Discovery and Development of the Natural Product Derivative SPI

Downloaded by COLUMBIA UNIV on December 12, 2016 | http://pubs.acs.org Publication Date (Web): December 9, 2016 | doi: 10.1021/bk-2016-1239.ch010

Chapter 10

Discovery and Development of the Natural Product Derivative SPI-1865 as a Gamma Secretase Modulator for Alzheimer’s Disease: Part I Jed L. Hubbs,*,1 Nathan O. Fuller,2 Wesley F. Austin,3 Ruichao Shen,4 and Brian S. Bronk5 Satori Pharmaceuticals Inc., 281 Albany Street, Cambridge, Massachusetts 02139, United States 1Laboratory of Organic Chemistry, ETH Zürich, HCI G336, Vladimir-Prelog-Weg 3, 8093 Zürich, Switzerland. 2Rodin Therapeutics, 300 Technology Square, Cambridge, Massachusetts 02139, United States 3Celgene, 200 Cambridge Park Drive, Cambridge, Massachusetts 02140, United States 4Enanta Pharmaceuticals, 500 Arsenal Street, Watertown, Massachusetts 02472, United States 5Sanofi, 640 Memorial Drive, Cambridge, Massachusetts 02139, United States *E-mail: [email protected].

This chapter describes the discovery of the gamma-secretase modulator SPI-1865 by Satori Pharmaceuticals and is followed by a chapter on its development. Satori was a 15-person company based in Cambridge, MA with all of its resources devoted to discovering and developing this compound. The project began by isolation of highly active phytosterol gamma secretase modulator (GSM) identified by fractionation of black cohosh extract. Exploratory SAR work established tolerable structural changes and improved the stability and physicochemical characteristics of the molecule. Efforts were then devoted to decrease liver metabolism and improve the blood brain penetration of the series. In the final push, © 2016 American Chemical Society Abdel-Magid et al.; Comprehensive Accounts of Pharmaceutical Research and Development: From Discovery to Late-Stage ... ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

cytochrome P450 inhibition was reduced to minimize risk of drug-drug interactions. This work gave rise to a viable gamma-secretase modulator: SPI-1865.


Introduction Gamma secretase modulators (GSMs) continue to be a promising drug class for disease modifying treatment of Alzheimer’s disease (AD). The peptide amyloid-beta (Aβ) is implicated in onset and progression of AD and is produced by the enzymes beta-secretase (BACE) and gamma-secretase (1). The most advanced BACE inhibitor verubecestat (Merck) is currently in two Phase 3 clinical trials, one for prodromal AD and one for mild to moderate AD. The results of these trials should be available in 2018. A positive outcome would be fundamental advance in AD treatment and would validate a tremendous amount of research and development efforts focused on BACE inhibitors. It would also encourage the development of other amyloid-targeting small molecules such as GSMs, the object of our work. Gamma secretase modulators change the composition of Aβ produced by neurons (2). This is in contrast to BACE inhibitors and gamma secretase inhibitors (GSIs), which stop Aβ production. This is important because evidence suggests that longer Aβ peptides, such as Aβ42, are more neurotoxic than shorter peptides such as Aβ40 (3). GSMs shift the ratio of Aβ42/ Aβ40 towards Aβ40 by binding to an allosteric site on the presenilin component of gamma secretase (4). It has unfortunately proven quite challenging to find robust clinical candidates to test gamma secretase modulation in humans. The compounds have suffered from poor efficacy and/or negative preclinical toxicity issues. When we started our program, the existing GSM leads belonged to two compounds classes: • •

those based on non-steroidal anti-inflammatory drugs.. those based on an arylimidazole pharmacophore (5).

It was therefore highly desirable to find new leads which may overcome the limitations of the known GSMs. In this chapter, we describe the discovery of a new class of gamma secretase modulators based on a phytosterol natural product that led to a viable candidate, SPI-1865.

Activity-Guided Fractionation of Black Cohosh Extract and Isolation of Lead Compound 1 A screen of natural product extracts was conducted to search for compounds that lowered Aβ42 production in a cell-based screen while sparing Aβ40 production (6). Only one extract tested from the black cohosh (Actaea racemosa) was found that selectively lowered Aβ42. Fractionation by normal phase chromatography gave 10 fractions (Figure 1) that were tested for their ability to inhibit Aβ42 production (Table 1). Fractions 5 and 6 were selected for further 254 Abdel-Magid et al.; Comprehensive Accounts of Pharmaceutical Research and Development: From Discovery to Late-Stage ... ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


fractionation based on their Aβ42 IC50 values (6.3 and 2.7 µg/mL respectively) and the size of the fractions (238 and 475 mg respectively).

