Quantitative structure-selectivity relationship for M2 selectivity between M1 and M2 of piperidinyl piperidine derivatives as muscarinic antagonists

Muscarinic M2 receptor antagonists with high subtype selectivity (M2/M1) will decrease the toxicity in central nervous system in treatment of AD. The exploration of quantitative structure-selectivity relationship (QSSR) to muscarinic M2 receptor antagonists will provide design information for drug with fewer side effects. In this paper, CoMFA models of pK(i)(M1), pK(i)(M2) and p[K(i)(M2)/K(i)(M1)] (pK(i)(M2)-pK(i)(M1)) were used to study the subtype selectivity (M2/M1) of piperidinyl piperidine derivatives as muscarinic M2 subtype receptor antagonists. The parameters of the three models are: 0.633, 0.636 and 0.726 for cross-validated r(2) (r(cv)(2)), 0.109, 0.204 and 0.09 for the Standard error of estimate (SD), respectively. The results show the model of p[K(i)(M2)/K(i)(M1)] is the best one for design of piperidinyl piperidine derivatives as muscarinic antagonists with high subtype selectivity (M2/M1).     

Benzylidene ketal derivatives as M2 muscarinic receptor antagonists

Benzylidene ketal derivatives were investigated as selective M₂ receptor antagonists for the treatment of Alzheimer's disease. Compound 10 was discovered to have subnanomolar M₂ receptor affinity and 100-fold selectivity against other muscarinic receptors. Also, 10 demonstrated in vivo efficacy in rodent models of muscarinic activity and cognition.     

Muscarinic M2 antagonists: anthranilamide derivatives with exceptional selectivity and in vivo activity

Anthranilamide analogues such as 23 are potent and highly selective muscarinic M2 antagonists that also show good oral bioavailability and in vivo activity.     

Design and synthesis of piperidinyl piperidine analogues as potent and selective M2 muscarinic receptor antagonists

Identification of a number of highly potent M2 receptor antagonists with >100-fold selectivity against the M1 and M3 receptor subtypes is described. In the rat microdialysis assay, this series of compounds showed pronounced enhancement of brain acetylcholine release after oral administration.     

Isopropyl amide derivatives of potent and selective muscarinic M2 receptor antagonists

Low molecular weight amide derivatives were synthesized and evaluated as M(2) receptor antagonists for the treatment of Alzheimer's disease. Isopropyl amides 19 and 31 are highly potent, selective and low molecular weight M(2) receptor antagonists with structural features different from our clinical candidate 1.     

J-104129, a novel muscarinic M3 receptor antagonist with high selectivity for M3 over M2 receptors

A new class of 4-acetamidopiperidine derivatives has been synthesized and investigated for human muscarinic receptor subtype selectivity. Introduction of a hydrocarbon chain of appropriate length into the piperidine nitrogen of the racemic N-(piperidin-4-yl)-2-cyclobutyl-2-hydroxy-2-phenylacetamide platform conferred up to 70-fold selectivity for human muscarinic M3 receptors over M2 receptors. Subsequent synthetic derivatizations resulted in highly potent M3 receptor antagonists with selectivity greater than two orders of magnitude for M3 over M2 receptors, from which the analogue 4r was selected. Preparation of both enantiomers of 4r led to the identification of (2R)-N-[1-(4-methyl-3-pentenyl)piperidin-4-yl]-2-cyclopentyl-2-hyd roxy-2-phenylacetamide (J-104129, (R)-4r), which exhibited 120-fold selectivity for M3 receptors (Ki = 4.2 nM) over M2 receptors (Ki = 490 nM). In isolated rat trachea, (R)-4r potently and specifically antagonized acetylcholine (ACh)-induced responses with a K(B) value of 3.3 nM. The highly subtype-selective profile was also seen in isolated rat tissue assays (50-fold) and in anesthetized rats (> 250-fold). Oral administration of J-104129 ((R)-4r) antagonized ACh-induced bronchoconstriction with an ED50 value of 0.58 mg/kg in rats. Thus, J-104129 ((R)-4r) may effectively facilitate bronchodilation in the treatment of obstructive airway disease.     

