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A JOURNEY FROM DRUG
DISCOVERY TO MARKET,
SITAGLIPTIN CASE STUDY
SPECIALLY FOR
SEMINAR AT DR. L. H. HIRANANDANI COLLEGE OF ...
2
" API- From lead optimization
to patent filing".
3
A National level seminar on 17th December, 2016.
The Theme for the seminar is " API- From Lead
optimization to Patent fi...
4
Anita Ayre
Assistant Professor at
Dr.L.H.Hiranandani College of Pharmacy
THANKS
TO
VEDIKA
DADLANI,
KUNAL GOKHALE
AND
ANITA
AYRE
Good
planning
5
PRINCIPAL AT 
DR.L.H.HIRANANDANI COLLEGE
OF PHAR
Thanks
6
7
W
HY
I CHOSE
SITAGLIPTIN
AS
EXAM
PLE
SEE
NEXT
SLIDE
8
GODDESS
SITA
FROM
RAM
AYAN
Our
role
m
odel JAI SRI RAM
, and
SITA
M
AIYA
9
10
RAMIPRIL, has LORD RAM NAME IN THE NAME
STRUCTURE
11
12
Januvia (Sitagliptin Phosphate) Tablets
Company: Merck & Co., Inc.
Application No.: 021995
Approval Date: 10/16/2006
Ap...
13
14
• In October 2006, the U.S. Food and Drug Administration
(FDA) approved Sitagliptin as monotherapy and as add-on
therap...
15
16
Dipeptidyl Peptidase 4 (DPP-4)
Inactivates GLP-1
Mixed meal
Intestinal
GLP-1
release
Rapid inactivation
Excreted by kidney...
Drug Review.2008;10(2):97-98
• Reduces hemoglobin A1c (HbA1c), fasting and
postprandial glucose by glucose dependant stimu...
19
Sitagliptin is a triazolopiperazine based inhibitor of DPP-IV,
which was discovered byMerck. It is a potent (IC50= 18 n...
20
The exhibited binding interactions of the trifluoromethyl
group with the Arg358 and Ser209 are responsible for
its high...
21
22
http://www.druglead.com/cds/sitagliptin.html
Title: Sitagliptin
CAS Registry Number: 486460-32-6
CAS Name: 7-[(3R)-3-Am...
23
Derivative Type: Monophosphate monohydrate
CAS Registry Number: 654671-77-9; 654671-78-0 (anhydrous)
Additional Names: ...
24
Orange book
NDA 021995
JANUVIA (SITAGLIPTIN PHOSPHATE)
EQ 25MG BASE
Active Ingredient: SITAGLIPTIN PHOSPHATE
Proprietar...
25
26
Product No Patent No
Patent
Expiration
Drug
Substance
Claim
Drug Product
Claim
Patent Use
Code
Delist
Requested
001 669...
27
Patent Data
U-774
METHOD OF TREATING TYPE 2 DIABETES MELLITUS BY
ADMINISTERING A DIPEPTIDYL PEPTIDASTE-IV INHIBITOR
US ...
28
29
NDA CHEMISTRY REVIEWS           
http://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021995s000_Chem
R.pdf
30
31
DISCOVERY SYNTHESIS
PATENT WO2003004498
SCOTT D EDMONDSON,
MICHAEL H FISHER, DOOSEOP KIM,
MALCOLM MACCOSS, EMMA R PARMEE,
...
33
34
                                                                   
A new synthesis of sitagliptin (MK-0431), a DPP-IV ...
35
36
37
The synthesis of 1 was completed using a four-step 
through-process 
Lactam 5 or ester 13 was hydrolyzed to amino acid ...
38
Following an aqueous workup, the organic extracts were distilled 
into ethanol and the solution was subjected to hydrog...
39
SYNTHESIS 2
COMPD NUMBERING DIFFERENT
40
41
42
The second approach for synthesis of sitagliptin was 
started from asymmetric reduction of β-ketoester 15 using 
the (S...
43
Treatment of a catalytic amount of 0.1% NaOH with lactam 
17 hydrolyzed and directly afforded the β-amino acid 18. 
Thi...
44
45
The third approach towards the synthesis of sitagliptin is 
outlined in scheme 3. 
Meldrum adduct 22 (Hunig’s base salt...
46
β-keto amide 24 was formed on reaction of 23 with 
triazolopiperazine 5. 
