test this proposal the acenaphthene derivative and the 4,5-dihydro-3H-naphtho [1,8-bc]thiophene derivative were prepared. The acenaphthene derivative (+)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro [4.5]dec-8-yl]acenaphthenecarboxamide monohydrochloride (9) was found to have high kappa opioid receptor affinity and selectivity (kappa Ki = 0.37 +/- 0.05 nM, mu/kappa = 659, delta/kappa = 1562) and is 100 times more potent than morphine as an analgesic in the rat paw pressure test for analgesia after intravenous administration (MPE50 = 0.014 and 1.4 mg/kg, respectively). The 4,5-dihydro-3H-naphtho[1,8-bc]thiophene derivative (-)-4,5-dihydro-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro [4.5]dec-8-yl]-3H-naphthol[1,8-bc]thiophene-5-carboxamide p-toluenesulfonate (17) also has high kappa opioid receptor affinity and selectivity (kappa Ki = 4.65 nM, mu/kappa = 109).     

Highly selective kappa-opioid analgesics. 3. Synthesis and structure-activity relationships of novel N-[2-(1-pyrrolidinyl)-4- or -5-substituted-cyclohexyl]arylacetamide derivatives

This paper describes the chemical synthesis, mu/kappa opioid receptor selectivity and analgesic activity of 14 novel N-[2-(1-pyrrolidinyl)-4- or -5-substituted-cyclohexyl]arylacetamide derivatives. The prototype kappa-selective agonist, PD117302 (trans-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzo[b]thiophene-4- acetamide, 2) has been regio- and stereoselectively substituted in the C-4 and C-5 positions of the cyclohexyl ring with the methyl ether and spiro tetrahydrofuran groups. It is observed that optimal mu/kappa-receptor selectivity is obtained when the oxygen atom of the methyl ether or the tetrahydrofuran ring is joined to the equatorial C-4 position. Hence, (-)-(5 beta,7 beta,8 alpha)-N-methyl-N-[7-(1-pyrrolidinyl)-1- oxaspiro[4.5]dec-8-yl]benzo[b]furan-4-acetamide monohydrochloride (21) has exceptionally high kappa opioid receptor affinity and selectivity in vitro (kappa Ki = 0.83 nM, mu/kappa ratio = 1520) is the most potent kappa-selective analgesic ever reported. Compound 21 is 25 times more potent than morphine and 17 times more potent than U-62066 (spiradoline, 19) when assayed by the rat paw pressure test by intravenous administration (MPE50 = 0.024, 0.6, and 0.4 mg/kg, respectively).     

4-Hydroxy-1-[2-(4-hydroxyphenoxy)ethyl]-4-(4-methylbenzyl)piperidine: a novel, potent, and selective NR1/2B NMDA receptor antagonist.

A structure-based search and screen of our compound library identified N-(2-phenoxyethyl)-4-benzylpiperidine (8) as a novel N-methyl-D-aspartate (NMDA) receptor antagonist that has high selectivity for the NR1/2B subunit combination (IC(50) = 0.63 microM). We report on the optimization of this lead compound in terms of potency, side effect liability, and in vivo activity. Potency was assayed by electrical recordings in Xenopus oocytes expressing cloned rat NMDA receptors. Side effect liability was assessed by measuring affinity for alpha(1)-adrenergic receptors and inhibition of neuronal K(+) channels. Central bioavailability was gauged indirectly by determining anticonvulsant activity in a mouse maximal electroshock (MES) assay. Making progressive modifications to 8, a hydroxyl substituent on the phenyl ring para to the oxyethyl tether (10a) resulted in a approximately 25-fold increase in NR1A/2B potency (IC(50) = 0.025 microM). p-Methyl substitution on the benzyl ring (10b) produced a approximately 3-fold increase in MES activity (ED(50) = 0.7 mg/kg iv). Introduction of a second hydroxyl group into the C-4 position on the piperidine ring (10e) resulted in a substantial decrease in affinity for alpha(1) receptors and reduction in inhibition of K(+) channels with only a modest decrease in NR1A/2B and MES potencies. Among the compounds described, 10e (4-hydroxy-N-[2-(4-hydroxyphenoxy)ethyl]-4-(4-methylbenzyl)piperid ine, Co 101244/PD 174494) had the optimum pharmacological profile and was selected for further biological evaluation.     

