Design and synthesis of selective alpha1B adrenoceptor antagonists

A series of novel indolylpiperidine derivatives were synthesized and assessed for their pharmacological profiles at alpha1 adrenoceptor subtypes by in vitro binding studies at rat alpha1A and alpha1B receptors. Compound 11 was a potent (Ki=0.63 nM) and selective (approximately 30-fold more selective for the alpha1B receptor than for the alpha1A receptor) alpha1B adrenoceptor antagonist.     

Quantitative structure-activity relationship study of novel alpha1a-selective adrenoceptor antagonists

Two series of compounds were recently reported as novel alpha1a-selective adrenoceptor antagonists. In the first series, a dihydropyrimidone moiety is attached to a 4-phenyl piperidine containing side chain, while in the second, it is linked to a 4-substituted phenyl piperazine containing side chain. These compounds having potential for the treatment of benign prostatic hyperplasia, a urological disorder in the older age male population, were subjected to a quantitative structure-activity relationship study. The analysis has helped to ascertain the role of different substituents in explaining the observed binding potencies of these analogues. In the first category of compounds, three sites R1, R2, and X were varied and from the quantitative structure-activity relationship, it emerged that X- and R1-substituents having respectively, the high values of field and resonance effects may lead to more potent alpha1a-antagonists. The substituent of R2, being either CH3 or C2H5, does not add to improve the activity and thus the site, at present, becomes redundant. This site may, however, be explored for some additional substituents in future. In the second series of compounds, the phenyl ring, linked to a piperazine moiety at the end of a side chain, was substituted with various groups onto different positions. From derived significant correlations, it appeared the less polar and/or bulky substituents at the meta- and para-positions and a more hydrophobic substituent at the para-position are advantageous.     

A new class of selective, non-basic 5-HT2A receptor antagonists

Based on an existing series of 5-HT2A receptor ligands containing a basic nitrogen, we designed a non-basic lead that had reduced affinity for both the 5-HT2A receptor and the IKr potassium channel. The present paper describes the development of this lead to a novel series of non-basic piperidine sulfonamides and amides that have high affinity for the 5-HT2A receptor, whilst maintaining excellent selectivity over off target activities such as the IKr channel. This work has shown that the proposed pharmacophore model for the 5-HT2A receptor which suggests that a basic nitrogen is required for the binding of ligands is questionable.     

Novel 2-imidazoles as potent and selective alpha1A adrenoceptor partial agonists

Novel 2-imidazoles have been identified as potent partial agonists of the α_1A adrenergic receptor, with good selectivity over the α_1B, α_1D and α_2A receptor sub-types. Sulfonamide 23 possessed attractive drug-like properties with respect to physicochemical and ADME properties and wide ligand selectivity.     

Reduced peptide bond pseudopeptide analogues of secretin. A new class of secretin receptor antagonists.

The ability to assess the importance of secretin in various physiological processes is limited by the lack of specific potent antagonists. Recently, reduced peptide bond (psi) analogues of bombesin or substance P in which the -CONH- bond is replaced by -CH2NH- are reported to be receptor antagonists. To attempt to develop a new class of secretin receptor antagonists, we have adopted a similar strategy with secretin and sequentially altered the eight NH2-terminal peptide bonds, the biological active portion of secretin. In guinea pig pancreatic acini, secretin caused a 75-fold increase in cyclic AMP (cAMP). Secretin inhibited 125I-secretin binding with a half-maximal effect at 7 nM. Each of the psi analogues inhibited 125I-secretin binding. [psi 4,5]Secretin was the most potent, causing the half-maximal inhibition at 4 microM, and was 2-fold more potent than the [psi 1,2]secretin; 7-fold more than [psi 3,4]secretin, [psi 5,6]secretin, and [psi 8,9]secretin; 9-fold more than [psi 7,8]secretin; 13-fold more potent [psi 6,7]secretin, and 17-fold more than [psi 2,3]secretin. Secretin caused a half-maximal increase in cAMP at 1 nM. At concentrations up to 10 microM, [psi 2,3]secretin, [psi 4,5]secretin, and [psi 8,9]secretin did not alter cAMP whereas [psi 1,2]secretin and [psi 6,7]secretin caused a detectable increase in cAMP at 10 nM, [psi 7,8]secretin at 300 nM, [psi 5,6]secretin at 1 microM, and [psi 3,4]secretin at 10 microM. The [psi 4,5], [psi 2,3], and [psi 8,9] analogues of secretin each inhibited 1 nM secretin-stimulated cAMP as well as [psi 3,4]secretin, which functioned as a partial agonist. [psi 4,5]Secretin was the most potent, causing half-maximal inhibition at 3 microM whereas [psi 8,9]secretin was 6-fold less potent, and [psi 2,3]secretin and [psi 3,4]secretin were 17-fold less potent. [psi 4,5]Secretin inhibited secretin-stimulated cAMP and binding of 125I-secretin in a competitive manner. [psi 4,5]Secretin did not interact with cholecystokinin, bombesin, calcitonin gene-related peptide, or cholinergic receptors but did interact with receptors for vasoactive intestinal peptide, causing half-maximal inhibition at 72 microM and thus had a 18-fold higher affinity for secretin than vasoactive intestinal peptide receptors. These results indicate that reduced peptide bond analogues of the NH2 terminus of secretin represent a new class of secretin receptor antagonists. It is likely that in the future even more potent members of this class can be developed which may be useful to investigate the role of secretin in various physiological processes.     