β-keto amide 24 on treatment with ammonium ac...
47
OMARIGLIPTIN VS SITAGLIPTIN
48
ONCE A DAY SITAGLIPTIN
For patients with moderate renal insufficiency (CrCl greater than or...
49
50
51
Omarigliptin (MK-3102, Merck) Omarigliptin is a novel
aminotetrahydropyran based structurally distinct rigid analogue o...
52
https://newdrugapprovals.org/
https://newdrugapprovals.org/2014/04/18/o
marigliptin-mk-3102-in-phase-3-for-type-2-
diab...
53
Pharmacokinetics
 Bioavailability of Sitagliptin is approximately 87% .
 Half life is between 8-14 hours.
 It is 38% bo...
55
Sitagliptin (Januvia) has a novel structure with β-amino amide derivatives
Since sitagliptin has shown excellent select...
56
It has been shown with an X-ray crystallography how
sitagliptin binds to the DPP-4 complex:
1.The trifluorophenyl group...
57
a) reducing both fasting and postprandial glucose
concentration,
b) clinically meaningful reductions in glycosylated
he...
58
• The recommended dose of Sitagliptin is 100 mg once
daily. It may be taken with or without food.
Recommended Dosage
59
Marketed Brands
 Januvia (Sitagliptin)
 Janumet (Sitagliptin and Metformin)
9323115463 amcrasto@gmail.com
60
Summary of Sitagliptin
 No clinically meaningful hypoglycemia
 Weight neutral
 DPP-4 Inhibitor
 Good tolerability
...
CLINICAL TRIALS
61
62
https://clinicaltrials.gov/search/intervention
=sitagliptin+phosphate
63
64
http://www.centerwatch.com/drug-information/fda-approved-
drugs/drug/935/januvia-sitagliptin-phosphate#
65
66
67
68
GREEN CHEMISTRY
69https://orgspectroscopyint.blogspot.in/2015/03/sitagliptin.html
70
Recently, large pharmaceutical process chemists have relied heavily on the
development of enzymatic reactions to produc...
71
Merck’s process chemistry department contracted Codexis, a medium-sized
biocatalysis firm, to develop a large-scale bio...
72
GREENING UP DRUGS Merck process chemists redesigned and significantly
shortened the original synthesis of type 2 diabet...
73
SOM
E
CLIPS
74
75
Despite this process being a considerable improvement over its predecessor,
the late-stage hydrogenation was only moder...
76
Enzymatic synthesis of sitagliptin [152].
http://rspa.royalsocietypublishing.org/content/471/2183/20150502
77
The final version of the sitagliptin synthesis avoided this
hydrogenation by using a transaminase enzyme to directly
am...
DMF
79
80
http://www.pharmacompass.com/us-drug-master-files-dmfs/sitagliptin-
phosphate
81
http://www.usactives.com/z1/search.php?
zoom_query=sitagliptin&zoom_per_page=10&zoom_and=0&zoom_sort=0
82
http://www.pharmacompass.com/pharma/ingredients/Sitagliptin_Phosphate
FORMULATIONS
84
85
http://www.rxlist.com/janumet-xr-drug.htm
ANALYSIS
87
http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0100-
46702010000300003
New Drug Approvals
https://newdrugapprovals.org/
MY BLOGS
ORGANIC SPECTROSCOPY INTERNATIONAL
LINK….. http://orgspectroscopyint.blogspot.in/
ORGANIC SPECTROSCOPY INTERNATIO...
LIONEL MY SON
He was only in first standard in school when I
was hit by a deadly one in a million spine
stroke called acut...
To take full advantage of Chemical Web content, it is essential
to use several Software:Winzip,Chemscape Chime, Shockwave,...
