Calcium-channel modulators

A -(l-Haloalkyl)pyridinium halides have been advantageously employed in the Hantzsch multicomponent synthesis, yielding alkyl 1,4-dihydropyri-dine-3,5-dicarboxylates, which are a well-known class of calcium channel modulators (81AGE762). Tire halides readily interact with an excess of an ethyl 3-aminobut-2-enoate 82 (R = H) in dichloromethane at room temperature to afford the heterocycles 83 (R = H) in good to excellent yields (65-95%) (92T1263). Tliis observation has been exploited to perform a quantitative study of the reactivity of the salts (93CB1251).Tlie results have... 

Reynolds, I.J., Snowman, A.M. and Snyder, S.H. (1986) (-)-[3H] desmethoxyverapamil labels multiple calcium channel modulator receptors in brain and skeletal muscle membranes differentiation by temperature and dihydropyridines. The Journal of Pharmacology and Experimental Therapeutics, 237, 731—738. 

Safinamide is in Phase 111 clinical trials for Parkinson disease. The molecule possesses multiple mechanisms of action it combines inhibition of dopamine uptake and potent, selective, and reversible inhibition of MAO-B, sodium (Na" ") channel blockage, and calcium channel modulation, while being devoid of a MAO-A inhibitory effect (Figure 8.37). 

Kappe et al. (103,104) approached dihydropyrimidines, a potent group of calcium channel modulators, through the use of an isomiinchnone-type cyclization. Kappe prepared the cyclization precursor 195 in the course of a three component Biginelli condensation process (Scheme 4.49). 

Kappe et al. (166) employed an isomilnchnone generation-trapping sequence to access conformationally restricted dihydropyrimidine derivatives as novel calcium channel modulators. For example, the conformationally restricted analogues 269 were prepared via intramolecular cycloadditions from the isomiinchnones generated from a-diazo imides 268. The structures of these cycloadducts were established by X-ray crystallography. 

Padwa et al. (187,188) concisely summarized his domino cycloaddition/ A -acyliminium ion cyclization cascade process, which involves sequentially the generation of an isomiinchnone 1,3-dipole, intramolecular 1,3-dipolar cycloaddition reaction, 77-acyliminium ion formation, and, hnally, Mannich cyclization. Kappe and co-workers (189) utilized Padwa s cyclization-cycloaddition cascade methodology to construct several rigid compounds that mimic the putative receptor-bound conformation of dihydropyridine-type calcium channel modulators. 

Nifedipine is a dihydropyridine calcium channel modulator, often used in the treatment of hypertension and angina. CYP3A4, with a minor contribution from CYP3A5, is the principal enzyme involved in the metabolism of nifedipine (81). Smith et al. examined the effect of St. John s wort (900mg/day... 

Dierssen, M., Florez, J., Hurle, M.A. Calcium channel modulation by dihydropyridines modifies sufentanil-induced antinociception in acute and tolerant conditions, Naunyn-Schmiedeberg s Arch. Pharmacol. 1990, 342, 559-565. 

Nearly a century later with the recognition that DHPMs possessed similar pharmacological profiles to the Nifedipine class [9a] of DHP calcium channel modulators 2 (formed via the Hantzsch condensation 1882, Scheme 11.2 [9b]), the Biginelli reaction witnessed a dramatic upsurge in popularity [10],... 

Young, K., Lin, S., Sun,L.,etal. (1998) Identification of a calcium channel modulator using a high throughput yeast two-hybrid screen. Nat. Biotechnol. 16, 946-950. 

Fig. 4 Structures of selected Cav3 calcium channel modulators...

Thienopyridine derivatives have been prepared for use as anticonvulsants (134) <86EUP183994>, and for use as calcium channel modulators (135) <90USP4902694>. 

S. Abraham and G. Amitai (Eds.), Calcium Channel Modulators in Heart and Smooth Muscle, Balaban Publ. VCH, Weinheim, 1990. 

Iqbal N, Akula MR, Vo D et al (1998) Synthesis, rotamer orientation, and calcium channel modulation activities of alkyl and 2-phenethyl 1, 4-dihydro-2, 6-dlmethyl-3-nltro-4-(3- or 6-substltuted-2-pyrldyl)-5-pyridinecarboxylates. J Med Chem 41 1827-1837 LI RWS, Tse CM, Man RYK et al (2007) Inhibition of human equilibrative nucleoside transporters by dihydropyridine-type calcium channel antagonists. Eur J Pharmacol 568 75-82 Cosconatl S, Marlnelli L, Lavecchia A et al (2007) Characterizing the 1,4-dlhydropyrldlnes... 

Jauk B, Pemat T, Kappe CO (2000) Design and synthesis of a conformationally rigid mimic of the dihydropyrimidine calcium channel modulator SQ 32, 926. Molecules 5 227-239... 

Anticonvulsant, voltage-sensitive sodium channel modulator T-type calcium channel modulator structurally a sulfonamide... 

Kappe, C. 0.4-Aryldihydropyrimidines via the Biginelli condensation aza analogs of nifedipine-type calcium channel modulators. 

Budriesi R, Carosati E, Chiarini A, Cosimelli B, Cruciani G, loan P, et al. A new class of selective myocardial calcium channel modulators 2. Role of the acetal chain in oxadiazol-3-one derivatives. / Med Chem 2005 48 2445-56. 

Ambler, S.J., Dell, C.P., Gilmore, J., Hotten, T.M., Sanchiz Suarez, A., Simmonds, R.G., Timms, G.H., Tupper, D.E., and Urquhart, M.W.J., Novel N-substituted a-amino acid amides as calcium channel modulators, Lilly Industries, Eur. Patent Appl. EP 805147, 1997 Chem. Abstr., 128, 13437, 1997. 

Dihydropyridine (1,4-DHP) derivatives have been widely explored as a consequence of their pharmacological profile and as the most important calcium channel modulators. Nifedipine 2 represents the prototype 1,4-DHP structure found useful in both antianginal and antihypertensive treatment that has been approved for clinical use. The liquid phase-bound )3-keto esters 31(a-c) were prepared by transesterification of methyl or terf-butyl )3-oxo carboxylates 30(a, b) with the ionic liquid phases [HOC mimJlPFg] 29a and [HOC mimJlBF ] 29b under solvent-free microwave irradiations (Fig. 12.49) [33],... 

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