discovery of dpp-4 inhibitors as antidiabetic agents · 2019-11-04 · copyright © 2010 merck...

Copyright © 2010 Merck & Co., Inc., Whitehouse Station, New Jersey, USA All rights Reserved

Discovery of DPP-4 Inhibitors as Antidiabetic Agents

Tesfaye Biftu Merck & Co., Inc.


•  c. 1552 B.C. – 1st reference to Rx for polyuria by Hesy-Ra, 3rd Dynasty Ebers Papyrus

•  c. 100 B.C. – The father of medicine in India, Susruta of the Hindus, diagnosed diabetes

•  c. 30 B.C. ~ 50 A.D. – 1st clinical description of diabetes, Aulus Cornelius Celsus

•  c. 150 A.D. – The name “diabetes” was first introduced from the Greek word for “siphon” by Aretaeus of Cappadocia

History of Diabetes


•  Discovery of Insulin (1921) – An Instant Hit –  First Human Clinical Trial 1922 –  Noble Price 1923 Benting & MacLoed –  Commercial Production 1923 Eli Lilly –  First Total Synthesis 1965 Chinese Team

•  Discovery of Glucagon (1923) – Largely Unnoticed –  Sequenced in 1957 –  Rediscovered in 1970’s for its role in diabetes

•  Discovery of Incretins – Gastrointestinal Hormones –  1932 The term “incretin” was first used –  1970 GIP was isolated –  1982 GLP-1 was sequenced

……….continued


•  2000: 171 million cases worldwide; 2030: 366 million cases predicted

•  >90% is Type 2 diabetes: obesity is a major risk factor

Diabetes is a Growing Worldwide Epidemic

The Americas 2000: 33 million 2030: 66.8 million

Europe 2000: 33.3 million 2030: 48 million

Middle East 2000: 15.2 million 2030: 42.6 million

Africa 2000: 7 million 2030: 18.2 million

Asia and Australia 2000: 82.7 million 2030: 190.5 million

<3 3-5 6-8 >8

Prevalence (%) in persons 35-64 yrs

WHO


<4% 4-4.9% 6+%

1994 2004

5-5.9%

Ø  20,800,000 People in US (7%) have diabetes (2005) Ø  6th Leading cause of death in US (2002), by death certificate Ø  >90% Type 2, associated with metabolic syndrome

Taken from CDC diabetes website: http://www.cdc.gov/diabetes

missing data

Trends among U.S. Adults: 1994 to 2004


Current Medications for Treatment of Diabetes

Safer and more effective medications are needed

Sulfonylureas Meglitinides Metformin Thiazolidinediones α-Glucosidase inhibitors Insulin

Hypoglycemia, weight gain Hypoglycemia, weight gain GI intolerance Edema, weight gain GI intolerance Hypoglycemia, weight gain

Drug Class Side Effects


Role of Active GLP-1 and GIP in Glucose Homeostasis

•  Glucagon-Like-Peptide (GLP-1) and Glucose-Dependent-Insulotropic-Polypeptide (GIP) are secreted in response to food intake (glucose-dependent mechanism)

•  GLP-1 and GIP - (↑)stimulate insulin biosynthesis & secretion

•  GLP-1 inhibits - (↓) glucagon secretion

•  GLP-1 and GIP - (↓)lower blood sugar level


…. but Active GLP-1 (or GIP) is Cleaved Rapidly by DPP-4

GLP-1 (Active) HA EGTFTSDVSSYLEGQAAKEFIAWLVKGR-NH2

GLP-1 (Inactive) EGTFTSDVSSYLEGQAAKEFIAWLVKGR-NH2

DPP-4 t½ ~ 1 min Inhibit

Stabilize


Dipeptidyl Peptidase IV (DPP-4)

•  First Isolated from rat liver in 1966

•  Identical to CD26, a marker for activated T cells

•  Its role in energy homeostasis was discovered which led to the first patent application in 1996