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Drug discovery to Market, Sitagliptin case study

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Drug discovery to Market, Sitagliptin case study, Presented at At H( S ) NCB 's Dr L H Hiranandani college of pharmacy , ulhasnagar, India for key note speech in a one day symposium on APi synthesis from lead optimisation to patent filing 17 dec 2016...Dept of Pharmaceutical chemistry

Published in: Health & Medicine

Drug discovery to Market, Sitagliptin case study

  1. 1. A JOURNEY FROM DRUG DISCOVERY TO MARKET, SITAGLIPTIN CASE STUDY SPECIALLY FOR SEMINAR AT DR. L. H. HIRANANDANI COLLEGE OF PHARMACY, DEPT OF PHARMACEUTICAL CHEMISTRY, DLHHCOP, ULHASNAGAR, MAHARASHTRA, INDIA A JOURNEY FROM DRUG DISCOVERY TO MARKET, SITAGLIPTIN CASE STUDY SPECIALLY FOR SEMINAR AT DR. L. H. HIRANANDANI COLLEGE OF PHARMACY, DEPT OF PHARMACEUTICAL CHEMISTRY, DLHHCOP, ULHASNAGAR, MAHARASHTRA, INDIA DR ANTHONY MELVIN CRASTO PRINCIPAL SCIENTIST WORLDDRUGTRACKER 17 DEC, 2016 1
  2. 2. 2 " API- From lead optimization to patent filing".
  3. 3. 3 A National level seminar on 17th December, 2016. The Theme for the seminar is " API- From Lead optimization to Patent filing" at Dr. L. H. Hiranandani College of Pharmacy, Dept of pharmaceutical chemistry, DLHHCOP, Ulhasnagar, Maharashtra, India
  4. 4. 4 Anita Ayre Assistant Professor at Dr.L.H.Hiranandani College of Pharmacy
  5. 5. THANKS TO VEDIKA DADLANI, KUNAL GOKHALE AND ANITA AYRE Good planning 5
  6. 6. PRINCIPAL AT  DR.L.H.HIRANANDANI COLLEGE OF PHAR Thanks 6
  7. 7. 7
  8. 8. W HY I CHOSE SITAGLIPTIN AS EXAM PLE SEE NEXT SLIDE 8
  9. 9. GODDESS SITA FROM RAM AYAN Our role m odel JAI SRI RAM , and SITA M AIYA 9
  10. 10. 10 RAMIPRIL, has LORD RAM NAME IN THE NAME
  11. 11. STRUCTURE 11
  12. 12. 12 Januvia (Sitagliptin Phosphate) Tablets Company: Merck & Co., Inc. Application No.: 021995 Approval Date: 10/16/2006 Approval Letter(s) (PDF) Printed Labeling (PDF) Medical Review(s) (PDF) Chemistry Review(s) (PDF) Pharmacology Review(s) (PDF) Statistical Review(s) (PDF) Clinical Pharmacology Biopharmaceutics Review(s) (PDF) Administrative Document(s) & Correspondence (PDF)
  13. 13. 13
  14. 14. 14 • In October 2006, the U.S. Food and Drug Administration (FDA) approved Sitagliptin as monotherapy and as add-on therapy to either of two other types of oral diabetes medications. • In April, 2007 FDA approved the combination product of Sitagliptin and Metformin for type 2 diabetes. • In March, 2007 it was approved in European Union. • Sitagliptin is currently approved in 70 Countries. Regulatory Affairs
  15. 15. 15
  16. 16. 16
  17. 17. Dipeptidyl Peptidase 4 (DPP-4) Inactivates GLP-1 Mixed meal Intestinal GLP-1 release Rapid inactivation Excreted by kidneys GLP-1 Active DPP-4 GLP-1 Actions GLP-1 Inactive Diabetes.1995;44:1126 Clinical Therapeutics.2006;28(1):55 Pharmacology & Therapeutics.2010:125;328–361
  18. 18. Drug Review.2008;10(2):97-98 • Reduces hemoglobin A1c (HbA1c), fasting and postprandial glucose by glucose dependant stimulation of insulin secretion and inhibition of glucagon secretion. • Sitagliptin is selective inhibitor of the enzyme DPP-4. • Delays gastric emptying and reduce appetite. 18 SITAGLIPTIN 18 Mechanism of action (MOA)
  19. 19. 19 Sitagliptin is a triazolopiperazine based inhibitor of DPP-IV, which was discovered byMerck. It is a potent (IC50= 18 nM) and highly selective over DPP-8 (48000 nM), DPP-9 (>100000 nM) and other isozymes. It enhances the pancreatic β-cell functions, fasting and post-prandial glycemic control in type 2 diabetic patients. In the crystal structure with DPP-IV, unlike other substrate-based DPP-IV inhibitors, the binding orientation of the amide carbonyl of sitagliptin is reversed, i.e. the aromatic trifluorophenyl moiety occupies S1 pocket and the β-amino amide moiety fits into S2 pockets. The amino group forms a salt bridge and hydrogen bonding interactions with Glu205 and Glu206, and Tyr662, respectively. The triazolopiperazinemoiety occupies the S2 extended pocket and stacks against Phe357.
