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PICLAMILAST

An antiasthmatic agent and phosphodiesterase 4 inhibitor.
144035-83-6

SANOFI

  • 3-(Cyclopentyloxy)-N-(3,5-dichloro-4-pyridinyl)-4-methoxybenzamide
  • 3-(Cyclopentyloxy)-N-(3,5-dichloro-4-pyridyl)-p-anisamide
  • Benzamide, 3-(cyclopentyloxy)-N-(3,5-dichloro-4-pyridinyl)-4-methoxy-
  • C18-H18-Cl2-N2-O3
  • 381.2572
  • CCRIS 8304
  • Cpodpmb
  • Piclamilast
  • RP 73-401
  • RP 73401
  • RP-73-401
  • RPR 73401
  • UNII-WM58D7C3ZT

Piclamilast (RP 73401), is a selective PDE4 inhibitor.[1] It is comparable to other PDE4 inhibitors for its anti-inflammatory effects. It has been investigated for its applications to the treatment of conditions such as chronic obstructive pulmonary diseasebronchopulmonary dysplasia andasthma. It is a second generation compound that exhibits structural functionalities of the PDE4 inhibitors cilomilast and roflumilast. The structure for piclamilast was first elucidated in a 1995 European patent application.[2] The earliest mention of the name “piclamilast” was used in a 1997 publication.[3]

Piclamilast functions through the selective inhibition of the four PDE4 isoforms (PDE4A-D). It shows no inhibition of the other PDEs. The PDE4 isoforms are especially important to inflammatory and immunomodulatory cells. They are the most common PDE in inflammatory cells such as mast cellsneutrophilsbasophilseosinophilsT lymphocytesmacrophages, and structural cells such as sensory nerves and epithelial cells. PDE4hydrolyzes cyclic adenosine monophosphate (cAMP) to inactive adenosine monophosphate (AMP). Inhibition of PDE4 blocks hydrolysis of cAMP thereby increasing levels of cAMP within cells. cAMP suppresses the activity of immune and inflammatory cells. PDE4 inhibition in an induced chronic lung disease murine model was shown to have anti-inflammatory properties, attenuate pulmonary fibrin deposition and vascular alveolar leakage, and prolong survival in hyperoxia-induced neonatal lung injury. A study of PDE4 inhibition in a murine model of allergic asthma showed that piclamilast significantly improves the pulmonary function, airway inflammation and goblet cell hyperplasia.[4][5]

Emesis is the most commonly cited side effect of piclamilast. It has proven difficult to separate the emetic side effects from the therapeutic benefits of several PDE4 inhibitors, including piclamilast.[6]

Chemical synthesis

The preparation steps for synthesis of piclamilast are as follows (both discovery[7] and production[8] routes have been documented)

Piclamilast synthesis.png

  1. Addition of cyclopentyl to isovanillin via Williamson ether synthesis.
  2. Oxidation of aldehyde group to carboxylic acid.
  3. Formation of acid chloride by treatment with thionyl chloride.
  4. Formation of amide by reaction with deprotonated 4-amino-3,5-dichloropyridine.

SEE

J Med Chem 1994, 37(11): 1696

http://pubs.acs.org/doi/abs/10.1021/jm00037a021

AND

Org Process Res Dev 1998, 2(3): 157

http://pubs.acs.org/doi/full/10.1021/op9700385

Figure

3-(cyclopentyloxy)-N-(3,5-dichloropyrid-4-yl)-4-methoxybenzamide (1) (26.4 g, 69%) as an off-white solid, mp 155−157 °C (lit.1 mp 155−157 °C). 1H NMR:  δ 1.55−2.05 (m, 8H), 3.93 (s, 3H), 4.87 (m, 1H), 6.95 (d, 1H, J = 8 Hz), 6.98−7.53 (m, 2H), 7.65 (s, 1H), 8.56 (s, 2H). Anal. Calcd for C18H18Cl2N2O3:  C, 56.7; H, 4.76; Cl, 18.6; N, 7.35. Found:  C, 56.3; H, 4.7; Cl, 18.4; N, 7.2.

References

  1.  Beeh, K. M.; Beier, J.; Lerch, C.; Schulz, A. K.; Buhl, R. (2004). “Effects of Piclamilast, a Selective Phosphodiesterase-4 Inhibitor, on Oxidative Burst of Sputum Cells from Mild Asthmatics and Stable COPD Patients”. Lung 182 (6): 369–377. doi:10.1007/s00408-004-2518-zPMID 15765929edit
  2.  EP application 0497564
  3.  Souness, J. E.; Houghton, C.; Sardar, N.; Withnall, M. T. (1997). “Evidence that cyclic AMP phosphodiesterase inhibitors suppress interleukin-2 release from murine splenocytes by interacting with a ‘low-affinity’ phosphodiesterase 4 conformer”British Journal of Pharmacology 121 (4): 743–750. doi:10.1038/sj.bjp.0701200PMC 1564751PMID 9208143edit
  4.  Sun, J.; Deng, Y.; Wu, X.; Tang, H.; Deng, J.; Chen, J.; Yang, S.; Xie, Q. (2006). “Inhibition of phosphodiesterase activity, airway inflammation and hyperresponsiveness by PDE4 inhibitor and glucocorticoid in a murine model of allergic asthma”. Life Sciences 79 (22): 2077–2085. doi:10.1016/j.lfs.2006.07.001PMID 16875702edit
  5.  De Visser, Y. P.; Walther, F. J.; Laghmani, E. H.; Van Wijngaarden, S.; Nieuwland, K.; Wagenaar, G. T. M. (2008). “Phosphodiesterase-4 inhibition attenuates pulmonary inflammation in neonatal lung injury”. European Respiratory Journal 31 (3): 633–644. doi:10.1183/09031936.00071307PMID 18094015edit
  6.  Hirose, R.; Manabe, H.; Nonaka, H.; Yanagawa, K.; Akuta, K.; Sato, S.; Ohshima, E.; Ichimura, M. (2007). “Correlation between emetic effect of phosphodiesterase 4 inhibitors and their occupation of the high-affinity rolipram binding site in Suncus murinus brain”. European Journal of Pharmacology 573 (1–3): 93–99. doi:10.1016/j.ejphar.2007.06.045PMID 17658510edit
  7.  Ashton, M. J.; Cook, D. C.; Fenton, G.; Karlsson, J. A.; Palfreyman, M. N.; Raeburn, D.; Ratcliffe, A. J.; Souness, J. E.; Thurairatnam, S.; Vicker, N. (1994). “Selective Type IV Phosphodiesterase Inhibitors as Antiasthmatic Agents. The Syntheses and Biological Activities of 3-(Cyclopentyloxy)-4-methoxybenzamides and Analogs”. Journal of Medicinal Chemistry 37 (11): 1696.doi:10.1021/jm00037a021edit
  8.  Cook, D. C.; Jones, R. H.; Kabir, H.; Lythgoe, D. J.; McFarlane, I. M.; Pemberton, C.; Thatcher, A. A.; Thompson, D. M.; Walton, J. B. (1998). “Process Development of the PDE IV Inhibitor 3-(Cyclopentyloxy)-N-(3,5-dichloropyrid-4-yl)-4-methoxybenzamide”. Organic Process Research & Development 2 (3): 157. doi:10.1021/op9700385


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DR ANTHONY CRASTO

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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