•  Cell surface serine dipeptidase belonging to the prolyl oligopeptidase family

•  Widely expressed, and has Specificity for P1 Pro >> Ala


N

O

SNH2

NS

I

O

O

QPP Selective DPP-8/9 Selective

N

OMeMe

NH2

DPP-4 Selective

DPP-9 > 100,000 11,000 55

DPP-8 69,000 22,000 38

FAP > 100,000 > 100,000 > 100,000

DPP-4 27 1900 30,000

PEP > 100,000 > 100,000 > 100,000

QPP/DPP-2 > 100,000 19 14,000

APP > 100,000 > 100,000 > 100,000

prolidase > 100,000 > 100,000 > 100,000

IC50, nM Enzyme

N

ONH2

NN

N

CF3

F

FSelective Inhibitors


2 wk. Rat Toxicity QPP

Selective DPP-8/9

Selective DPP-4

Selective

Alopecia ü

Thrombocytopenia ü

Reticulocytopenia ü ü

Enlarged spleen ü

Mortality ü

Acute dog toxicity

Bloody diarrhea ü

G. Lankas, et al., Diabetes 2005, 54, 2988

Comparative Toxicity Study


Potential Importance of Selective Inhibition for the Treatment of Type 2 Diabetes

•  Conclusion –  “Off-target” peptidase inhibition (i.e. inhibition of other DPP family

peptidases such as DPP8/9) can produce severe toxicity in preclinical species

•  Variables that may determine degree of toxicity –  Cell penetration

•  Unlike DPP-4, DPP8/9 are intracellular proteins

–  Extent of inhibition of DPP8 and/or DPP9 •  Not known if inhibition of both enzymes

(or how much) is required to produce toxicities

–  Intraspecies differences in DPP8/9 inhibition from Demuth et al. Biochim. Biophys. Acta 2005, 1751, 33

DPP-4


DPP-4 Inhibitor Program - Objective   Identify a potent and selective DPP-4 inhibitor for the

treatment of type 2 diabetes mellitus with the following characteristics:

•  >1000-fold selectivity over other proline peptidases, especially DPP-8 and DPP-9

•  Half-life suitable for BID or preferably QD dosing

•  Structure lacking reactive electrophile as a serine trap, e.g.,

N

OHN

X

CN

RN

OH2N

R

B(OH)2

R'


Common Lead Discovery Methods

•  Biological screening of compounds

•  Substrate or active-structure based design

•  Enzyme – inhibitor crystal structure


•  β-Amino acid proline amides

IC50 = 1.9 µM

•  β-Amino piperazines

IC50 = 11 µM H2NN

N

O

NH

NHSO2Me

N

HNO

Cl

OO

NH

ONH2

Screening Leads


Radioactivity Recovered in 24 hrs (% Dose)

Collection Period Intravenous Oral Bile 28.3 ± 2.6% 38.2 ± 4.7% Urine 18.1 ± 2.0% 14.0 ± 4.2% Feces 1.0 ± 0.2% 1.4 ± 0.6% Total 47.4 ± 3.9% 54.6 ± 4.9%

N

NH

ONH2

F

T

Recovery of Radioactivity after IV (1 mg/kg) or Oral (2 mg/kg) Administration to Rats

Y. Teffera

PK Rat: •  high clearance (>150 mL/min/kg) and •  short half-life.


Microsomes: piperazine ring oxidation. Hepatocytes: Conjugation of the primary amino group (glucuronic acid and glucose). Oxidation of the piperazine, the phenyl and the fluoro-phenyl rings. Glutathione conjugation on the fluoro-phenyl ring; d) amide bond hydrolysis. Bile of PO treated rats: carbamoyl glucuronide conjugate on the piperazine ring. Glutathione conjugation of the fluoro-phenyl ring, piperazine ring oxidation, and N-glucuronidation of the primary amine were also observed. Bile of IV treated rats: Glutathione conjugation on the fluoro-phenyl ring, piperazine and phenyl ring oxidation, and N-glucuronidation of the primary amine. Urine of PO treated rats: Acid formed by the de-ethylation and oxidative de-amination of the piperazine ring. Oxidation of the piperazine ring, glucuronidation of the primary amine, and amide bond hydrolysis were also observed. Urine of IV treated rats: excreted mainly parent compounds

Metabolites identified in microsomes, hepatocites, and bile of PO/IV treated rats


N

X = NH, O

ONH2

F

Efforts made to stabilize metabolism

N

N

ONH2

F


Bicyclic Piperazine Replacements

N

NN

R"

R

R'

N

N

NR"

R

R'

N

NO

R

N

NN

NR

R'

NN

N

R"

R

R'

NN

O

R'