  20. 20. 20 The exhibited binding interactions of the trifluoromethyl group with the Arg358 and Ser209 are responsible for its high selectivity profile. The presence of the trifluoromethyl group in the triazole ring also improvesthe oral bioavailability in animal models. Sitagliptin inhibited the plasma DPP-IV up to 80% and 47% at 2 and 24 h, respectively, after a single dose of 25.0 mg in a dose-dependent manner. In a 24-week study, sitagliptin significantly decreased fasting glucose levels and HbA1c levels (0.8%) at doses of 100 mg q.d. Thus, sitagliptin is well tolerated and body weight neutral. It is the first DPP-IV inhibitor in the class approved by USFDA in 2006 and is used as either a monotherapy or in combination with metformin
  21. 21. 21
  22. 22. 22 http://www.druglead.com/cds/sitagliptin.html Title: Sitagliptin CAS Registry Number: 486460-32-6 CAS Name: 7-[(3R)-3-Amino-1-oxo-4-(2,4,5-trifluorophenyl)butyl]-5,6,7,8- tetrahydro-3-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyrazine Additional Names: (2R)-4-oxo-4-[3-(trifluoromethyl)-5,6- dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2- amine Molecular Formula: C16H15F6N5O Molecular Weight: 407.31 Percent Composition: C 47.18%, H 3.71%, F 27.99%, N 17.19%, O 3.93% Literature References: Selective inhibitor of dipeptidyl peptidase IV (DPP-IV). Prepn: S. D. Edmondson et al., WO 03004498; eidem, US 6699871 (2003, 2004 both to Merck & Co.); and enzyme inhibitory profile: D. Kim et al., J. Med. Chem. 48, 141 (2005). Improved process: K. B. Hansen et al., Org. Process Res. Dev. 9, 634 (2005). Clinical pharmacokinetics and pharmacodynamics: G. A. Herman et al., Clin. Pharmacol. Ther. 78, 675 (2005). Review: C. F. Deacon, Curr. Opin. Invest. Drugs 6, 419-426 (2005). Properties: Viscous oil.
  23. 23. 23 Derivative Type: Monophosphate monohydrate CAS Registry Number: 654671-77-9; 654671-78-0 (anhydrous) Additional Names: Sitagliptin phosphate Manufacturers' Codes: MK-0431 Trademarks: Januvia (Merck & Co.) Molecular Formula: C16H15F6N5O.H3PO4.H2O Molecular Weight: 523.32 Percent Composition: C 36.72%, H 3.85%, F 21.78%, N 13.38%, O 18.34%, P 5.92% Properties: mp 215-217°. [a]D -74.4° (c = 1.0 in water). Melting point: mp 215-217° Optical Rotation: [a]D -74.4° (c = 1.0 in water)
  24. 24. 24 Orange book NDA 021995 JANUVIA (SITAGLIPTIN PHOSPHATE) EQ 25MG BASE Active Ingredient: SITAGLIPTIN PHOSPHATE Proprietary Name: JANUVIA Dosage Form; Route of Administration: TABLET; ORAL Strength: EQ 25MG BASE Reference Listed Drug: No TE Code: Application Number: N021995 Product Number: 001 Approval Date: Oct 16, 2006 Applicant Holder Full Name: MERCK SHARP AND DOHME CORP Marketing Status: Prescription Patent and Exclusivity Information http://www.accessdata.fda.gov/scripts/cder/ob/
  25. 25. 25
  26. 26. 26 Product No Patent No Patent Expiration Drug Substance Claim Drug Product Claim Patent Use Code Delist Requested 001 6699871 Jul 26, 2022 DS DP U-774   001 7125873 Jul 26, 2022     U-775 U-1036  U-1037 U-1038   001 7326708 Nov 24, 2026 DS DP U-802
  27. 27. 27 Patent Data U-774 METHOD OF TREATING TYPE 2 DIABETES MELLITUS BY ADMINISTERING A DIPEPTIDYL PEPTIDASTE-IV INHIBITOR US 7125873 http://www.google.co.in/patents/US7125873 CA2450740A1, CA2450740C, CN1290848C, CN1524082A, CN1861077A,  DE60210093D1, DE60210093T2, DE60236767D1, DE122007000056I1, DE122008000046I1,  EP1412357A1, EP1412357B1, EP1625847A1, EP1625847B1, EP2226324A1, EP2292232A1,  EP2292232B1, US6699871, US8168637, US8440668, US20030100563, US20040167133,  US20060270679, US20100130504, US20110190308, US20130217695, US20150359793,  WO2003004498A1
