Please Wait
Applying Filters...
Menu
$ API Ref.Price (USD/KG) : 578Xls
2D Structure
Also known as: 96829-58-2, Tetrahydrolipstatin, Xenical, Alli, Orlipastat, (-)-tetrahydrolipstatin
Molecular Formula
C29H53NO5
Molecular Weight
495.7  g/mol
InChI Key
AHLBNYSZXLDEJQ-FWEHEUNISA-N
FDA UNII
95M8R751W8

A lactone derivative of LEUCINE that acts as a pancreatic lipase inhibitor to limit the absorption of dietary fat; it is used in the management of obesity.
Orlistat is an Intestinal Lipase Inhibitor. The mechanism of action of orlistat is as a Lipase Inhibitor.
1 2D Structure

2D Structure

2 Identification
2.1 Computed Descriptors
2.1.1 IUPAC Name
[(2S)-1-[(2S,3S)-3-hexyl-4-oxooxetan-2-yl]tridecan-2-yl] (2S)-2-formamido-4-methylpentanoate
2.1.2 InChI
InChI=1S/C29H53NO5/c1-5-7-9-11-12-13-14-15-16-18-24(34-29(33)26(30-22-31)20-23(3)4)21-27-25(28(32)35-27)19-17-10-8-6-2/h22-27H,5-21H2,1-4H3,(H,30,31)/t24-,25-,26-,27-/m0/s1
2.1.3 InChI Key
AHLBNYSZXLDEJQ-FWEHEUNISA-N
2.1.4 Canonical SMILES
CCCCCCCCCCCC(CC1C(C(=O)O1)CCCCCC)OC(=O)C(CC(C)C)NC=O
2.1.5 Isomeric SMILES
CCCCCCCCCCC[C@@H](C[C@H]1[C@@H](C(=O)O1)CCCCCC)OC(=O)[C@H](CC(C)C)NC=O
2.2 Other Identifiers
2.2.1 UNII
95M8R751W8
2.3 Synonyms
2.3.1 MeSH Synonyms

1. 1-((3-hexyl-4-oxo-2-oxetanyl)methyl)dodecyl-2-formamido-4-methylvalerate

2. Alli

3. Ro 18 0647

4. Ro-18-0647

5. Tetrahydrolipastatin

6. Tetrahydrolipstatin

7. Thlp

8. Xenical

2.3.2 Depositor-Supplied Synonyms

1. 96829-58-2

2. Tetrahydrolipstatin

3. Xenical

4. Alli

5. Orlipastat

6. (-)-tetrahydrolipstatin

7. Orlipastatum [inn-latin]

8. Ro-18-0647

9. Ro 18-0647/002

10. (2s)-1-[(2s,3s)-3-hexyl-4-oxooxetan-2-yl]tridecan-2-yl (2s)-2-formamido-4-methylpentanoate

11. [(2s)-1-[(2s,3s)-3-hexyl-4-oxooxetan-2-yl]tridecan-2-yl] (2s)-2-formamido-4-methylpentanoate

12. N-formyl-l-leucine (1s)-1-[[(2s,3s)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl Ester

13. Orlistat (alli, Xenical)

14. Mls002207022

15. N-formyl-l-leucine, Ester With (3s,4s)-3-hexyl-4-((2s)-2-hydroxytridecyl)-2-oxetanone

16. Chembl175247

17. 95m8r751w8

18. Nsc-758881

19. Orlipastatum

20. Smr000466339

21. Thlp

22. Ro-180647002

23. Ro-180647-002

24. Ro-18-0647/002

25. (s)-1-((2s,3s)-3-hexyl-4-oxooxetan-2-yl)tridecan-2-yl Formyl-l-leucinate

26. L-leucine, N-formyl-, (1s)-1-(((2s,3s)-3-hexyl-4-oxo-2-oxetanyl)methyl)dodecyl Ester

27. Tetrahydrolipastatin

28. Mfcd05662360

29. (s)-((s)-1-((2s,3s)-3-hexyl-4-oxooxetan-2-yl)tridecan-2-yl) 2-formamido-4-methylpentanoate

