Methyl in Medicinal Chemistry

 Medicinal Chemistry Cases

The methyl group is one of the most commonly occurring carbon fragments in small-
molecule drugs. This simple alkyl fragment appears in more than 60% of the top-selling
drugs, highlighting the importance of the simple methyl group as a very useful
structural modification in the rational design of bioactive compounds and drugs. One
reason the methyl group is so popular in drug discovery is the magic methyl effect: a
rare but welcome phenomenon where installation of a methyl group can increase
potency, improve selectivity, increase solubility, increase permeability, decrease
metabolism or address toxicity issues. [1-2] In Figure 1, several drug molecules and
clinical candidate molecules which contain methyl group are listed. For each case,
methyl group(s) were incorporated into molecules with different purposes which will
be introduced below. [3-10]

Figure 1. Representative drug and clinical candidate molecules containing methyl group

Compound 1 was identified as a potent and selective JAK3 covalent inhibitor. However,
it suffers from moderate to poor PK in rat despite very reasonable oxidative stability
as judged by liver microsomes. It was speculated that glutathione-S-transferase (GST)
mediated glutathione (GSH) addition to the acrylamide is accounted for this
discrepancy. Stability of compound 1 in rat blood is only 98 min, which explained the
observed poor PK profile in rat. In order to decrease GSH addition, the team attempted
to inhibit chemical reactivity by adding substituents to the acrylamide, as steric hinder
around the electrophile should reduce the ability of GST to catalyze GSH addition. As
depicted in Figure 2, methyl groups were introduced on piperidine ring adjacent to
acrylamide in compound 2, 3 and 4. Compound 2 lost potency completely due to a
potential steric clash between the methyl group with protein side chain residue
Leu956 in the ATP pocket. The hypothesis was realized in compound 3 which displayed
comparable enzymatic potency and 3-fold higher HWB potency which was consistent
with higher stability in HWB assay. It was interesting to found that chirality of the
methyl group impacted potency significantly, as seen in compound 4 where the methyl
group had an opposite chirality, resulting in potency loss completely. [9-10]

Figure 2. Methyl groups on piperidine ring modulated whole blood stability.

In the course of discovery of a potent, oral and CNS-penetrant EGFR inhibitor,

compound 5 was identified as a promising lead with high potency, idea efflux ratio and
excellent BBB-penetration. Metabolite identification of compound 5 suggested that
the piperazine oxidation was the main metabolic pathway. With this in mind, the team
incorporated methyl groups into molecules to block metabolic sites on piperazine ring
in compound 6, 7, 8 and 9. Potency of compound 6 and 7 was decreased by 3-4 fold,
and PK profile was worse than compound 5. Although efflux ratio of compound 6 and
7 was decreased, plasma-to-brain ratio was not affected. Both compound 8 and 9 kept
comparable potency, while compound 8 had improved both blood exposure and brain
exposure comparing to compound 5 and 9 (Figure 3). [6] The promising data package
of compound 8 (AZD3759, Zorifertinib) which has excellent central nervous system
penetration, strongly supported its selection as a clinical candidate for development
for the treatment of brain metastases. Methyl piperazine building blocks played crucial
roles in quick access of designed molecules and systematic SAR and SPR studies.
 Figure 3. Methyl groups on piperazine modulated potency and PK profile of EGFR inhibitor.

As shown in Figure 1, there was also a chiral methyl group on piperazine ring in
chemical structure of Sotorasib. In the course of discovery of Sotorasib, compound 10
was identified as one of promising hit compounds with high potency. However, PK
profile was poor (data not shown). Employing similar strategy in the discovery of
compound 8 (AZD3759, Zorifertinib) described above (Figure 3), a chiral methyl group
was incorporated on piperazine ring in compound 11 which had increased cellular
potency by 3-fold while oral bioavailability was improved (F = 12%). Comparing
compound 12 and 13, the same trend was observed with cellular potency and oral
bioavailability both increased, especially oral bioavailability, in compound 13 bearing
a chiral methyl group on piperazine ring (Figure 4). [8]

Figure 4. Methyl groups on piperazine ring modulated potency and PK profile of KARS G12C
inhibitors.
In the course of discovery of a potent and reversible dual orexin receptor antagonist,
compound 14 was identified as a promising lead. As shown in Figure 5, both trans-
methyl groups in compound 15 and 16 increased potency significantly by 96-fold for
OX1R, 145-fold for OX2R and by 505-fold for OX1R, 6-fold for OX2R respectively. This
observation is consistent with structural hypothesis that alpha-methylation favors the
trans-diaxially substituted piperidine with axial orientation for the 3-CH2OAr group. [11]

Figure 5. Methyl groups on piperidine ring increased potency.