RN

ON

R

N

O

NR N

ON

R

NR

N

NR

N

N

NRN

N

NR

NNRN

NR

N

N

NR

N

N

SR

N

S

NR

N

N

OR

N

N

NR

NN N

NR

NN

NN

R

NN

NR

NN

N

R

NN

N

R


MK-0431 = JANUVIA™ (sitagliptin phosphate)

Left Hand Side SAR

N

ONH2

NN

N

CF3

R

D. Kim, et al., J. Med. Chem. 2005, 48, 141

Rat PK

R DPP-4 IC50 Clp t½ Frat (nM) (mL/min/kg) (h) (%)

3,4-diF 130 51 1.8 44

2,5-diF 27 43 1.6 50

2,4,5-triF 18 60 1.7 76 100


Sitagliptin: In Vitro Potency and Selectivity N

ONH2

NN

N

CF3

F

FF

DPP-9

DPP-8

FAP

DPP-4

DPP-6

PEP

QPP/DPP-2

APP

prolidase

not active

DPP-4 Gene Family

Other Proline Specific Enzymes

IC50, (nM)

> 100000

48000

> 100000

> 100000

18

> 100000

> 100000

> 100000

not active

Selectivity Ratio

> 5000

2700

> 5000

> 5000

1

> 5000

> 5000

> 5000


PK Properties of Sitagliptin 1 mg/kg IV, 2 mg/kg PO

Clp Vd t½ PO AUCnorm PO Cmax F species (mL/min/kg) (mL/kg) (h) (µM·h/mpk) ( µ M ) ( % )

M o u s e 6 4 3 . 8 0 . 8 0 . 4 1 0 . 5 1 6 1

R a t 6 0 6 . 4 1 . 7 0 . 5 2 0 . 3 3 7 6

D o g 6 . 0 9 . 0 4 . 9 8 . 3 2 . 2 1 0 0

M o n k e y 2 8 2 . 3 3 . 7 1 . 0 0 . 3 3 6 8

N

ONH2

NN

N

CF3

F

FF


Pharmacodynamics of Sitagliptin: OGTT in Lean Mice

Dose, mg/kg [sitagliptin], nM

0.1 19

0.3 52

1 190

3 600 Mouse DPP-4: IC50 = 69 nM

Glucose AUC DPP-4 Inhibition (uncorrected)

Active GLP-1

20 min post Glucose, 80 min post Compound

0

20

40

60

80

100

0 0.1 0.3 1 3

Glu

cose

AU

C, %

veh

icle

L-224715, mg/kg

0

2

4

6

8

0 0.1 0.3 1 3

Pla

sma

[GLP

-1] in

tact, p

M

L-224715, mg/kg

0

20

40

60

80

100

0 0.1 0.3 1 3

Pla

sma

DP

-IV %

inhi

bitio

n(u

ncor

rect

ed)

L-224715, mg/kgSitagliptin, mg/kg Sitagliptin, mg/kg

Sitagliptin, mg/kg

DPP-4 Inhibition


Diabetic Mice

Chronic Efficacy with a Sitagliptin Analog in Mice Restoration of Pancreatic Islet β Cells

Diabetic Mice + Sitagliptin analog Lean Control Mice

Islets from HFD/STZ mice +/- 10 weeks of treatment with sitagliptin analog

Green: Insulin-producing β cell Red: Glucagon-producing α cell


JANUVIATM

(sitagliptin)

Launched, Oct. 2006 N

ONH2

NN

N

CF3

F

FF

H3PO4 H2O

•  Selective inhibition of DPP-4, in particular with respect to DPP-8 and/or DPP-9, provides an improved safety profile in preclinical species.

•  Sitagliptin is a potent and selective DPP-4 inhibitor, very well tolerated in pre-clinical toxicity studies and in human clinical trials.

•  In patients with type 2 diabetes, once daily administration of sitagliptin stabilizes active GLP-1 and GIP, reduces glucose excursion, enhances insulin levels, suppresses glucagon levels, and improves glycemic control.

•  JANUVIA™ (sitagliptin) was approved by the FDA as a new treatment for type 2 diabetes.