30. L-leucine, N-formyl-, (1s)-1-[[(2s,3s)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl Ester

31. Xenical (tn)

32. Sr-01000759417

33. Orlistatum

34. Orlistat [usan:inn:ban]

35. Unii-95m8r751w8

36. Hsdb 7556

37. N-formyl-l-leucine (1s)-1-{[(2s,3s)-3-hexyl-4-oxo-2-oxetanyl]methyl}dodecyl Ester

38. Thl

39. Ks-1183

40. Lipase Inhibitor, Thl

41. Orlistat [hsdb]

42. Orlistat [usan]

43. Orlistat [inn]

44. Orlistat [jan]

45. Orlistat [mi]

46. (-)-tetrahydrolipostatin

47. Orlistat [vandf]

48. R-212

49. Orlistat [mart.]

50. Orlistat [usp-rs]

51. Orlistat [who-dd]

52. Orlistat (jan/usp/inn)

53. Orlistat [ema Epar]

54. Orlistat, >=98%, Solid

55. Schembl16408

56. L-leucine, N-formyl-, 1-((3-hexyl-4-oxo-2-oxetanyl)methyl)dodecyl Ester, (2s-(2alpha(r*),3beta))-

57. Mls000759448

58. Mls001423955

59. Bidd:gt0853

60. Orlistat [orange Book]

61. Gtpl5277

62. Dtxsid8023395

63. Orlistat [usp Monograph]

64. Bdbm24567

65. Chebi:94686

66. Tetrahydrolipstatin;ro-18-0647

67. Hms2051i08

68. Hms3413p06

69. Hms3677p06

70. Hy-b0218

71. Zinc8214635

72. S1629

73. Akos015894875

74. Bcp9001031

75. Ccg-100851

76. Db01083

77. Nc00101

78. Nsc 758881

79. Ro18-0647

80. (2s)-1-[(2s,3s)-3-hexyl-4-oxooxetan-2-yl]tridecan-2-yl N-formyl-l-leucinate

81. Ncgc00165856-01

82. Ncgc00165856-02

83. Ncgc00165856-15

84. [(1s)-1-[[(2s,3s)-3-hexyl-4-oxo-oxetan-2-yl]methyl]dodecyl] (2s)-2-formamido-4-methyl-pentanoate

85. Bo164179

86. R212

87. Bcp0726000044

88. O0381

89. Sw197481-2

90. D04028

91. Ab00639987-09

92. Ab00639987_10

93. 829o582

94. Q424163

95. Q-201519

96. Sr-01000759417-5

97. Sr-01000759417-7

98. Z2379810072

99. Orlistat, United States Pharmacopeia (usp) Reference Standard

100. Orlistat, Pharmaceutical Secondary Standard; Certified Reference Material

101. 2-formamido-3-[(3-hexyl-4-oxo-oxetan-2-yl)methyl]-2-isobutyl-tetradecanoate

102. N-formyl-l-leucine (s)-1-[[(2s,3s)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl Ester

103. N-formyl-l-leucine-(s)-1-[[(2s,3s)-3-hexyl-4-oxo-2-oxetanyl]methyl]-dodecyl Ester

104. (2s)-2-formamido-4-methylpentanoic Acid [(2s)-1-[(2s,3s)-3-hexyl-4-oxo-2-oxetanyl]tridecan-2-yl] Ester

105. [(2s)-1-[(2r,3s)-3-hexyl-4-oxooxetan-2-yl]tridecan-2-yl] (2r)-2-formamido-4-methylpentanoate