Metabolic studies confirmed that the pyrrolidine moiety in compound 17 was

exceptionally metabolically active. Therefore, the initial structural modification was to
introduce substituents onto the pyrrolidine to directly block its metabolism.
Considering the profile that small substituents on pyrrolidine were preferred for
potency against PI3Kdelta along with the availability of starting material, a small (S)-
methyl group was introduced onto the pyrrolidine ring in compound 18. Compound
18 gave improved clearance compared to compound 17, which demonstrated the
rationality of modification strategy. Moreover, the results of this comparison are
reminiscent of the methyl effect in the molecular modification strategy, also known as
the magic methyl effect, where the addition of a methyl group in place of hydrogen
leads to a dramatic improvement in metabolic stability due to an additional labile
group for CYP oxidation (Figure 6). [12]

Figure 6. A methyl group increased metabolic stability significantly.

Modifying the initial lead compound 19 to compound 21 resulted in 0.6 log

improvement in bioactivity due to the (R)-Me substitution on piperazine ring.
Moreover, a stereochemical SAR on piperazine ring methyl substitution was evident
with the order of antagonist bioactivity as follows: (R)-Me (compound 21) > des-Me
(compound 19) > (S)-Me (compound 20), with compound 21 10-fold more potent than
compound 20 (Figure 7). [4-5]

Figure 7. Methyl groups with opposite chirality impacted potency in different way.

In the course of discovery of DNA-PK inhibitors, compound 22 was identified as a

promise lead. Ortho- methyl group was added into compound 23 and compound 24,
which confirmed a significant boost in potency for compound 24, but not compound
23. Comparing compound 25 and compound 26, the same trend was observed. The
ortho- methyl group on the aniline group gave at least 10-fold increase in biochemical
potency while maintaining LogD, thus could be described as “magic methyl”. This
striking increase in potency suggests that, in addition to making an effective lipophilic
interaction in the hydrophobic pocket consisting of Tyr3791, Leu3806 and Ile3940, the
methyl group may also confer a beneficial conformational effect, by favoring a
bioactive conformation where there is a twist between the aromatic amine and the
purinone core (Figure 8). [13]

Figure 8. Methyl groups on aniline increased potency by at least 10-fold. (PDB code: 6T3C)

In the course of discovery of Tazemetostat, “magic methyl” effect was observed as

shown in Figure 9. Comparing compound 27 and compound 28, lacking a methyl group
for compound 27, the activity is significantly decreased by 190-fold. The “magic methyl”
effect was magnified in comparison of compound 29 and compound 30, with a
significant 1400-fold difference observed. The steric-directing effect of the methyl
group is not limited to the amide moiety, but also has a profound effect on the adjacent
aniline substituent. This optimized substitution pattern led to a significant potency
breakthrough allowing the team to drive potency to the threshold of single-digit
nanomolar levels for the first time (Figure 9). Further optimization of compound 30
led to discovery of Tazemetostat which was approved as a first EZH2 inhibitor. [7]

Figure 9. Methyl groups on phenyl ring increased potency significantly.

It is extremely supportive if medicinal chemists have convenient access of diverse

building blocks containing methyl groups which could potentially exert “magic methyl”
effect to impact positively activity, selectivity or properties of molecules. As mentioned
in section “Dihedral Angle in Medicinal Chemistry”, modulating dihedral angle
through steric hinder between methyl group and adjacent moieties can influence a lot
of properties of molecules.

With lead compound 31 in hand, the team turned their attention to modification of
the benzylic linker, based on hypothesis that the incorporation of an appropriate
substituent on the alpha-position of the benzylic amine liker could constrain the linker
to adopt the bioactive conformation and, therefore reduce the entropic cost of ligand
binding. Moreover, methyl substitution could also block the metabolism at the alpha-
position of then benzylic group. Based on modeling, the methyl-substituted linker with
(S) stereochemistry is more conformationally constrained, and the bioactive
conformation is still near an energy minimum. This extra constraint on the linker
conformation would be expected to modestly improve the potency. By contrast, the
(R) enantiomer is expected to be substantially less potent, because it has an energy
minimum that does not resemble the bioactive conformation observed in the crystal
structure. For the (R) enantiomer to adopt the bioactive conformation, there would be
a steric clash between the methyl group and the carbonyl oxygen of the quinolinone.
As X-ray structure of analogue suggests that the protein can only accommodate a small
group in the vicinity of the benzylic group linker, the team selected and investigated
small methyl group in compound 32 and compound 33. As depicted in Figure 10, the
(S)-methyl group in compound 33 was favored, whereas the (R)-methyl group in
compound 32 lost most of its activity. Compound 33 also demonstrated excellent
metabolic stability in human microsome and improved solubility. Taken together, the
data showed that an (S)-methyl-substituted benzylic linker in compound 33 was the
optimal choice, not only providing very potent inhibitory activity against the R132H
and R132C mutants but also conferring excellent metabolic stability and enhanced
solubility (Figure 10). [14] In this context, amine building blocks containing chiral methyl
groups at alpha-position of benzylic linker played critical roles in quick synthesis of
designed molecules.