  28. 28. 28
  29. 29. 29 NDA CHEMISTRY REVIEWS            http://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021995s000_Chem R.pdf
  30. 30. 30
  31. 31. 31
  32. 32. DISCOVERY SYNTHESIS PATENT WO2003004498 SCOTT D EDMONDSON, MICHAEL H FISHER, DOOSEOP KIM, MALCOLM MACCOSS, EMMA R PARMEE, ANN E WEBER, JINYOU XU 32Emma Parmee Ann E Weber Scott D. Edmondson
  33. 33. 33
  34. 34. 34                                                                     A new synthesis of sitagliptin (MK-0431), a DPP-IV inhibitor and potential  new treatment for type II diabetes, suitable for the preparation of multi- kilogram quantities is presented. The triazolopyrazine fragment of  sitagliptin was prepared in 26% yield over four chemical steps using a  synthetic strategy similar to the medicinal chemistry synthesis. Key  process developments were made in the first step of this sequence, the  addition of hydrazine to chloropyrazine, to ensure its safe operation on a  large scale. The beta-amino acid fragment of sitagliptin was prepared by  asymmetric reduction of the corresponding beta-ketoester followed by a  two-step elaboration to an N-benzyloxy beta-lactam. Hydrolysis of the  lactam followed by direct coupling to the triazolopiperazine afforded  sitagliptin after cleavage of the N-benzyloxy group and salt formation.  The overall yield was 52% over eight steps.
  35. 35. 35
  36. 36. 36
  37. 37. 37 The synthesis of 1 was completed using a four-step  through-process  Lactam 5 or ester 13 was hydrolyzed to amino acid 2b with  LiOH in THF/water by either stirring at room temperature  or, in the case of 13, heating to 40 °C.  While the benzyloxy group of 2b could be cleaved by  hydrogenacoupling to triazole 3, the benzyloxy group of 2b was found to sufficiently tion and then protected with Boc2O  to prevent side reactions during the protect the amino  group to allow the desired amide to be formed.  Thus, triazole 3 was coupled to 2b at 0 °C using EDC−HCl  and N-methylmorpholine (NMM) as base to afford 14 in  >99% assay yield. 
  38. 38. 38 Following an aqueous workup, the organic extracts were distilled  into ethanol and the solution was subjected to hydrogenation with  10% Pd on carbon.  The presence of water in the hydrogenation was found to be crucial  to the reaction success; anhydrous solutions of 14 hydrogenated  with dry Pd on carbon proceeded only to low levels of conversion to  1, and addition of water to these reductions resulted in restored  performance of the catalyst.  Following hydrogenation, the catalyst was removed by filtration to  provide an ethanol solution of 1. Sitagliptin was isolated in >99.5% purity as its anhydrous  phosphoric acid salt by crystallizing from aqueous ethanol.
  39. 39. 39
  40. 40. SYNTHESIS 2 COMPD NUMBERING DIFFERENT 40
  41. 41. 41
  42. 42. 42 The second approach for synthesis of sitagliptin was  started from asymmetric reduction of β-ketoester 15 using  the (S)-BinapRuCl2 complex with a catalytic amount of  HBr in methanol  followed by hydrolysis afforded the β-hydroxy acid 16.  Lactam 17 was synthesized by coupling of 16 with  BnONH2 •HCl using N-(3- dimethylaminopropyl)-N- ethylcarbodiimide hydrochloride (EDC),  Followed by cyclization reaction with diisopropyl  azodicarboxylate (DIAD) and PPh3 .  