106. 104872-04-0

107. L-leucine, N-formyl-, 1-((3-hexyl-4-oxo-2-oxetanyl)methyl)dodecyl Ester, (2s-(2.alpha.(r*),3.beta.))-

2.4 Create Date
2005-08-08
3 Chemical and Physical Properties
Molecular Weight 495.7 g/mol
Molecular Formula C29H53NO5
XLogP310
Hydrogen Bond Donor Count1
Hydrogen Bond Acceptor Count5
Rotatable Bond Count23
Exact Mass495.39237379 g/mol
Monoisotopic Mass495.39237379 g/mol
Topological Polar Surface Area81.7 Ų
Heavy Atom Count35
Formal Charge0
Complexity579
Isotope Atom Count0
Defined Atom Stereocenter Count4
Undefined Atom Stereocenter Count0
Defined Bond Stereocenter Count0
Undefined Bond Stereocenter Count0
Covalently Bonded Unit Count1
4 Drug and Medication Information
4.1 Drug Information
1 of 4  
Drug NameAlli
PubMed HealthOrlistat (By mouth)
Drug ClassesDietary Fat Absorption Inhibitor
Active IngredientOrlistat
Dosage FormCapsule
RouteOral
Strength60mg
Market StatusOver the Counter
CompanyGlaxosmithkline Cons

2 of 4  
Drug NameXenical
PubMed HealthOrlistat (By mouth)
Drug ClassesDietary Fat Absorption Inhibitor
Drug LabelXENICAL (orlistat) is a gastrointestinal lipase inhibitor for obesity management that acts by inhibiting the absorption of dietary fats.Orlistat is (S)-2-formylamino-4-methyl-pentanoic acid (S)-1-[[(2S, 3S)-3-hexyl-4-oxo-2-oxetanyl] methyl]-dodecyl e...
Active IngredientOrlistat
Dosage FormCapsule
RouteOral
Strength120mg
Market StatusPrescription
CompanyHoffmann La Roche

3 of 4  
Drug NameAlli
PubMed HealthOrlistat (By mouth)
Drug ClassesDietary Fat Absorption Inhibitor
Active IngredientOrlistat
Dosage FormCapsule
RouteOral
Strength60mg
Market StatusOver the Counter
CompanyGlaxosmithkline Cons

4 of 4  
Drug NameXenical
PubMed HealthOrlistat (By mouth)
Drug ClassesDietary Fat Absorption Inhibitor
Drug LabelXENICAL (orlistat) is a gastrointestinal lipase inhibitor for obesity management that acts by inhibiting the absorption of dietary fats.Orlistat is (S)-2-formylamino-4-methyl-pentanoic acid (S)-1-[[(2S, 3S)-3-hexyl-4-oxo-2-oxetanyl] methyl]-dodecyl e...
Active IngredientOrlistat
Dosage FormCapsule
RouteOral
Strength120mg
Market StatusPrescription
CompanyHoffmann La Roche

4.2 Therapeutic Uses

Anti-Obesity Agents

National Library of Medicine's Medical Subject Headings online file (MeSH, 1999)


The Food and Drug Administration (FDA) today-(February 07, 2007) approved orlistat capsules as an over-the-counter (OTC) weight loss aid for overweight adults. Orlistat was initially approved in 1999 as a prescription drug to treat obesity, and remains a prescription drug for obesity at a higher dose than the OTC version. OTC orlistat will be manufactured by GlaxoSmithKline under the name Alli and is indicated for use in adults ages 18 years and older along with a reduced-calorie, low-fat diet, and exercise program.