Figure 10. Methyl group at alpha-benzylic position impacted activity and properties.

It was observed from crystal structure of compound 34 bound to FXIa that a water
molecule was located between the thiazole ring of compound 34 and Leu415, which
precluded tight binding and resulted in the loss of potency. Hence, displacement of
this water molecule by the inhibitor should lead to a significant free-energy gain. This
prediction was validated by compound 35 with a methyl substituent on the thiazole
ring, which indeed displaced the unstable water and improved the FIXa inhibitory
potency by 20-fold (Figure 11). [15]

S N S N
N N N N N N
N -O N N -O N
N N+ N N+

F Cl F Cl

34 35
FXIa Ki = 6.4 nM FXIa Ki = 0.3 nM

Figure 11. A methyl increased potency by displacing unstable water molecule. PDB code: 7V14
and 7V15.
In the course of discovery of PCSK9 inhibitor MK-0616, the addition of an alpha-Me
proline to the peptide 37 provided two advantages over proline peptide 36: 1) 8-fold
potency enhancement, and 5-fold stability in mouse whole blood (Figure 12). [16]

O
O
N O
H
O N
N+ O NH
N N Cl- O
N
H
O O O NH OH HN
O O H F
N N
NH
36 37 O N O
O
proline alpha-Me-proline O O
LDLR Ki = 110 nM LDLR Ki = 14 nM HN
N
MWB T1/2 = 63 min MWB T1/2 = 311 min O O
HN
MK-0616
Figure 12. alpha-Me proline improved both potency and stability in whole blood.

Based on the known preference of structural motifs present in CYP substrates, it was
hypothesized that the observed CYP2D6 inhibition of compound 38 was caused by the
basic nitrogen present in the pyridine ring connected to the core at the C8-position
serving as heme-ligating moiety. Therefore, steric shielding could be employed to
address this critical issue. Introduction of steric bulkiness next to the basic nitrogen in
compounds 39, 40 and 41 greatly reduced CYP2D6 inhibition, with IC50 values in the
low nM range determined for compound 38 while becoming > 350-fold weaker and
reading out in the uM range as methyl groups were introduced next to the nitrogen
(Figure 13). [17]

Figure 13. Addition of methyl reduced CYP2D6 inhibition.

Comparing compounds 42 and 43, the binding affinity of JAK1 was markedly improved
when a trans-methyl was introduced to the C2-position of piperidine. It is clear that
the “magic methyl” effect exists. The methyl substituent on piperidine occupies the
tiny hydrophobic pocket around the middle of the ATP-binding pocket of JAK1,
according to the docking analysis. The methyl group on the piperidine of Tofacitinib
also occupies this binding pocket (Preface). Addition of a meta-Cl on benzyl ring of
compound 44 further increased potency. The cis-isomer 45 displayed greater potency
than trans-isomer 44 (Figure 14). [18]

Figure 14. Methyl on the piperidine ring increased potency by occupying a hydrophobic pocket.

Compound 46 was identified as a potent 5HT2B agonist with an EC50 of 160 nM. As
5HT2B agonist activity has been strongly implicated in valvular heart disease, the team
focused optimization to remove this deleterious off-target activity. A working model
based on a published structure was developed. The team hypothesized that there
would a closed side of the pocket where substitution on piperidine would be less
tolerated. Addition of a methyl on 4-position of piperidine ring of Darovasertib
dramatically reduced 5HT2B potency. This was in line with the hypothesis that the
piperidine ring would be bound in a closed side of the 5HT2B pocket, and this
additional steric bulk in this region would not be tolerated for 5HT2B agonism (Figure
15). [19]

Figure 15. A methyl on piperidine reduced 5HT2B agonism.

Given the presence of a small hydrophobic pocket around cyclobutane ring, the
removal of the methyl on cyclobutane ring in compound 48 led to a 4-fold drop in
potency as displayed by compound 47. It was also observed that stability in human
liver microsome was decreased caused by removal of the methyl group. This can be
explained that the methyl blocks metabolism site on cyclobutane ring (Figure 16). [20]

H H
N O N O

N N
F3C N F3C N
N N

47 48
IC50 = 340 nM IC50 = 85 nM
HLM CL = 14 uL/min/mg HLM CL = 2.5 uL/min/mg

Figure 16. A methyl on cyclobutane ring increased both potency and stability in human liver
microsome. PDB code: 8QTG

Although all 3-methylpiperidine analogs 49, 50, 51 and 52 displayed a marked

improvement in potency, they demonstrated much different microsome stability and
CYP3A4 inhibition profiles, with compound 52 showing best profile (Figure 17). [21]

Figure 17. 3-Methylpiperidine impacted microsome stability and CYP3A4 inhibition.