Synthesis and structure-activity relationship of new analogues of antistasin.

Intensive investigation connected with the development of new anticoagulant agents for the treatment of cardiovascular diseases was carried out. Direct and specific inhibition of thrombin and Factor Xa-like serine proteases in the coagulation cascade has been the focus of many efforts to design novel anticoagulants over the past decade. This work reports the synthesis and biological activity of new anticoagulant peptide analogues of natural isoforms 2 and 3 of antistasin. In addition they include different tripeptide sequences in their molecules, which are highly active inhibitors of different serine proteases such as plasmin, trypsin, thrombin and Factor Xa.     

Phenyl ureas of creatinine as mGluR5 antagonists. A structure-activity relationship study of fenobam analogues

Fenobam (1) was developed by McNeil Laboratories as an anxiolytic agent with an unknown molecular target in the late 1970s. In a recent publication, it was revealed that fenobam is a non-competitive mGluR5 antagonist. Herein, we present the structure-activity relationship of fenobam and its analogues and similarities between the SAR of mGluR5 antagonism and the SAR of CNS properties originally reported by McNeil are discussed.     

Arylpiperazide derivatives of phenylpiperazines as a new class of potent and selective 5-HT1B receptor antagonists

A new series of arylpiperazide derivatives of phenylpiperazines of general formula 4 has been prepared and evaluated as 5-HT_1B receptor antagonists. In vitro experiments at human cloned 5-HT_1B receptors show that these derivatives are potent and selective 5-HT_1B receptor antagonists. Among them, compound 4f was found to be orally active, to gain access to the CNS and more importantly to induce an increase in extracellular brain 5-HT upon systemic administration.     

Novel 2-imidazoles as potent, selective and CNS penetrant alpha1A adrenoceptor partial agonists

A novel series of central nervous system (CNS) penetrant indane 2-imidazoles have been identified as potent, partial agonists of the alpha(1A) adrenergic receptor, having good selectivity over the alpha(1B), alpha(1D) and alpha(2) sub-types. A key structural motif to impart selectivity is a methylene spacer between the indane and a pendant substituent, which includes heterocycles, sulphones and ethers. Introduction of an ortho-halogen to this group led to a lowering of intrinsic efficacy (E(max)).     

Quantitative structure-activity relationship study of new potent and selective antagonists at the 5-HT(1A) and adrenergic alpha(1d) receptors: Derivatives of spiroethyl phenyl(substituted)piperazine

The antagonistic activities of derivatives of spiroethyl phenyl(substituted)piperazine at the 5-HT(1A) and adrenergic alpha(1d) receptors is quantitatively analyzed employing physicochemical and structural parameters. The derived correlation equation revealed that a substituent, other than 2-CH3 in the phenyl ring, having higher molar refraction, MR, and a substituent producing higher positive field effect at the 3-position are beneficial in increasing the binding affinity at the 5-HT(1A) receptor. In addition, a less hydrophobic substituent at the 4-position is also helpful in augmenting the binding affinity. The 5-R substituents which have higher MR values, however, elicit a detrimental effect. Two disubstituted compounds which are not present in the original data-set and have higher theoretical binding affinities are designed from the correlation equation. These compounds consisting of 2-OCH(CH3)2, 3-Cl and 2-C3H7, 3-Cl in the phenyl ring, have theoretical pK(i) values 10.57 and 10.12 respectively. For the adrenergic alpha(1d) receptor, a less bulky group at the 3-position with 5-Cl (or simply a 3-Cl) is advantageous in increasing the binding affinity. Likewise, a substituent exhibiting a less negative resonance effect at the 4-position and the substituent with low polarizability and showing more a negative resonance effect at the 5-position are suitable for enhancement of the binding affinity. The analysis provides the grounds for rationalizing substituent selection in designing better potency antagonists in the series.     