For more info: www.januvia.com


Back-up Objective

Identify a specific DPP-4 inhibitor as a back-up to sitagliptin

•  Potency equivalent to or better than sitagliptin

•  Increased half-life suitable for QD dosing

•  Structural diversity


α-Amino Acid Series Revisited

•  Allo isomer is ~10-fold more toxic than threo

•  Incorporate “threo” bias into α-amino acid series?

threo Ile-thiazolidide

N

O

SNH2

MeMe

N

O

SNH2

MeMe

allo Ile-thiazoldide

Enzyme IC50 (nM) IC50 (nM)

DPP-4 440 460 QPP 14,000 18,000

DPP-8 2,200 220 DPP-9 1,600 320


N

O

SNH2

MeMe

Enzyme IC50 (nM)

DPP-4 420 QPP 14,000

DPP-8 2,200 DPP-9 1,600

J. Xu et al. Bioorg. Chem. Med. Lett. 2005, 15, 2533; S. D. Edmondson et al., J. Med. Chem. 2006, 49, 3614

β-Substituted Phenylalanine Derivatives

N

O

NH2

Me

FF

Enzyme IC50 (nM)

DPP-4 64 QPP 2,700

DPP-8 88,000 DPP-9 86,000

Rat PK Clp 8.6

t1/2 (h) 2.2 F (%) 85

hERG IC50 = 1.1 µM


N

O

SNH2

MeMe

Enzyme IC50 (nM)

DPP-4 420 QPP 14,000

DPP-8 2,200 DPP-9 1,600


N

O

NH2

Me

FF

Enzyme IC50 (nM)

DPP-4 64 QPP 2,700

DPP-8 88,000 DPP-9 86,000

Rat PK Clp 8.6

t1/2 (h) 2.2 F (%) 85

hERG IC50 = 1.1 µM

•  Optimization Goals

–  Increase potency and selectivity

–  Decrease ion channel binding

–  Maintain good oral bioavailability


N

O

SNH2

MeMe

Enzyme IC50 (nM)

DPP-4 420 QPP 14,000

DPP-8 2,200 DPP-9 1,600


N

O

NH2

Me

FF

Enzyme IC50 (nM)

DPP-4 64 QPP 2,700

DPP-8 88,000 DPP-9 86,000

Rat PK Clp 8.6

t1/2 (h) 2.2 F (%) 85

hERG IC50 = 1.1 µM

N

O

NH2N

N O

N

N

Me

Me

FF

Enzyme IC50 (nM)

DPP-4 8.8 QPP ~100,000

DPP-8 >100,000 DPP-9 >100,000

Rat PK Clp 2.8

t1/2 (h) 1.6 F (%) 100

hERG IC50 = >100 µM


α-Amino Amide Back Up

•  Criteria ✔ Potency equivalent to or better than sitagliptin –  Increased t1/2 ✔ Potential for balanced renal/hepatic clearance ✔ Structural diversity

•  Potential Liabilities –  Modest QTc prolongation in CV dog

•  Strategy –  Position as an insurance back-up, should unexpected safety

issues arise with sitagliptin –  Bulk drug prepared for 14-wk safety studies

Ø  Identify an additional back up compound lacking QTc liability

N

O

NH2N

N O

N

N

Me

Me

FF


Active-Structure Based Design

•  Sitagliptin is a triazolopyrazine

•  Triazolopyrazines are reported as bioisosters of amides

N

N

N

O

O

N

N TL, 41, (2000) 4533 & Ann Rep Med Chem

F

F

N

O

NN

N

CF3

NH2F


N N

ON

N

ONN

O

IC50, nM 160 89 14

R R R

DPP-4

R = Di-Fluoro phenyl β-AA series

F

F

N

O

NN

N

CF3

NH2

R = H, IC50 = 27 nMR = Me, IC50 = 7.2 nM

R

F

F

N

O

NH

O

NH2

R = H, IC50 = 140 nMR = Me, IC50 = 89 nM

R

Design


Activity vs. Stereochemistry

F

F

N

O

NH

ONH2

F

F

N

O

NH

ONH2

F F

DPP-4 IC50 = 6.6 nM DPP-4 IC50 = 150nM

**(R) (S)

F

F

N

O

NH

ONH2

F

F

N

O

NH

ONH2

F F

DPP-4 IC50 = 67,000 nM DPP-4 IC50 = 2,300 nM

(R) (S)

(R) (R)

(S) (S)

F

F

N

O

NH

ONH2

F

(R)

F

F

N

O

NH

ONH2

F

DPP-4 IC50 = 403 nM

DPP-4 IC50 = 140 nM

Activity: R,R > R,S > S,S > S,R


R DPP-4 QPP DPP8 (nM) (nM) (nM)

