Discovery and synthesis of methyl 2,5-dimethyl-4-[2-(phenylmethyl)benzoyl]-1H-pyrrole-3-carboxylate (FPL 64176) and analogs: the first examples of a new class of calcium channel activator

Baxter, Andrew; Dixon, John R.; Ince, Francis; Manners, Carol N.; Teague, Simon J.

doi:10.1021/jm00071a004

Cited by 40 publications

(23 citation statements)

References 7 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Ab initio calculations were good predictors of the great asymmetry in the bond angles around the carbonyl group. As expected, because of the conforma- [7]. Between the bonds C(1)ÀN(1) and C(4)ÀN(1) (1.351(3) and 1.388(3) ä, resp.…”

supporting

confidence: 81%

Structural Studies of aN-[(N-Unsubstituted Pyrrole-3-carbonyl)oxy]benzamide and its Precursor Spiro[isoxazole-4,3′-pyrrole]

Grassi¹,

Cordaro²,

Brunò³

et al. 2002

HCA

View full text Add to dashboard Cite

The structures of 6-methyl-4,8,9-triphenyl-2-oxa-3,7-diazaspiro[4.4]nona-3,6-dien-1-one (3) and N-[(2-Methyl-4,5-diphenyl-1H-pyrrole-3-carbonyl)oxy]benzamide (4) were established by X-ray crystal-structure analysis. A significant improvement in the procedure currently available for the synthesis of these compounds is described. Ab initio and DFT calculations were carried out on the compound 4 and its precursor 3, and compared with X-ray results. In particular, to relate structural features to biological properties, the conformational characteristics and rotational barrier of compound 4 were studied.Introduction. ± Hydroxamic acid derivatives are synthetic targets of interest, not least because of their biological activity, especially as enzyme inhibitors [1] and metal chelators [2].We recently described the regioselective synthesis of N-(pyrrolecarbonyl)oxy amides by sequential oxazol-5(4H)-one cycloaddition and nitrile oxide addition starting from (Z)-4-(arylmethylidene)isoxazol-5(4H)-ones 1 [3] (Scheme). These novel amides 4 appear to have promising biological activity; indeed, one of the derivatives (Ar 3-MeOC 6 H 4 ) was selected for further in vivo testing on the basis of initial anticancer screening 2 ).In light of these results, we were encouraged to undertake a study of the molecular structure of compounds 3 and 4 by X-ray crystal-structure analysis. Thus, for the compound 3, to understand the nature of the geometric distortion due to molecular packing and H-bonds, and to confirm the reliability of the carbonyl bond angle, we describe an ab initio geometry optimization. Moreover, since detailed knowledge of the conformational behavior and rotational potential-energy surface is of great importance because various physicochemical and biological properties are strongly influenced by molecular conformations, for compound 4, we computed the internal rotational barrier around the OÀN bond by scanning the corresponding torsional angle with X-raystructural data as the starting geometry.

show abstract

supporting

confidence: 81%

Structural Studies of aN-[(N-Unsubstituted Pyrrole-3-carbonyl)oxy]benzamide and its Precursor Spiro[isoxazole-4,3′-pyrrole]

Grassi¹,

Cordaro²,

Brunò³

et al. 2002

HCA

View full text Add to dashboard Cite

show abstract

“…FPL is a calcium channel modulator specific for the L-type family of voltage-gated calcium channels (6, 66). Like the more commonly used agonist Bay K, FPL prolongs the opening of single calcium channels during depolarization and slows channel closing upon repolarization.…”