Anti-inflammatory 1-aroyl-4-(m-aminomethylphenyl)piperidine derivatives

A series of 1-aroyl-4-(m-aminomethylphenyl)piperidine derivatives and their 1-heteroaroyl analogues are claimed. These amines are low molecular weight inhibitors of tryptase, some of which have reasonable potency. If combined with good pharmacokinetic properties this class of compounds may prove to be therapeutically useful in the treatment of asthma or allergic rhinitis.     

1-Aryl-2-(aminomethyl)cyclopropanecarboxylic acid derivatives. A new series of potential antidepressants

A series of 1-aryl-2-(aminomethyl)cyclopropanecarboxylic acid derivatives were synthesized and evaluated as potential antidepressants. Compounds with the Z configuration were synthesized from 1-aryl-2-oxo-3-oxabicyclo[3.1.0]hexane and those with the E configuration from (E)-1-phenyl-2-(hydroxymethyl)cyclopropanecarboxylic acid. The compounds were evaluated in animal tests designed to reveal potential antidepressant activity and the existence of undesirable side effects. Several derivatives were more active than imipramine and desipramine. On the basis of its activity in pharmacological animal tests of antidepressant activity and its potential lack of side effects, 1-phenyl-1-[(diethylamino)carbonyl]-2- (aminomethyl)cyclopropane hydrochloride, midalcipran (INN), was selected for further development. This compound is currently in phase III clinical evaluation.     

2',6'-Dimethyltyrosine]dynorphin A(1-11)-NH2 analogues lacking an N-terminal amino group: potent and selective kappa opioid antagonists.

Recent studies showed that dermorphin and enkephalin analogues containing two methyl groups at the 2',6'-positions of the Tyr(1) aromatic ring and lacking an N-terminal amino group were moderately potent delta and mu opioid antagonists. These results indicate that a positively charged N-terminal amino group may be essential for signal transduction but not for receptor binding and suggested that its deletion in agonist opioid peptides containing an N-terminal 2',6'-dimethyltyrosine (Dmt) residue may represent a general way to convert them into antagonists. In an attempt to develop dynorphin A (Dyn A)-derived kappa opioid antagonists, we prepared analogues of [Dmt(1)]Dyn A(1-11)-NH2 (1), in which the N-terminal amino group was either omitted or replaced with a methyl group. This was achieved by replacement of Tyr(1) with 3-(2,6-dimethyl-4-hydroxyphenyl)propanoic acid (Dhp) or (2S)-2-methyl-3-(2,6-dimethyl-4-hydroxyphenyl)propanoic acid [(2S)-Mdp]. Compounds were tested in the guinea pig ileum and mouse vas deferens bioassays and in rat and guinea pig brain membrane receptor binding assays. All analogues turned out to be potent kappa antagonists against Dyn A(1-13) and the non-peptide agonist U50,488 and showed only weak mu and delta antagonist activity. The most potent and most selective kappa antagonist of the series was [(2S)-Mdp(1)]Dyn A(1-11)-NH2 (5, dynantin), which showed subnanomolar kappa antagonist potency against Dyn A(1-13) and very high kappa selectivity both in terms of its K(e) values determined against kappa, mu, and delta agonists and in terms of its ratios of kappa, mu, and delta receptor binding affinity constants. Dynantin is the first potent and selective Dyn A-derived kappa antagonist known and may complement the non-peptide kappa antagonists norbinaltorphimine and GNTI as a pharmacological tool in opioid research.     

Gamma-amino-substituted analogues of 1-[(S)-2,4-diaminobutanoyl]piperidine as highly potent and selective dipeptidyl peptidase II inhibitors

Using 1-[(S)-2,4-diaminobutanoyl]piperidine as lead compound, we developed a large series of highly potent and selective dipeptidyl peptidase II (DPP II) inhibitors. gamma-Amino substitution with arylalkyl groups, for example, a 2-chlorobenzyl moiety, resulted in a DPP II inhibitor with an IC(50) = 0.23 nM and a high selectivity toward DPP IV (IC(50) = 345 microM). Furthermore, it was shown that the basicity of the gamma-amino is important and that alpha-amino substitution is not favorable. Piperidine-2-nitriles did not show an increase in potency but rather reduced the selectivity. Introduction of a 4-methyl or a 3-fluorine on piperidine improved selectivity and preserved the high potency.     