Design of novel melanotropin agonists and antagonists with high potency and selectivity for human melanocortin receptors

alpha-MSH and gamma-MSH are the natural endogenous hormones for the human melanocortin-1, 3, 4 and 5 receptors (hMC1R, hMC3R, hMC4R and hMC5R). These and more potent, stable and prolonged acting analogues such as NDP-alpha-MSH, MT-II and SHU-9119 are not very receptor selective. To develop potent and selective agonist and antagonist ligands for the melanocortin receptors we have used state-of-the-art biophysical studies, computational chemistry, and design of conformational and topographical constraints with novel templates.     

4-N-linked-heterocyclic piperidine derivatives with high affinity and selectivity for human dopamine D4 receptors.

The syntheses of a number of different N-linked heterocyclic pyrazole replacements based on the structure 1 are described (compounds 3-12) as hD4 ligands. After further optimisation the best compound identified was 13 which has high affinity for hD4 (5.2 nM) and >300-fold selectivity for hD4 receptors over hD2 and hD3 receptors.     

Synthesis and biological evaluation of phenyl piperidine derivatives as CCR2 antagonists

A series of phenyl piperidine derivatives possessing potent and selective CCR2 antagonist activity is reported. Structure-activity relationship (SAR) studies have established that incorporation of a second ring system adjacent to the aryl piperidine plays an important role in determining the CCR2 potency. Both a second piperidine ring and a 1,3-substituted cyclopentylamine have been probed as linkers. For the cyclopentylamine series, the 1S,3R-configuration exhibits much higher affinity for hCCR2 than the 1R,3S-configuration. Compound 3g shows good selectivity over CCR1, CCR3, 5-HT and has an excellent P450 profile.     

Synthesis and structure-activity relationship of 7-azaindole piperidine derivatives as CCR2 antagonists

The synthesis and structure-activity relationship of a series of 7-azaindole piperidine derivatives are described. SAR studies led to the discovery of the potent CCR2 antagonists displaying IC(50) values in the nanomolar range. The representative compound 15 showed reasonable P450 and pharmacokinetics profile.     

The effect of absolute configuration on activity,subtype selectivity (M3/M2) of 3α-acyloxy-6β-acetoxyltropane derivatives as muscarinic M3 receptor antagonists

Both enantiomers of 3α-acyloxy-6β-acetoxyltropane derivatives 1–4 were prepared respectively and underwent functional studies and radioreceptor binding assays. 6S Enantiomers showed obvious muscarinic M3, M2 antagonistic activity, while the 6R ones elicited little muscarinic activity by functional studies. Besides, the affinity of 6S enantiomers to muscarinic M3 receptors of rat submandibulary gland, M2 receptors of rat left atria was much larger than that of corresponding 6R enantiomers. All these pharmalogical results indicated 6S configuration was favorable for 3α-acyloxy-6β-acetoxyltropane derivatives to bind with muscarinic M3 or M2 receptors and elicited antagonistic activity. Furthermore, the muscarinic M3 activity and subtype selectivity (M3/M2) of 6S enantiomers could be improved by increasing the electron density of carbonyl oxygen or introducing methylene group between the carbonyl and phenyl ring in C-3α position. Understanding the effect of absolute configuration on activity, subtype selectivity (M3/M2) of 3α-acyloxy-6β-acetoxyltropane derivatives will provide the clues for designing muscarinic M3 antagonists with high activity and low side effects or toxicity.     

1,5-Benzodioxepin derivatives as a novel class of muscarinic M3 receptor antagonists

The structure-activity relationships of novel 1,5-benzodioxepin derivatives as muscarinic M(1)-M(3) receptor antagonists are reported. Some of these compounds were found to possess high binding affinity for the muscarinic M(3) receptor and potent effect on rhythmic increase in bladder pressure in unanesthetized rats following oral administration. These compounds displayed selectivity for the bladder over the salivary gland.     

Nonpeptide oxytocin antagonists: analogs of L-371,257 with improved potency.

Structure-activity studies on the oxytocin antagonist 1 (L-371,257; Ki = 9.3 nM) have led to the identification of a related series of compounds containing an ortho-trifluoroethoxyphenylacetyl core which are orally bioavailable and have significantly improved potency in vitro and in vivo, e.g., compound 8 (L-374,943; Ki = 1.4 nM).     