Short and efficient syntheses of analogues of WAY-100635: new and potent 5-HT1A receptor antagonists

Simple syntheses of four new and potent analogues of the 5-HT1A receptor ligand, WAY-100635 are described, namely the 6-(pyridinyl)-bromo-, the 6-(pyridinyl)-fluoro-, the pyrimidine- and the 5-(pyridinyl)-bromo-analogues. The first three analogues were obtained by aromatic nucleophilic substitution of the 2,6-dihalogenopyridine (activated or not as an N-oxide) or of the 2-chloropyrimidine with the corresponding amine nucleophile as a key step. The fourth analogue, the 5-(pyridinyl)-bromo-analogue, was synthesized from the 2-amino-5-bromopyridine via a progressive elongation of the skeleton. The four compounds described are all full antagonists and show good in vitro binding affinities (Ki).     

Hydrazides of clozapine: a new class of D1 dopamine receptor subtype selective antagonists

Acylated and aroylated hydrazinoclozapines are highly potent dopamine D(1) antagonists that show remarkable selectivity over other dopamine receptors. The most potent compound in this series is the 2,6-dimethoxybenzhydrazide 33 with a D(1)K(i) of 1.6 nM and 212-fold selectivity over D(2) receptor.     

Synthesis and evaluation of furo[3,4-d]pyrimidinones as selective alpha1a-adrenergic receptor antagonists

Furo[3,4-d]pyrimidinones were found to be metabolites of dihydropyrimidinones such as 1a-b that are subtype-selective antagonists of the alpha1a-adrenergic receptor. A versatile synthesis that provides access to furo[3,4-d]pyrimidinones in high yield and in enantiomerically pure forms is described along with structure-activity relationships in the series.     

N-Methylbenzanilide derivatives as a novel class of selective V(1A) receptor antagonists.

During our efforts to develop a novel class of selective V(1A) receptor antagonists, the N-methylbenzanilide structure was applied to a 4,4-difluoro-1-benzazepine derivative, 4, which is a selective V(1A) receptor antagonist. Further structural modifications gave 16a with high V(1A) affinity and V(2)/V(1A) selectivity (K(i)=5.71 nM, V(2)/V(1A)=140) and potent V(1A) receptor antagonist activity (ID(50)=0.0080 mg/kg iv).     

Discovery of 3-aryl-3-methyl-1H-quinoline-2,4-diones as a new class of selective 5-HT6 receptor antagonists

A 5,7-dichloro-3-phenyl-3-methyl-quinoline-2,4-dione (11a) has been identified in a random screen as a lead for 5-HT(6) antagonist. During the lead optimization process, several analogs were synthesized and their biological activities were investigated. Within this series, several compounds display high binding affinity and selectivity for the 5-HT(6) receptor. In particular, 3-(4-hydroxyphenyl)-3-methyl-quinoline-2,4-dione (12f) exhibits high affinity (K(i)=12.3 nM) for 5-HT(6) receptor with good selectivity over other serotonin and dopamine (D(1)-D(4)) receptor subtypes. In a functional adenylyl cyclase stimulation assay, this compound exhibited considerable antagonistic activity (IC(50)=0.61 microM).     

Synthesis and structure-affinity relationships of 4-(5-Aryl-1,2,3,6-tetrahydropyridino)pyrimidine derivatives as corticotropin-releasing factor(1) receptor antagonists

Recently, various non-peptide corticotropin-releasing factor(1) (CRF(1)) receptor antagonists have been reported. Structure-affinity relationships (SARs) of non-peptide CRF(1) antagonists suggest that such antagonists can be constructed of three units: a hydrophobic unit (Up-Area), a proton accepting unit (Central-Area), and an aromatic unit (Down-Area). We previously presented 4-aryl-1,2,3,6-tetrahydropyridinopyrimidine derivatives including potent CRF receptor ligands 1a and 1b and proposed that the 4-aryl-1,2,3,6-tetrahydropyridino moiety might be useful as a substituent in the Up-Area. Our interest shifted to 5-aryl-1,2,3,6-tetrahydropyridinopyrimidine derivatives 2, among which compound 2m (CRA0165) had highest affinity for CRF(1) receptors (IC(50)=11nM). We report here the design, synthesis and SARs of derivatives 2.     