FDA; FDA News. FDA Approves Orlistat for Over-the-Counter Use (P07-15). Available from, as of November 6, 2007: https://www.fda.gov/bbs/topics/NEWS/2007/NEW01557.html


Orlistat is indicated for the management of obesity in persons with an initial body mass index (BMI) greater than or equal to 30 kg per square meter of body surface area (kg/sq m), or a BMI greater than or equal to 27 kg/sq m when other risk factors (such as hypertension, diabetes, or dyslipidemia are present. Orlistat should be use in conjunction with a reduced calorie diet for management of obesity, including weight loss, weight maintenance, and reduction of the risk of weight gain following previous weight loss. Weight loss has been observed within 2 week of initiation or orlistat therapy. /Included in US product label/

Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2007., p. 2224


4.3 Drug Warning

Chronic malabsorption syndrome or cholestasis /are contraindications for orlistat therapy/

McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information. American Society of Health-System Pharmacists, Bethesda, MD. 2007., p. 3020


/Orlistat is contraindicated in patients with/ known hypersensitivity to orlistat or any ingredient in the formulation.

McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information. American Society of Health-System Pharmacists, Bethesda, MD. 2007., p. 3020


Caution /is advised/ in patients with a history of hyperoxaluria or calcium oxalate nephrolithiasis.

McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information. American Society of Health-System Pharmacists, Bethesda, MD. 2007., p. 3020


/Clinician should/ rule out organic causes of obesity (e.g., hypothyroidism) /before initiating treatment/.

McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information. American Society of Health-System Pharmacists, Bethesda, MD. 2007., p. 3020


For more Drug Warnings (Complete) data for ORLISTAT (12 total), please visit the HSDB record page.


4.4 Drug Indication

Orlistat is indicated for obesity management including weight loss and weight maintenance when used in combination with calorie reduction in overweight and obese adults; this indication applies to both the prescription formulation of 120 mg and the over the counter formulation of 60 mg. Orlistat in the 120 mg prescription formulation is also indicated to reduce the risk for weight regain following weight loss.


FDA Label


Xenical is indicated in conjunction with a mildly hypocaloric diet for the treatment of obese patients with a body mass index (BMI) greater or equal to 30 kg/m2, or overweight patients (BMI > 28 kg/m2) with associated risk factors.

Treatment with orlistat should be discontinued after 12 weeks if patients have been unable to lose at least 5% of the body weight as measured at the start of therapy.


5 Pharmacology and Biochemistry
5.1 Pharmacology

Orlistat helps with weight reduction and maintenance by inhibiting the absorption of dietary fats via the inhibition of lipase enzymes.


5.2 MeSH Pharmacological Classification

Anti-Obesity Agents

Agents that increase energy expenditure and weight loss by neural and metabolic regulation. (See all compounds classified as Anti-Obesity Agents.)


Enzyme Inhibitors

Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction. (See all compounds classified as Enzyme Inhibitors.)


Lipid Regulating Agents

Substances that alter the metabolism of LIPIDS. (See all compounds classified as Lipid Regulating Agents.)


5.3 FDA Pharmacological Classification
5.3.1 Active Moiety
ORLISTAT
5.3.2 FDA UNII
95M8R751W8
5.3.3 Pharmacological Classes
Lipase Inhibitors [MoA]; Intestinal Lipase Inhibitor [EPC]
5.4 ATC Code

A08AB01


A08AB01

S76 | LUXPHARMA | Pharmaceuticals Marketed in Luxembourg | Pharmaceuticals marketed in Luxembourg, as published by d'Gesondheetskeess (CNS, la caisse nationale de sante, www.cns.lu), mapped by name to structures using CompTox by R. Singh et al. (in prep.). List downloaded from https://cns.public.lu/en/legislations/textes-coordonnes/liste-med-comm.html. Dataset DOI:10.5281/zenodo.4587355


A - Alimentary tract and metabolism

A08 - Antiobesity preparations, excl. diet products

A08A - Antiobesity preparations, excl. diet products

A08AB - Peripherally acting antiobesity products

A08AB01 - Orlistat


5.5 Absorption, Distribution and Excretion

Absorption

The systemic absorption and exposure of orlistat is low, however, systemic absorption of the drug is not required for orlistat activity. After an oral dose with 360 mg of radiolabeled orlistat, plasma radioactivity achieved a peak at about 8 hours. Plasma concentrations of unchanged parent drug were close to the lower end of detection limits (<5 ng/mL). In plasma samples of patients taking orlistat, the detection of unchanged drug was sporadic and very low concentrations were detected (<10 ng/mL or 0.02 M) with no evidence suggesting drug accumulation.