Cyclopropane-based conformational restriction of histamine. (1S,2S)-2-(2-aminoethyl)-1-(1H-imidazol-4-yl)cyclopropane,a highly selective agonist for the histamine H3 receptor,having a cis-cyclopropane structure

A series of cyclopropane-based conformationally restricted analogues of histamine, the "folded" cis-analogues, i.e., (1S,2R)-2-(aminomethyl)-1-(1H-imidazol-4-yl)cyclopropane (11), (1S,2S)-2-(2-aminoethyl)-1-(1H-imidazol-4-yl)cyclopropane (13), and their enantiomers ent-11 and ent-13, and the "extended" trans-analogues, i.e., (1R,2R)-2-(aminomethyl)-1-(1H-imidazol-4-yl)cyclopropane (12) and its enantiomer ent-12, were designed as histamine H(3) receptor agonists. These target compounds were synthesized from the versatile chiral cyclopropane units, (1S,2R)- and (1R,2R)-2-(tert-butyldiphenylsilyloxy)methyl-1-formylcyclopropane (14 and 15, respectively) or their enantiomers ent-14 and ent-15. Among the conformationally restricted analogues, the "folded" analogue 13 (AEIC) having the cis-cyclopropane structure was identified as a potent H(3) receptor agonist, which showed a significant binding affinity (K(i) = 1.31 +/- 0.16 nM) and had an agonist effect (EC(50) value of 10 +/- 3 nM) on the receptor. This compound owes its importance to being the first highly selective H(3) receptor agonist to have virtually no effect on the H(4) subtype receptor. These studies showed that the cis-cyclopropane structure is very effective in the conformational restriction of histamine to improve the specific binding to the histamine H(3) receptor.     

Identification of (3R)-7-hydroxy-N-((1S)-1-[[(3R,4R)-4-(3-hydroxyphenyl)- 3,4-dimethyl-1-piperidinyl]methyl]-2-methylpropyl)-1,2,3,4-tetrahydro- 3-isoquinolinecarboxamide as a novel potent and selective opioid kappa receptor antagonist

(3R)-7-Hydroxy-N-((1S)-1-[[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl]-2-methylpropyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxamide (JDTic) was identified as a potent and selective kappa opioid receptor antagonist. Structure-activity relationship (SAR) studies on JDTic analogues revealed that the 3R,4R stereochemistry of the 3,4-dimethyl-4-(3-hydroxyphenyl)piperidine core structure, the 3R attachment of the 7-hydroxy-1,2,3,4-tetrahydroisoquinoline group, and the 1S configuration of the 2-methylpropyl (isopropyl) group were all important to its kappa potency and selectivity. The results suggest that, like other kappa opioid antagonists such as nor-BNI and GNTI, JDTic requires a second basic amino group to express potent and selective kappa antagonist activity in the [(35)S]GTPgammaS functional assay. However, unlike previously reported kappa antagonists, JDTic also requires a second phenol group in rigid proximity to this second basic amino group. The potent and selective kappa antagonist properties of JDTic can be rationalized using the "message-address" concept wherein the (3R,4R)-3,4-dimethyl-4-(hydroxyphenyl)piperidinyl group represents the message, and the basic amino and phenol group in the N substituent constitutes the address. It is interesting to note the structural commonality (an amino and phenol groups) in both the message and address components of JDTic. The unique structural features of JDTic will make this compound highly useful in further characterization of the kappa receptor.     

N-substituted 4beta-methyl-5-(3-hydroxyphenyl)-7alpha-amidomorphans are potent, selective kappa opioid receptor antagonists

In a previous study, we identified (-)-N-[(1R,4S,5S,7R)-5-(3-hydroxyphenyl)-4-methyl-2-(3-phenylpropyl)-2-azabicyclo[3.3.1]non-7-yl]-3-(1-piperidinyl)propanamide (5a, KAA-1) as the first potent and selective kappa opioid receptor antagonist from the 5-(3-hydroxyphenyl)morphan class of opioids. In this study we report an improved synthesis of this class of compounds. The new synthetic method was used to prepare analogues 5b-r where the morphan N-substituent and 7alpha-amido group were varied. Most of the analogues showed sub-nanomolar potency for the kappa opioid receptor and were highly selective relative to the mu and delta opioid receptors. (-)-3-(3,4-Dihydroisoquinolin-2(1H)-yl)-N-{(1R,4S,5S,7R)-5-(3-hydroxyphenyl)-4-methyl-2-[2-(2-methylphenyl)ethyl]-2-azabicyclo[3.3.1]non-7-yl}propanamide (5n, MTHQ) is at least as potent and selective as nor-BNI as a kappa opioid receptor antagonist in the [35S]GTP-gamma-S in vitro functional test.