Comparing compounds 53 and 54, a trans-methyl group in the 5-position of the

piperidine of compound 54 gave a 20-fold increase in biochemical potency. Based on
crystal structure, this improvement can be explained by that the methyl group
occupied a small hydrophobic pockect (Figure 18). [22]

Figure 18. A methyl group improved potency by occupying a small pocket. PDB code: 8VEU

Discovery of covalent inhibitors is often associated with low GSH stability issue, as
displayed by compound 55. Like the case shown in Figure 2, a methyl group was
introduced on cyclobutane ring in compounds 56 and 57 respectively. This strategy
worked very well in compound 57 with GSH stability increased significantly, while GSH
stability increased slightly for compound 56 (Figure 19). [23]

N N N

O O O O O O

N N N
N N N N N N
N N N
N N N

55 56 57
GSH T1/2 = 2.4 h GSH T1/2 = 4.2 h GSH T1/2 = 15 h

Figure 19. A methyl group on cyclobutane ring increased GSH stability.

The interaction between amino group on the pyrazolo[3,4-d]pyrimidine of compound

58 was presumed to be critical for HER2 potency, but its necessity remained unknown.
Surprisingly, replacement of the NH2 of compound 58 with a hydrophobic methyl
group in compound 59 restored potent HER2 inhibition levels. The introduced methyl
group restores a significant van der Waals contact to the side chain methyl of Thr802.
More importantly, compound 59 demonstrated much lower efflux ratio than
compound 58 (Figure 20). [24]

N N
N N
O O

NH2

N N
N N
N N N N

O O
N N

58 59
HER2WT pHER2 IC50 = 41 nM HER2WT pHER2 IC50 = 100 nM
HER2YVMA pHER2 IC50 = 29 nM HER2YVMA pHER2 IC50 = 44 nM
MDCK MDR1 ER = 8.1 MDCK MDR1 ER = 1.3

Figure 20. A methyl group reduced reflux ratio while keeping comparable potency. PDB code:
8U8X

In a recent work shown in Figure 21, modification of the methylene spacer in

compound 60 to incorporate a methyl substituent was conducted to examine the
effect on activity, but also with the view of removing a potential metabolic liability in
the unsubstituted attached to the heteroaryl group. N-methyl derivative compound 61
was an order of magnitude more potent on inclusion of the alpha-methyl substituent.
Closer examination of the amino acid interactions between compound 61 and the core
protein shows that the alpha-methyl group incorporated within the spacing element
is in-plan with the isoquinolinone ring and the (R)-stereochemistry is confirmed and in
agreement with the single crystal data, and likely assists in achieving a conformation
that allows the isoquinolinone phenyl ring to position between F110 and Y118 (Figure
21). [25]

Figure 21. An alpha-methyl increased potency. PDB code: 9C9V

Comparing compounds 62 and 63, the methyl on core structure increased potency by
almost 100-fold, and chirality preference was observed by comparing compounds 63
and 64 (Figure 22). [26]

Figure 22. A methyl on core structure increased potency.

 Related Building Blocks from PharmaBlock

Methyl piperidine amine building blocks

Methyl piperazine building blocks

Methyl piperidine carboxylic acid building blocks

Unnatural proline building blocks

OH OH OH OH OH OH OH OH

N O N O N O N O N O N O N O N O
Boc Boc Boc Boc Boc Boc Boc Boc

PBXA3036 PBXA3037 PBU1714 PBXA8068 PB07181 PB06655 PB07182 PB07191

OH OH OH OH OH OH OH OH

N O N O N O N O N O N O N O N O
Boc Boc Boc Boc Boc Boc Boc Boc

PBN2011964 PBN20121207 PBN20121206 PBN20121205 PBXA3187 PBXA3186 PBLJ0274 PBLJ0273

Methyl scaffold building blocks

O
OH N N N
N N
N
N N N N N N
N N N N Br H 2N Br
N N H2N Br

PBZ3167 PB06208 PBZ6320 PBZ0769 PBXA311 PBZ0779

Br Cl Cl
N Cl
N N N N N
N N N
N N N N N
N N Br N N
Br Br N
Br

PBU0246 PB03921 PB03919 PBS62613 PBN2011828 PBN2011829

Cl Cl Cl Cl Br
N N N N
COOEt Cl N N N N
N N N N N H H
N N Cl N

PBTEN19332 PB03228 PB03835 PBTEN18800 PBLJ1026 PBY2010141

Br Cl Cl Cl Cl
N H H
N N N N
N N
Cl N N
N N Cl N N H N N N
H H H Cl N

PBN2011454 PB03271 PB03272 PBLJ0176 PBLJ3290 PB90928

Building blocks containing an alpha-methyl

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