H 0.91 17,000 21,000

2-Me 0.26 7,600 21,000

2-F 0.33 21,000 25,000

2-CF3 0.35 5,100 36,000

[2-Pyridine] 0.49 89,000 53,000

[2-Pyrrazole] 0.29 75,000 80,000

α-Substituted Aryl Diazepanone Derivatives

N

ONH2

F

FF

NH

O

R


α-Alkylation of Diazepanone Derivatives

R DPP-4 (nM) QPP (nM) DPP8 (nM)

H 140 >100,000 82,000

Me 6.6 59,000 46,000

Et 16 47,000 13,000

CH2CF3 2.6 59,000 28,000

iBu* 25 35,000 79,000

CH2(cPr) 4.8 27,000 11,000

* N-methyl diazepanone

N

ONH2

F

FF

NH

OR


N-Alkylation of Diazepanone Derivatives

R DPP-4 (nM)

QPP (nM)

DPP8 (nM)

H 6.6 59,000 46,000

Me 6.6 >100,000 21,000

CH2CH2OH 16 78,000 53,000

CH2CF3 19 56,000 43,000

iPr 44 18,000 >100,000

cPr 8 46,000 22,000

N

ONH2

F

FF

N

O

R


5,6 or 7-Alkylated Diazepanone Derivatives


5α-Me/5β-Me 765/1050

6α-Me/6β-Me 13/33 56,000 70,000

6,6-di Me 140 17,000 26,000

7α –Me/7β-Me 15/400 73,000 79,000

7-CF3 140 >100,000 76,000

7-(2-F-Bn) 130 8,700 19,000

N

ONH2

F

FF

NH

O

56 7


Phenyl Substituents


2-F 84 >100,000 27,000

2,5-Di F 7.4 >100,000 22,000

2,4,5-Tri F 2.6 59,000 28,000

N

ONH2

NH

O

R

CF3


SAR Summary

N

O

N

ONH2

R'

RR

Loss of potency Not promising

Less potent

α isomer more potent than β

Less potent, Good selectivity Improved PK

α isomer more potent than β

R-isomer more potent than S-isomer Substituted benzyl/aryl most potent

Less potent Short half-life

R = 2,4,5 tri-F Best potency and PK


Pharmacokinetics…

T1/2(h)

1

2

4.3

1.5

Clp(mL/min/kg)

88

94

93

51

N

O

NH

OCF3

Foral(%)

41%

94%

45%

49%

nAUC(µM h/mpk)

0.18

0.16

0.39

0.25

N

O

N

O

N

O

NH

O

N

O

NH

O

*PK parameters were obtained following a iv (1 mg/kg) or po (2 mg/kg) dose

Rat PK


IC50 (nM) BU

IKr >90,000 Ca 11,000 Na ~50,000

Off-target Activity:

Potency and selectivity: IC50 (nM) BU

DPP-4 2.6 QPP 59,000 DPP8 28,000 DPP9 41,000 PEP >100,000 APP >100,000 Prolidase >100,000 FAP 23,000

N

ONH2

NH

OCF3

F

FF

Trifluroethyl Diazepanone Candidate

•  Pharma services >10,000 nM except Ca channel (Ki=5.5 µM)


Prot.Binding Clp Vd t½ PO AUCnorm PO Cmax F Species (% bound) (mL/min/kg) (L/kg) (h) (µM·h/mpk) (µM) (%)

Rat 89 94 12 1.9 0.157 0.085 36

Dog 91 18 11 8.9 2.19 0.522 95

Rhesus 90 53 18 5.4 0.15 0.162 20**

Human 91 [6-23]*

Oral Bioavailability

* Estimated ** Low %F due to first pass effect


Stability in Liver Microsomes and Hepatocytes

Liver Microsomes at 1 µM, 1 mg/mL protein

Hepatocytes at 1 µM, 1 M cells/mL

0.0

20.0

40.0

60.0

80.0

100.0

0 10 20 30 40 50 60 70 Time (min)

% P

aren

t Rem

aini

ng

RLM DLM MLM HLM

0.0

20.0

40.0

60.0

80.0

100.0

0 20 40 60 80 100 120 Time (min)