Section: Resultsmentioning

confidence: 99%

Ionic currents in intimal cultured synoviocytes from the rabbit

Large

Hollywood

Sergeant

et al. 2010

American Journal of Physiology-Cell Physiology

View full text Add to dashboard Cite

Hyaluronan, a joint lubricant and regulator of synovial fluid content, is secreted by fibroblast-like synoviocytes lining the joint cavity, and secretion is greatly stimulated by Ca2+-dependent protein kinase C. This study aimed to define synoviocyte membrane currents and channels that may influence synoviocyte Ca2+ dynamics. Resting membrane potential ranged from −30 mV to −66 mV (mean −45 ± 8.60 mV, n = 40). Input resistance ranged from 0.54 GΩ to 2.6 GΩ (mean 1.28 ± 0.57 GΩ; ν = 33). Cell capacitance averaged 97.97 ± 5.93 pF. Voltage clamp using Cs+ pipette solution yielded a transient inward current that disappeared in Ca2+-free solutions and was blocked by 1 μM nifedipine, indicating an L-type calcium current. The current was increased fourfold by the calcium channel activator FPL 64176 (300 nM). Using K+ pipette solution, depolarizing steps positive to −40 mV evoked an outward current that showed kinetics and voltage dependence of activation and inactivation typical of the delayed rectifier potassium current. This was blocked by the nonspecific delayed rectifier blocker 4-aminopyridine. The synoviocytes expressed mRNA for four Kv1 subtypes (Kv1.1, Kv1.4, Kv1.5, and Kv1.6). Correolide (1 μM), margatoxin (100 nM), and α-dendrotoxin block these Kv1 subtypes, and all of these drugs significantly reduced synoviocyte outward current. The current was blocked most effectively by 50 nM κ-dendrotoxin, which is specific for channels containing a Kv1.1 subunit, indicating that Kv1.1 is critical, either as a homomultimeric channel or as a component of a heteromultimeric Kv1 channel. When 50 nM κ-dendrotoxin was added to current-clamped synoviocytes, the cells depolarized by >20 mV and this was accompanied by an increase in intracellular calcium concentration. Similarly, depolarization of the cells with high external potassium solution caused an increase in intracellular calcium, and this effect was greatly reduced by 1 μM nifedipine. In conclusion, fibroblast-like synoviocytes cultured from the inner synovium of the rabbit exhibit voltage-dependent inward and outward currents, including Ca2+ currents. They thus express ion channels regulating membrane Ca2+ permeability and electrochemical gradient. Since Ca2+-dependent kinases are major regulators of synovial hyaluronan secretion, the synoviocyte ion channels are likely to be important in the regulation of hyaluronan secretion.

show abstract

“…The fact that the FPL concentrations required to activate RyR2 are ϳ500-fold higher than for I Ca,L (1,14) raises the possibility that the effects of FPL on RyR2 are nonspecific. Several observations argue against this point.…”

Section: Mechanisms Of Ryr2 Channel Activation By Fplmentioning

confidence: 99%

“…FPL is structurally unrelated to DHPs and is thought to bind to a separate site from DHPs on the I Ca,L in a noncompetitive manner (1,4,15,16,23). However, several reports (11,15,22) suggest that there is an allosteric interaction between the binding sites for FPL and DHPs even if they do not share a common receptor on the channel protein itself.…”

Section: Mechanisms Of Ryr2 Channel Activation By Fplmentioning

confidence: 99%

Activation of cardiac ryanodine receptors by the calcium channel agonist FPL-64176

Wasserstrom

Lokuta

et al. 2002

American Journal of Physiology-Heart and Circulatory Physiology

View full text Add to dashboard Cite

]ryanodine binding and of Po was altered by FPL, suggesting that the mechanism by which FPL increases channel activity is by an increase in Ca 2ϩ -induced activation at low [Ca 2ϩ ] (without a change in threshold) and suppression of Ca 2ϩ -induced inactivation at high [Ca 2ϩ ]. However, the fact that inactivation was restored at elevated [Ca 2ϩ ] suggests a competitive interaction between Ca 2ϩ and FPL on inactivation. FPL had no effect on RyR skeletal channels (RyR1), where Po was 0.039 Ϯ 0.005 in control versus 0.030 Ϯ 0.006 in 150 M FPL (no significant difference). These results suggest that, in addition to its ability to activate the L-type Ca 2ϩ channels, FPL activates cardiac RyR2 primarily by reducing the Ca 2ϩ sensitivity of inactivation. sarcoplasmic reticulum; heart; calcium release channel; human; dog THERE ARE SEVERAL CLASSES of pharmacological agents known to activate L-type (voltage-gated) Ca 2ϩ chan-

show abstract

Discovery and synthesis of methyl 2,5-dimethyl-4-[2-(phenylmethyl)benzoyl]-1H-pyrrole-3-carboxylate (FPL 64176) and analogs: the first examples of a new class of calcium channel activator

Cited by 40 publications

References 7 publications

Structural Studies of aN-[(N-Unsubstituted Pyrrole-3-carbonyl)oxy]benzamide and its Precursor Spiro[isoxazole-4,3′-pyrrole]

Structural Studies of aN-[(N-Unsubstituted Pyrrole-3-carbonyl)oxy]benzamide and its Precursor Spiro[isoxazole-4,3′-pyrrole]

Ionic currents in intimal cultured synoviocytes from the rabbit

Activation of cardiac ryanodine receptors by the calcium channel agonist FPL-64176

Contact Info

Product

Resources

About