Discovery of a muscarinic M3 receptor antagonist with high selectivity for M3 over M2 receptors among 2-[(1S,3S)-3-sulfonylaminocyclopentyl]phenylacetamide derivatives

In the course of developing a metabolically stable M3 receptor antagonist from the prototype antagonist, J-104129 (1), introduction of certain substituents into the cyclopentane ring of 1 was found to be effective not only in improving metabolic stability but also in greatly enhancing the subtype selectivity. Among the cyclopentane analogues, sulfonamide derivatives (10f) and (10g) displayed 160- and 310-fold selectivity for M3 over M2 receptors, and both were significantly more selective than the prototype antagonist (120-fold). Subsequent derivatization of the sulfonamide series led to the highly selective M3 receptor antagonists (10h, 10i and 10j) with >490-fold selectivity for M3 over M2 receptors. Among them, p-nitrophenylsulfonamide (J-107320, 10h) exhibited 1100-fold selectivity for M3 receptors (Ki = 2.5 nM) over M2 receptors (Ki = 2800 nM) in the human muscarinic receptor binding assay using [3H]-NMS as a radio ligand.     

Discovery of benzothiazole-based adenosine A2B receptor antagonists with improved A2A selectivity

The highly potent but modestly selective N-(2-amino-4-methoxy-benzothiazol-7-yl)-N-ethyl-acetamide derivative 2 was selected as the starting point for the design of novel selective A_2B antagonists, due to its excellent potency, and good drug-like properties. A series of compounds containing nonaromatic amides or ureas of five- or six-membered rings, and also bearing an m-trifluoromethyl-phenyl group (shown to impart superior potency) was prepared and evaluated for their selectivity against the A_2A and A₁ receptors. This work resulted in the identification of compound 30, with excellent potency and high selectivity against both A_2A and A₁ receptors.     

Diphenyl sulfoxides as selective antagonists of the muscarinic M2 receptor

Structure activity studies on [4-(phenylsulfonyl)phenyl]methylpiperazine led to the discovery of 4-cyclohexyl-alpha-[4-[[4-methoxyphenyl(S)-sufinyl]phenyl]-1-pi perazineacetonitrile, 1, an M2 selective muscarinic antagonist. Affinity at the cloned human M2 receptor was 2.7 nM; the M1/M2 selectivity is 40-fold.     

M1 muscarinic antagonists interact with sigma recognition sites.

The M1-selective muscarinic antagonists aprophen, caramiphen, carbetapentane, 2-DAEX, dicyclomine, hexahydrosiladifenidol, iodocaramiphen, nitrocaramiphen, oxybutynin and trihexyphenidyl potently inhibited binding to sigma sites in brain. Both basic ester and non-ester structural type compounds which exhibit affinity for the muscarinic receptor also demonstrated affinity for the sigma site, while the classical antimuscarinic agents atropine and QNB, and the tricyclic pirenzepine, were ineffective in binding to this site. We also observed a significant correlation between the Ki values for sigma compounds to inhibit [3H]pirenzepine binding and their IC50 values to inhibit carbachol-stimulated phosphoinositide turnover. These observations may aid in elucidating the relationship of sigma binding to inhibition of phosphoinositide turnover stimulated by cholinergic agonists.     

Benzylidene ketal derivatives as M2 muscarinic receptor antagonists

Benzylidene ketal derivatives were investigated as selective M₂ receptor antagonists for the treatment of Alzheimer's disease. Compound 10 was discovered to have subnanomolar M₂ receptor affinity and 100-fold selectivity against other muscarinic receptors. Also, 10 demonstrated in vivo efficacy in rodent models of muscarinic activity and cognition.     

p-Fluoro-hexahydro-sila-difenidol exhibits poor selectivity between M3 and M1 muscarinic receptors

We investigated the potential ability of p-fluoro-hexahydro-sila-difenidol (p-F-HHSiD) to discriminate between M1 and M3 muscarinic receptor subtypes using Chinese hamster ovary cells stably transfected with the genes encoding the two receptors. Both radioligand binding and functional assays were utilized for this purpose. In contrast to initial reports of a 14-fold selectivity of this antagonist for M3 versus M1 receptors, we have detected a qualitatively similar selectivity that was markedly smaller in magnitude.     

Quinuclidin-2-ene-based muscarinic antagonists

A series of achiral 3-heteroaryl substituted quinuclidin-2-ene derivatives and related compounds have been synthesized by facile methods. The compounds were evaluated for muscarinic and antimuscarinic properties in receptor binding studies using (-)-[3H]-QNB as the radioligand and in a functional assay using isolated guinea pig urinary bladder. 3-(2-Benzofuranyl)-quinuclidin-2-ene (15) displayed the highest M1-receptor affinity in the present series (Ki = 9.6 nM).