Route of Elimination

After single oral dose of radiolabled orlistat in both normal weight and obese volunteers fecal excretion of the unabsorbed drug was found to be the major route of elimination with <2% urinary excretion. Fecal elimination of orlistat is estimated between 95-97%. Complete excretion by both routes occurs within in 3 to 5 days.


Volume of Distribution

Volume of distribution cannot be obtained because the absorption of orlistat is minimal. Orlistat is minimally distributed to erythrocytes and is primarily bound to proteins.


Orlistat works locally within the GI tract, and therefore systemic absorption of the drug is not required for activity. In fact, systemic absorption of orlistat is minimal, and effects on systemic lipases are unlikely. Fecal excretion of unabsorbed drug is the major route of elimination.

McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information. American Society of Health-System Pharmacists, Bethesda, MD. 2007., p. 3020


Systemic exposure to orlistat is minimal. Following oral dosing with 360 mg 14C-orlistat, plasma radioactivity peaked at approximately 8 hours; plasma concentrations of intact orlistat were near the limits of detection (<5 ng/mL). In therapeutic studies involving monitoring of plasma samples, detection of intact orlistat in plasma was sporadic and concentrations were low (<10 ng/mL or 0.02 uM), without evidence of accumulation, and consistent with minimal absorption.

Physicians Desk Reference 61st ed, Thomson PDR, Montvale, NJ 2007., p. 2831


The average absolute bioavailability of intact orlistat was assessed in studies with male rats at oral doses of 150 and 1000 mg/kg/day and in male dogs at oral doses of 100 and 1000 mg/kg/day and found to be 0.12%, 0.59% in rats and 0.7%, 1.9% in dogs, respectively.

Physicians Desk Reference 61st ed, Thomson PDR, Montvale, NJ 2007., p. 2831


In vitro orlistat was >99% bound to plasma proteins (lipoproteins and albumin were major binding proteins). Orlistat minimally partitioned into erythrocytes.

Physicians Desk Reference 61st ed, Thomson PDR, Montvale, NJ 2007., p. 2831


For more Absorption, Distribution and Excretion (Complete) data for ORLISTAT (6 total), please visit the HSDB record page.


5.6 Metabolism/Metabolites

Orlistat is hydrolyzed in the intestinal wall. In a radiolabeled orlistat mass balance study in obese patients, two metabolites were identified. The first metabolite, M1, was the hydrolyzed -lactone ring product of orlistat. The second metabolite, M3, was produced from M1s cleavage of the N-formyl leucine side-chain. Both metabolites accounted for about 42% of total plasma radioactivity. Both M1 and M3 are considered pharmacologically inactive.


Based on animal data, it is likely that the metabolism of orlistat occurs mainly within the gastrointestinal wall. Based on an oral 14C-orlistat mass balance study in obese patients, two metabolites, M1 (4-member lactone ring hydrolyzed) and M3 (M1 with N-formyl leucine moiety cleaved), accounted for approximately 42% of total radioactivity in plasma. M1 and M3 have an open beta-lactone ring and extremely weak lipase inhibitory activity (1000- and 2500-fold less than orlistat, respectively). In view of this low inhibitory activity and the low plasma levels at the therapeutic dose (average of 26 ng/mL and 108 ng/mL for M1 and M3, respectively, 2 to 4 hours after a dose), these metabolites are considered pharmacologically inconsequential. The primary metabolite M1 had a short half-life (approximately 3 hours) whereas the secondary metabolite M3 disappeared at a slower rate (half-life approximately 13.5 hours). In obese patients, steady-state plasma levels of M1, but not M3, increased in proportion to orlistat doses.