  43. 43. 43 Treatment of a catalytic amount of 0.1% NaOH with lactam  17 hydrolyzed and directly afforded the β-amino acid 18.  This wascoupled withtriazolopiperazine 5 using EDC•HCl  and N-ethylmorpholine to provide the N-benzyloxy protected  compound 19, Which after hydrogenation using Pd/C and by consequent  treatment with phosphoric acid provided the phosphate salt  of sitagliptin
  44. 44. 44
  45. 45. 45 The third approach towards the synthesis of sitagliptin is  outlined in scheme 3.  Meldrum adduct 22 (Hunig’s base salt) was synthesized from  trifluorophenylacetic acid 20 by the formation of a mixed  anhydride with pivaloyl chloride in the presence of Meldrum’s  acid 21, DIPEA and catalytic amount of dimethylamino  pyridine (DMAP) in acetonitrile.  Treatment of 22 with TFA resulted compound 23. β-keto  amide 24 was formed on reaction of 23 with  triazolopiperazine 5
  46. 46. 46 β-keto amide 24 was formed on reaction of 23 with  triazolopiperazine 5.  β-keto amide 24 on treatment with ammonium acetate in  methanol formed a key intermediate, dehydrositagliptin  25 (enamine amide).  This intermediate contains the entire structure of  sitagliptin 14 except two hydrogen atoms.  Thus, sitagliptin 14 was synthesized by enantioselective  hydrogenation of dehydrositagliptin 25 in the presence of  [Rh(COD)2 OTf]  and t Bu JOSIPHOS in excellent yield  with 95% ee.
  47. 47. 47
  48. 48. OMARIGLIPTIN VS SITAGLIPTIN 48 ONCE A DAY SITAGLIPTIN For patients with moderate renal insufficiency (CrCl greater than or equal to 30 to  less than 50 mL/min, approximately corresponding to serum creatinine levels of  greater than 1.7 to less than or equal to 3.0 mg/dL in men and greater than 1.5 to  less than or equal to 2.5 mg/dL in women), the dose of JANUVIA is 50 mg once  daily. MARIZEV® (Omarigliptin), Merck’s Once-Weekly DPP-4 Inhibitor for Type 2 Diabetes, Approved in Japan -Merck, known as MSD outside the United States and Canada, today  announced that the Japanese Pharmaceuticals and Medical Devices  Agency (PMDA) has approved MARIZEV®  (omarigliptin) 25 mg and 12.5  mg tablets, an oral, once-weekly DPP-4 inhibitor indicated for the  treatment of adults with type 2 diabetes. Japan is the first country to have  approved omarigliptin. 
  49. 49. 49
  50. 50. 50
  51. 51. 51 Omarigliptin (MK-3102, Merck) Omarigliptin is a novel aminotetrahydropyran based structurally distinct rigid analogue of sitagliptin in which the central linker of sitagliptin was modified to rigid cyclohexylamine. It is extremely potent (IC50=1.6 nM) and long acting with excellent selectivity profile against isopeptidases. It is once-a-week oral agent rather than once a day like existing therapies in DPP-IV inhibitor. Omarigliptin binds in the DPP-IV active site very similar to sitagliptin and share the same interactions. The 2-F atom in the trifluorophenyl group occupied in S1 pocket shows a hydrogen bonding with the side chain of Arg125. On the other hand, the aminotetrahydropyran group binds to S2 pocket where the primary amine group makes salt bridges with the carboxylates of Glu205 and Glu206. The fused ring π-π stacks with the side chain of Phe347.[65] Omarigliptin exhibited a unique PK and pharmacological profile with the half-life of ~68 h. It markedly lowered the blood glucose levels and 0.57% of HbA1c level at a dose of 25 mg in a 12 week study. It also exhibited 77- 89% inhibition of plasma DPP-IV up to 168 h and enhanced two folds of GLP-1 levels. Omarigliptin is generally well tolerated with excellent safety profiles in healthy subjects. Currently, omarigliptin is in clinical trial PhaseIII
  52. 52. 52 https://newdrugapprovals.org/ https://newdrugapprovals.org/2014/04/18/o marigliptin-mk-3102-in-phase-3-for-type-2- diabetes/
  53. 53. 53
  54. 54. Pharmacokinetics  Bioavailability of Sitagliptin is approximately 87% .  Half life is between 8-14 hours.  It is 38% bound to plasma proteins.  Elimination is mainly through urine. Drug Review.2008;10(2):97-9854
  55. 55. 55 Sitagliptin (Januvia) has a novel structure with β-amino amide derivatives Since sitagliptin has shown excellent selectivity and in vivo efficacy it urged researches to inspect the new structure of DPP-4 inhibitors with appended β-amino acid moiety. Further studies are being developed to optimize these compounds for the treatment of diabetes. In October 2006 sitagliptin became the first DPP-4 inhibitor that got FDA approval for the treatment of type 2 diabetes. Crystallographic structure of sitagliptin along with molecular modeling has been used to continue the search for structurally diverse inhibitors. A new potent, selective and orally bioavailable DPP-4 inhibitor was discovered by replacing the central cyclohexylamine in sitagliptin with 3- aminopiperidine. A 2-pyridyl substitution was the initial SAR breakthrough since that group plays a significant role in potency and selectivity for DPP-4.