% P

aren

t Rem

aini

ng

RLM DLM MLM HLM


Pharmacodynamics…

Glucose AUC DP-IV inhibition (uncorrected)

Active GLP-1

Lean Mice, 0 min post Glucose, 70 min post Compound

Dose, mg/kg Plasma Level, nM

0.1 7.5

0.3 24.8

1 84.2

3 266 Mouse DP-IV: IC50 = 26.8 nM 0

2

4

6

8

10

12

0 0.1 0.3 1 3

Plas

ma

[GLP

-1] in

tact, p

M

L-001169872, mg/kg

0

20

40

60

80

100

0 0.1 0.3 1 3

Plas

ma

DP-

IV %

inhi

bitio

n(u

ncor

rect

ed)

L-001169872, mg/kg

0

20

40

60

80

100

0 0.1 0.3 1 3

Glu

cose

AU

C, %

veh

icle

L-001169872, mg/kg

Dose, mg/kg

Dose, mg/kg Dose, mg/kg


Summary Results

•  Structurally diverse – unique right hand side •  Potent

•  Selective

•  Efficacious in OGTT model

•  Excellent PK profile

•  Metabolically stable in human microsome preparation

•  14 weeks rat and dog safety OK

Kept on hold as an insurance back-up to sitagliptin


Most Common Lead Discovery Methods

•  Biological screening of compounds

•  Substrate or active-structure based design

•  Enzyme – inhibitor crystal structure Crystal structure of DPP-4 reported in 2002


Structure of DPP-4 Complex with val-pyr and Sitagliptin

N

NN

N

CF3

F

F

FONH2

Sitagliptin IC50 = 18 nM

NH2

N

O

Me

Me

Val-pyr IC50 = 1600 nM


Computer Modeling

NH2

N

O

H-Bonding Salt Bridge

N

O NH2

F

FF

N

NN

F3C

IC50 = 4.4 nM



N

O NH2

F

F

F

N

NN

F3C

IC50 = 0.6 nM


No Room!!

N

ONH2

F

F

F

NN

N

CF3

Rotate

The Same Salt Bridge

New H-Bonds

Plenty of Room

Computer Modeling


Rigid Analogs: A New Generation of DPP-4 Inhibitors

A

NH2

N

O

F

F

B

B

NO

H2N

AC

N

H2N

C

F

F

F

F

F

F

F

Best Fit


Sitagliptin and Cyclohexylamine in the DPP-4 Active Site

F

F

NN

NN

CF3

NH2F

N

NH2 O

F

FF

SitagliptinIC50 = 18 nM

NN

N

CF3

F357Y547

S209

R358

E205

Y666

R125

E206

N710


Phenyl Substituents

R DPP-4 (nM) QPP (nM) DPP8 (nM) IKr (nM)

2-F 84 >100,000 27,000 -

2,5-Di F 7.4 >100,000 22,000 63,000

2,4,5-Tri F 2.6 59,000 28,000 90,000

N

NH2

NH

ORCF3

OH

Tri-F pheny results in better H-bond and enhances potency


Clp t½ PO AUCnorm PO Cmax F Species (mL/min/kg) (h) (µM·h/mpk) (µM) (%)

Rat 7.6 6.6 6.8 0.14 130 Dog 3.9 18 10.1 0.93 95 Rhesus 9.5 14 3.9 0.56 94

NH2

F

FN

NN

N

CF3

FEnzyme IC50 (nM)

DPP-4 21 QPP >100,000 DPP-8 >100,000 DPP-9 >100,000 IKr 40,000 Ca 12,000 Na >50,000

OGTT – maximum efficacious dose 1 mpk

Cyclohexylamine DPP-4 Inhibitor


?

5,6-Heterocycles: A Better Fit?

F

F

N

NH2F

CF3

F

F

NN

NN

CF3

NH2F

IC50 = 21 nM


H-bond acceptor H-bond donor

NH2

F

FN

F

R

Cyclohexylamine Derivatives

•  Increasing selectivity: 3D QSAR Model

R DPP-4 QPP DPP-8 (nM) (nM) (nM)