Structure-activity relationship studies on ortho-substituted cinnamic acids, a new class of selective EP(3) antagonists

A series of novel ortho-substituted cinnamic acids have been synthesized, and their binding activity and selectivity on the four prostaglandin E(2) receptors evaluated. Many of them are very potent and selective EP(3) antagonists (K(i) 3-10 nM), while compound 9 is a very good and selective EP(2) agonist (K(i) 8 nM). The biological profile of the EP(2) agonist 9 in vivo and the metabolic profile of selected EP(3) antagonists are also reported.     

Benzimidazole derivatives. Part 1: Synthesis and structure-activity relationships of new benzimidazole-4-carboxamides and carboxylates as potent and selective 5-HT4 receptor antagonists

New benzimidazole-4-carboxamides 1-16 and -carboxylates 17-26 were synthesized and evaluated for binding affinity at serotonergic 5-HT4 and 5-HT3 receptors in the CNS. Most of the synthesized compounds exhibited moderate-to-very high affinity (in many cases subnanomolar) for the 5-HT4 binding site and no significant affinity for the 5-HT3 receptor. SAR observations and structural analyses (molecular modeling, INSIGHT II) indicated that the presence of a voluminous substituent in the basic nitrogen atom of the amino moiety and a distance of ca. 8.0 A from this nitrogen to the aromatic ring are of great importance for high affinity and selectivity for 5-HT4 receptors. These results confirm our recently proposed model for recognition by the 5-HT4 binding site. Amides 12-15 and esters 24 and 25 bound at central 5-HT4 sites with very high affinity (Ki = 0.11-2.9 nM) and excellent selectivity over serotonin 5-HT3, 5-HT2A, and 5-HT1A receptors (Ki > 1000-10,000 nM). Analogues 12 (Ki(5-HT4) = 0.32 nM), 13 (Ki(5-HT4) = 0.11 nM), 14 (Ki(5-HT4) = 0.29 nM) and 15 (Ki(5-HT4) = 0.54 nM) were pharmacologically characterized as selective 5-HT4 antagonists in the isolated guinea pig ileum (pA2 = 7.6, 7.9, 8.2 and 7.9, respectively), with a potency comparable to the 5-HT4 receptor antagonist RS 39604 (pA2 = 8.2). The benzimidazole-4-carboxylic acid derivatives described in this paper represent a novel class of potent and selective 5-HT4 receptor antagonists. In particular, compounds 12-15 could be interesting pharmacological tools for the understanding of the role of 5-HT4 receptors.     

Synthesis of various 5-alkoxymethyluracil analogues and structure-cytotoxic activity relationship study

A number of 5-alkoxymethyluracil analogues were synthesized to evaluate their cytotoxic activity. 5-Alkoxymethyluracil derivatives 1 were prepared via known nucleophilic substitution of 5-chloromethyluracil 5 and subsequently transformed to their corresponding nucleosides 2. All prepared compounds were submitted to cytotoxic activity testing against drug sensitive and drug resistant leukaemia cells and solid tumour derived cell lines. In addition, the cytotoxic activity of 5-alkoxymethyluracil analogues 1 and 2 was compared with the previously published 5-[alkoxy(4-nitrophenyl)methyl]uracil analogues 3 and 4. Extensive structure–cytotoxic activity relationship studies are reported.     

Synthesis and structure-activity relationships of a new class of selective EP3 receptor agonist, 13,14-didehydro-16-phenoxy analogues of prostaglandin E1

A series of 13,14-didehydro-16-phenoxy analogues of prostaglandin E1 was synthesized and their agonistic activity on EP receptor subtypes was evaluated. 13,14-Didehydro-16-phenoxy-1-decarboxy analogues, 7e and 7f, display highly selective activity on the EP3 receptor subtype, thus, their utility as a selective anti-ulcer agent can be expected.