Physicians Desk Reference 61st ed, Thomson PDR, Montvale, NJ 2007., p. 2831


5.7 Biological Half-Life

The half-life of orlistat of the small amount of absorbed orlistat ranges between 1-2 hours.


Based on limited data, the half-life of the absorbed orlistat is in the range of 1 to 2 hours.

Physicians Desk Reference 61st ed, Thomson PDR, Montvale, NJ 2007., p. 2831


Based on an oral 14C-orlistat mass balance study in obese patients, ... the primary metabolite M1 had a short half-life (approximately 3 hours) whereas the secondary metabolite M3 disappeared at a slower rate (half-life approximately 13.5 hours). In obese patients, steady-state plasma levels of M1, but not M3, increased in proportion to orlistat doses.

Physicians Desk Reference 61st ed, Thomson PDR, Montvale, NJ 2007., p. 2831


5.8 Mechanism of Action

Orlistat is a potent and selective inhibitor of various lipase enzymes responsible for the metabolism of fat. It acts in the gastrointestinal (GI) tract via covalent binding to the serine residues located on the active site of both gastric and pancreatic lipase. When orlistat is taken with food containing fat, it partially inhibits the hydrolysis of triglycerides. This decreases absorption of monoaclglycerides and free fatty acids, contributing to weight maintenance and weight loss.


Orlistat is a reversible inhibitor of lipases. It exerts its therapeutic activity in the lumen of the stomach and small intestine by forming a covalent bond with the active serine residue site of gastric and pancreatic lipases. The inactivated enzymes are thus unavailable to hydrolyze dietary fat in the form of triglycerides into absorbable free fatty acids and monoglycerides. As undigested triglycerides are not absorbed, the resulting caloric deficit may have a positive effect on weight control. Systemic absorption of the drug is therefore not needed for activity. At the recommended therapeutic dose ... orlistat inhibits dietary fat absorption by approximately 30%.

Physicians Desk Reference 61st ed, Thomson PDR, Montvale, NJ 2007., p. 2831


Orlistat, a reversible inhibitor of gastric and pancreatic lipases, exhibits antiobesity and antilipemic activity. The drug also inhibits certain other (e.g., microbial, carboxylester [for hydrolysis of vitamin esters]) lipases. Orlistat is a synthetic derivative of naturally occurring lipstatin.

McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information. American Society of Health-System Pharmacists, Bethesda, MD. 2007., p. 3020


Unlike most other currently available antiobesity agents, orlistat does not exert anorexigenic (appetite suppressant) effects. Instead, orlistat exerts its antiobesity effect by decreasing the absorption of dietary fats (triacylglycerols) in the intestinal lumen via inhibition of triglyceride hydrolysis; at recommended dosages, approximately one-third of dietary fat will not be absorbed. By preventing triglyceride hydrolysis, the drug decreases intestinal concentrations of absorbable free fatty acids and monoglycerides.

McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information. American Society of Health-System Pharmacists, Bethesda, MD. 2007., p. 3020


Orlistat, an antiobesity drug, is cytostatic and cytotoxic to tumor cells. The antitumor activity of orlistat can be attributed to its ability to inhibit the thioesterase domain of fatty acid synthase (FAS). The objective of the present study was to test the effect of orlistat on endothelial cell proliferation and angiogenesis. Orlistat inhibits endothelial cell FAS, blocks the synthesis of fatty acids, and prevents endothelial cell proliferation. More significantly, orlistat inhibits human neovascularization in an ex vivo assay, which suggests that it may be useful as an antiangiogenic drug. The mechanism of these effects can be traced to the fact that orlistat prevents the display of the vascular endothelial growth factor (VEGF) receptor (VEGFR2/KDR/Flk1) on the endothelial cell surface. Thus, orlistat is an antiangiogenic agent with a novel mechanism of action.

PMID:17012255 Browne C, Hindmarsh E et al; FASEB J 20 (12): 2027-35 (2006)