  56. 56. 56 It has been shown with an X-ray crystallography how sitagliptin binds to the DPP-4 complex: 1.The trifluorophenyl group occupies the S1-pocket 2. The trifluoromethyl group interacts with the side chains of residues Arg358 and Ser209. 3. The amino group forms a salt bridge with Tyr662 and the carboxylated groups of the two glutamate residues, Glu205 and Glu206. 4. The triazolopiperazine group collides with the phenyl group of residue Phe357
  57. 57. 57 a) reducing both fasting and postprandial glucose concentration, b) clinically meaningful reductions in glycosylated hemoglobin (HbA1c) levels in type 2 diabetic patients. • Monotherapy with Sitagliptin 100 mg daily decreases mean HbA1c by 0.6-0.98%. CLINICAL EVIDENCE Drug Review.2008;10(2):97-98 Consultant.2009:S5-11 Pharmacology & Therapeutics.2010;25:328-361 • In very well controlled randomized clinical trials Sitagliptin (100 mg) treatment significantly improved glycemic control by • Improved Homeostasis model assessment of β cell and Proinsulin-to-insulin ratio.
  58. 58. 58 • The recommended dose of Sitagliptin is 100 mg once daily. It may be taken with or without food. Recommended Dosage
  59. 59. 59 Marketed Brands  Januvia (Sitagliptin)  Janumet (Sitagliptin and Metformin) 9323115463 amcrasto@gmail.com
  60. 60. 60 Summary of Sitagliptin  No clinically meaningful hypoglycemia  Weight neutral  DPP-4 Inhibitor  Good tolerability  Improves Blood pressure  Stimulate insulin secretion  Slows gastric emptying  Reduces food intake  Inhibit glucagon secretion  Reduces HbA1c  Improves inflammatory markers
  61. 61. CLINICAL TRIALS 61
  62. 62. 62 https://clinicaltrials.gov/search/intervention =sitagliptin+phosphate
  63. 63. 63
  64. 64. 64 http://www.centerwatch.com/drug-information/fda-approved- drugs/drug/935/januvia-sitagliptin-phosphate#
  65. 65. 65
  66. 66. 66
  67. 67. 67
  68. 68. 68 GREEN CHEMISTRY
  69. 69. 69https://orgspectroscopyint.blogspot.in/2015/03/sitagliptin.html
  70. 70. 70 Recently, large pharmaceutical process chemists have relied heavily on the development of enzymatic reactions to produce important chiral building blocks for API synthesis. Many varied classes of naturally occurring enzymes have been co- opted and engineered for process pharmaceutical chemistry applications. The widest range of applications come from ketoreductases and transaminases, but there are isolated examples from hydrolases, aldolases, oxidative enzymes, esterases and dehalogenases, among others.[11] One of the most prominent uses of biocatalysis in process chemistry today is in the synthesis of Januvia®, a DPP-4 inhibitor developed by Merck for the management of type II diabetes. The traditional process synthetic route involved a late-stage enamine formation followed by rhodium-catalyzed asymmetric hydrogenation to afford the API sitagliptin. This process suffered from a number of limitations, including the need to run the reaction under a high-pressure hydrogen environment, the high cost of a transition- metal catalyst, the difficult process of carbon treatment to remove trace amounts of catalyst and insufficient stereoselectivity, requiring a subsequent recrystallization step before final salt formation.[12][13]
  71. 71. 71 Merck’s process chemistry department contracted Codexis, a medium-sized biocatalysis firm, to develop a large-scale biocatalytic reductive amination for the final step of its sitagliptin synthesis. Codexis engineered a transaminase enzyme from the bacteria Arthrobacter through 11 rounds of directed evolution. The engineered transaminase contained 27 individual point mutations and displayed activity four orders of magnitude greater than the parent enzyme. Additionally, the enzyme was engineered to handle high substrate concentrations (100 g/L) and to tolerate the organic solvents, reagents and byproducts of the transamination reaction. This biocatalytic route successfully avoided the limitations of the chemocatalyzed hydrogenation route: the requirements to run the reaction under high pressure, to remove excess catalyst by carbon treatment and to recrystallize the product due to insufficient enantioselectivity were obviated by the use of a biocatalyst. Merck and Codexis were awarded the Presidential Green Chemistry Challenge Award in 2010 for the development of this biocatalytic route toward Januvia®.[14]