H 6.6 67,000 1700

CF3 7.6 88,000 5800

Y. Gao, et al., Bioorg. Med. Chem. Lett. 2007, 17, 3877

heteroatoms and/or polar groups preferred


NH2

F

FN

F

R



H 6.6 67,000 1700

CF3 7.6 88,000 5800


H 0.67 >100,000 5000

CF3 0.53 >100,000 4600

NH2

F

FN

F

N

NR





H 0.67 >100,000 5000

CF3 0.53 >100,000 4600

NH2

F

FN

F

N

NR


•  R = H –  Poor PK (high Clp, low %F) –  hERG IC50 = 37 µm

•  R = CF3 –  Good PK properties –  hERG IC50 = 4.8 µM –  ↑QTc in CV dog


N-Aryl Piperidines N

NH2

ArF

FF

Compound Ar DPP-4 DPP8/9 Cav1.2 Cyp2D6 t1/2 F (nM) (nM) (nM) (nM) (h) (%)

L-001331552 N

N

37 >59,000 27,000 950 0.46 98

L-001346262 N

N

N 31 >10,000 240 1,700 1.2 32

L-001427229 NN

N

NCF3

5.3 >100,000 960 110 4.9 87

L-001464016 N

N

NMe

1.9 >56,000 88 4,400 1.6 37

Ø  Compounds with increased selectivity have poor PK


Fused Imidazopyridines

Target IC50 (nM) IC50 (nM) IC50 (nM) IC50 (nM) DPP-4 330 51 8.3 15 QPP 23,000 >100,000 >100,000 19,000

DPP-8 >100,000 72,000 >100,000 >100,000 DPP-9 >100,000 8,400 >100,000 >100,000 Cav1.2 n.d. >100,000 >100,000 >100,000

Cyp2D6 n.d. 19,000 13,000 5,200

N

NH2

F

FF

NN

NN N


New Scaffold

•  Potent, selective DPP-4 inhibitor

•  Novel structure, distinct from other development candidates

•  Multiple routes of clearance

•  Human PK projections suggest QD dosing

F

FF

NH2

N

NN


Summary

•  Structurally diverse middle ring designed by collaboration between MedChem, Structural biology and modeling groups

•  Potent

•  Selective

•  Efficacious in OGTT model

•  Excellent PK profile

Promising novel lead for development of

a new generation of DPP-4 inhibitors


Comparative Medicine Irene Capodanno Paul Cunningham Marcie Donnelly William Feeney

Judy Fenyk-Melody James Hausamann

Donald Hora Christian Nunes

Allison Parlapiano Gina Seeburger

Xiaolan Shen John Strauss

Kenneth Valerich Zuliang Yao

Medicinal Chemistry Wally Ashton

Tes Biftu Linda Brockunier Chuck Caldwell

Ping Chen Hong Dong

Scott Edmondson Dennis Feng Mike Fisher Ed Gonzalez Jiafang He

Dooseop Kim Gui-Bai Liang

Tony Mastracchio Bob Mathvink

Hyun Ok You Jung Park Emma Parmee Xiaoxia Qian Leah Reigle

Rosemary Sisco Liping Wang

Lan Wei Ann Weber

Matt Wyvratt Jinyou Xu

Metabolic Disorders Savita Jagpal Joanne Jiang

David Kuo Barbara Leiting

Zhihua Li Frank Marsilio David Moller

Reshma Patel Kelly Ann Pryor

Ranabir Sinha Roy Nancy Thornberry

Kenny Wong Joe Wu

Bei Zhang Lan Zhu BCAS

Larry Colwell Huaibing He

Dorothy Levorse Kathy Lyons

Karen Owens

Synthetic Service Phil Eskola

Mark Levorse Bob Frankshun

Amanda Makarewicz

Drug Metabolism Maria Beconi Adria Colletti

Varsha Didolkar David Evans

Chris Kochansky Sanjeev Kumar

David Liu Tony Pereira

Ralph Stearns Yohannes Teffera

Regina Wang Sherrie Xu Wenji Yin

In Vivo Pharmacology Ed Brady

George Eiermann Judy Gorski

Gerry Hickey Peggy McCann

Joe Metzger Alex Petrov

Dick Saperstein Alison Strack

Immunology/Rheumatology Jerry Di Salvo Ruth Kilburn Greg Koch

Elizabeth Nichols Eugene O’Neill

Linda Wicker

X-Ray & Modeling Giovanna Scapin

Sangita Patel Suresh Singh Ying-duo Gao

Acknowledgements

discovery of dpp-4 inhibitors as antidiabetic agents · 2019-11-04 · copyright © 2010 merck...

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