Synthesis of mc 903, a biologically active vitamin D metabolite analogue

Calverley, Martin J.

doi:10.1016/s0040-4020(01)86903-9

Cited by 163 publications

(73 citation statements)

References 18 publications

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“…Calcipotriol is a synthetic vitamin D analogue [1]. The vitamin D analogues interfere with various characteristics of the psoriatic skin, i.e.…”

Section: Introductionmentioning

confidence: 99%

Topical Calcipotriol Combined with Phototherapy for Psoriasis

Molin

1999

Dermatology

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Background: Calcipotrial has a well-documented effect in the treatment of psoriasis. Objective: To confirm the beneficial effect of the combination of calcipotriol and UVB and to demonstrate that the combination is safe and well tolerated. Methods: Data from two randomized right/left studies were analysed. Patients included in the studies had chronic stable plaque-type psoriasis with symmetrical lesions on the arms, the legs and/or the trunk. In one study, 101 patients were treated with calcipotriol on one side and calcipotriol + UVB on the other side of the body (open study). In the other study, 77 patients were treated with calcipotriol + UVB on one side and vehicle + UVB on the other side of the body (double-blind study). Calcipotriol ointment, 50 μg/g, was applied twice daily and UVB 3 times weekly for 8 weeks. UVB was increased from 0.7 MED before treatment in rapid steps up to the erythema threshold. Result: In both treatment series the therapeutic effect of the combination of calcipotriol and UVB was enhanced as compared to calcipotriol alone and UVB alone. In the first series there was a significant reduction of the psoriasis area and severity index (PASI) with the combination after 2 weeks as compared to calcipotriol alone. At the end of treatment significantly more sides were cleared after calcipotriol + UVB than after calcipotriol alone. In the other series there was a significantly faster onset of improvement on the sides treated with calcipotriol + UVB than on those treated with vehicle + UVB. After 2 weeks there was a significant difference in PASI in favour of calcipotriol + UVB. At the end of treatment, however, there was no difference between the treatments. There was a similar adverse event profile with either treatment. The addition of UVB to calcipotriol did not alter the tolerability or safety of topically applied calcipotriol. Conclusions: The result indicates a beneficial effect of combining calcipotriol and phototherapy. The findings are compared to other published studies.

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“…Calcipotriol is a synthetic vitamin D analogue [1]. The vitamin D analogues interfere with various characteristics of the psoriatic skin, i.e.…”

Section: Introductionmentioning

confidence: 99%

Topical Calcipotriol Combined with Phototherapy for Psoriasis

Molin

1999

Dermatology

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“…Bromomethyl Cyclopropyl Ketone: [59] Br 2 (11.3 mL, 220 mmol, 1 equiv.) was added in one portion to a cold solution (-5°C) of cyclopropyl methyl ketone (20.7 mL, 220 mmol, 1 equiv.)…”

Section: Methodsmentioning

confidence: 99%

Synthesis of (1′R,3S,4S)‐3‐[1′‐(tert‐Butyldimethylsilyloxy)ethyl]‐ 4‐(cyclopropylcarbonyloxy)azetidin‐2‐one

Laurent

Cérésiat²,

Marchand‐Brynaert

2006

Eur J Org Chem

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The novel carbapenem precursor 1e has been synthesized from L‐threonine, cyclopropyl methyl ketone and benzhydrylamine (for the introduction of the azetidinone N‐protecting group). Two independently prepared building blocks – sodium (2R,3R)‐2,3‐epoxybutyrate as a mixed salt with NaBr (2b) and N‐(benzhydryl)aminomethyl cyclopropyl ketone (4e) – were coupled to give (2R,3R)‐N‐(benzhydryl)‐N‐(2‐cyclopropyl‐2‐oxoethyl)‐2,3‐epoxybutyramide (8e). This key intermediate gave a regio‐ and stereoselective C3–C4 ring closure on LiHMDS treatment in THF at 0 °C to yield(1′R,3S,4S)‐4‐cyclopropylcarbonyl‐1‐diphenylmethyl‐3‐(1‐hydroxyethyl)azetidin‐2‐one (13e). N‐Deprotection of 13e was performed by photochemical bromination and subsequent hydrolysis. The resulting (1′R,3S,4S)‐4‐(cyclopropylcarbonyl)‐3‐(1‐hydroxyethyl)azetidin‐2‐one (23e) reacted in a Baeyer–Villiger oxidation with a total control of the regioselectivity (due to the poor migratory aptitude of the cyclopropyl group) to furnish (1′R,3S,4S)‐3‐(1‐hydroxyethyl)‐4‐(cyclopropylcarbonyloxy)azetidin‐2‐one (24e), subsequent O‐silylation achieving the total synthesis of 1e (title compound).(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)

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“…[2,3] As a result, a great deal of attention is being focused on the synthesis of vitamin D analogues with selective properties, although few have proceeded beyond the preclinical stage. [4,5] Most of these analogues have been modified at the side chain, as exemplified by calcipotriol [6] (2 a, MC903, Dovonex, Leo Pharmaceuticals, Denmark), used topically for the treatment of psoriasis [7] and seocalcitol (2 b, EB1089, Abstract: Based on the crystal structures of human vitamin D receptor (hVDR) bound to 1a,25-dihydroxy-vitamin D 3 (1,25 D) and superagonist ligands, we previously designed new superagonist ligands with a tetrahydrofuran ring at the side chain that optimize the aliphatic side-chain conformation through an entropy benefit. Following a similar strategy, four novel vitamin D analogues with aromatic furan side chains (3 a, 3 b, 4 a, 4 b) have now been developed.…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, Evaluation, and Structure of Vitamin D Analogues with Furan Side Chains

Fraga

Zacconi

Sussman

et al. 2011

Chemistry A European J

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Based on the crystal structures of human vitamin D receptor (hVDR) bound to 1α,25-dihydroxy-vitamin D(3) (1,25 D) and superagonist ligands, we previously designed new superagonist ligands with a tetrahydrofuran ring at the side chain that optimize the aliphatic side-chain conformation through an entropy benefit. Following a similar strategy, four novel vitamin D analogues with aromatic furan side chains (3a, 3b, 4a, 4b) have now been developed. The triene system has been constructed by an efficient stereoselective intramolecular cyclization of an enol triflate (A-ring precursor) followed by a Suzuki-Miyaura coupling of the resulting intermediate with an alkenyl boronic ester (CD-side chain, upper fragment). The furan side chains have been constructed by gold chemistry. These analogues exhibit significant pro-differentiation effects and transactivation potency. The crystal structure of 3a in a complex with the ligand-binding domain of hVDR revealed that the side-chain furanic ring adopts two conformations.

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Synthesis of mc 903, a biologically active vitamin D metabolite analogue

Cited by 163 publications

References 18 publications

Topical Calcipotriol Combined with Phototherapy for Psoriasis

Topical Calcipotriol Combined with Phototherapy for Psoriasis

Synthesis of (1′R,3S,4S)‐3‐[1′‐(tert‐Butyldimethylsilyloxy)ethyl]‐ 4‐(cyclopropylcarbonyloxy)azetidin‐2‐one

Design, Synthesis, Evaluation, and Structure of Vitamin D Analogues with Furan Side Chains

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