  72. 72. 72 GREENING UP DRUGS Merck process chemists redesigned and significantly shortened the original synthesis of type 2 diabetes drug candidate sitagliptin (Januvia) to include an unprecedented efficient hydrogenation of an unprotected enamine. Chemical & Engineering News • ISSN 0009-2347 • Copyright © 2006 American Chemical Society
  73. 73. 73
  74. 74. SOM E CLIPS 74
  75. 75. 75 Despite this process being a considerable improvement over its predecessor, the late-stage hydrogenation was only moderately stereoselective and required high-pressure conditions [151]. The removal of the metal catalyst by absorption onto a polymer impregnated with activated carbon and the final recrystallization as the [H2PO4]− salt led to reduced yield [151].
  76. 76. 76 Enzymatic synthesis of sitagliptin [152]. http://rspa.royalsocietypublishing.org/content/471/2183/20150502
  77. 77. 77 The final version of the sitagliptin synthesis avoided this hydrogenation by using a transaminase enzyme to directly aminate the prositagliptin diketone precursor with iso- propylamine (scheme 10) [152], giving a highly enantiopure product. The enzymatic process gives a 10–13% increase in overall yield, a 53% increase in productivity (kgl  −1 day  −1 ), a 19% reduction in total waste and the elimination of all heavy metals. In addition to these environmental advantages, the biocatalytic process eliminated the need for specialized high-pressure equipment, leading to reductions in both capital and running costs.
  78. 78. DMF
  79. 79. 79
  80. 80. 80 http://www.pharmacompass.com/us-drug-master-files-dmfs/sitagliptin- phosphate
  81. 81. 81 http://www.usactives.com/z1/search.php? zoom_query=sitagliptin&zoom_per_page=10&zoom_and=0&zoom_sort=0
  82. 82. 82 http://www.pharmacompass.com/pharma/ingredients/Sitagliptin_Phosphate
  83. 83. FORMULATIONS
  84. 84. 84
  85. 85. 85 http://www.rxlist.com/janumet-xr-drug.htm
  86. 86. ANALYSIS
  87. 87. 87 http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0100- 46702010000300003
  88. 88. New Drug Approvals https://newdrugapprovals.org/
  89. 89. MY BLOGS ORGANIC SPECTROSCOPY INTERNATIONAL LINK….. http://orgspectroscopyint.blogspot.in/ ORGANIC SPECTROSCOPY INTERNATIONAL Organic Chemists from Industry and academics to Interact on Spectroscopy Techniques for Organic Compounds ie NMR, MASS, IR, UV Etc. Starters, Learners, advanced, all alike, contains content which is basic or advanced, by Dr Anthony Melvin Crasto, Worlddrugtracker, email me ........... amcrasto@gmail.com, call +91 9323115463
  90. 90. LIONEL MY SON He was only in first standard in school when I was hit by a deadly one in a million spine stroke called acute transverse mylitis, it made me 90% paralysed and bound to a wheel chair, He cried bitterly and we had never seen him so depressed Now I keep Lionel as my source of inspiration and helping millions, thanks to millions of my readers who keep me going and help me to keep my son and family happy.
  91. 91. To take full advantage of Chemical Web content, it is essential to use several Software:Winzip,Chemscape Chime, Shockwave, Adobe Acrobat, Cosmo Player, Web Lab Viewer, Paint Shop Pro, Rasmol, ChemOffice, Quick Time,etc amcrasto@gmail.com
  92. 92. SUCCESS FORMULA
  93. 93. 93THANK YOUTHANK YOU

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