Figure 1. TLC plates showing normal phase fractionation of black cohosh extract.

Table 1. Aβ42-Lowering Potency for Black Cohosh Fractions Fraction

Amount (mg)

IC50 (µg/mL)

3-1

239

n/a

3-2

86

36

3-3

51

77

3-4

140

7.4

3-5

238

6.3

3-6

475

2.7

3-7

67

8.8

3-8

43

15

3-9

242

7.9

3-10

38

6.4

This further fractionation afforded 10 pure triterpene glycosides (Scheme 1) (Figure 2) that were identified via a combination of NMR and mass spectrometry. This was expected based on the compounds that had been previously characterized from black cohosh root (7). Compound 1 was 10-fold more active (Aβ42 IC50 = 255 Abdel-Magid et al.; Comprehensive Accounts of Pharmaceutical Research and Development: From Discovery to Late-Stage ... ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


100 nM) than the next most active compounds (6 and 8, Aβ42 IC50 = 1000 nM) and consisted of our initial hit (Table 2). The structures of these compounds reveal the likely origin for 1, which could be formed by dehydration of the C16 hemiketal in sterol 5.

Scheme 1. Triterpene Glycosides Isolated from Black Cohosh Extract F3-6 and F3-5 These natural products also reveal interesting structure-activity relationships (SAR). For example, 8 (Aβ42 IC50 = 1000 nM) only differs by one stereocenter 256 Abdel-Magid et al.; Comprehensive Accounts of Pharmaceutical Research and Development: From Discovery to Late-Stage ... ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

by being substituted with an arabinose rather than a xylose sugar. Similarly, the stereocenter at C24 with its acetate substituent appears critical as inversion from its configuration in 1 (Aβ42 IC50 = 100 nM) to that in 6 (Aβ42 IC50 = 1000 nM) also leads to a ten-fold decrease in potency. The presence of compounds 3 and 4 is also noteworthy as these can be formed by removal of the acetate from 1 and 8 followed by cyclization.


Table 2. Pure Compounds Isolated from Black Cohosh with Aβ42 IC50 and Aβ40 IC50 IC50 (nM)

Compound #

Aβ40

Aβ42

1

6,300

100

2

>50,000

>50,000

3

>50,000

>50,000

4

>50,000

>50,000

5

50,000

5,600

6

>50,000

1,000

7

>50,000

32,000

8

16,000

1,000

9

16,000

3,000

With 1 as an initial screening hit, we set out to explore chemical modifications and SAR (Scheme 2) (8). This initial compound suffered from a number of limitations as a potential oral CNS therapeutic. Specific structural features of concern include:

• • •

the enol ether at C16-C17 is chemically unstable. the acetate at C24 is expected to be chemically and metabolically unstable. the sugar contributes to high polar surface area (PSA) and therefore the molecule is expected to be poorly CNS penetrant.

Enol Ether Reduction Under acidic conditions, 1 converted to ketal 11, which was significantly less active (Aβ42 IC50 = 3000 nM). However, Lewis acidic conditions using catalytic ZrCl4 in the presence of trace amounts of water, 1 converted to ketone 12. This compound was more active (Aβ42 IC50 = 600 nM) than the other isolated natural 257 Abdel-Magid et al.; Comprehensive Accounts of Pharmaceutical Research and Development: From Discovery to Late-Stage ... ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


products and was a promising intermediate for the synthesis of additional analogs as it was much more stable under acidic conditions. Even more promising, ketone 12 could be stereoselectively reduced to even more potent 13 (Aβ42 IC50 = 60 nM). This compound was Satori’s original lead molecule and was used to raise venture capital money for an expanded lead optimization program.

Scheme 2. Reactions and Replacement of the C16-C17 Enol Ether in 1

Replacement of the C3 Xyloside Group After removing the chemically unstable enol ether by two-step reduction, we turned our attention to the acetate and sugar moieties (Scheme 3). The xylosyl group in 13 was removed under acidic conditions to give 15 (Aβ42 IC50 = 600 nM), which was 10-fold less potent. The acetyl group in 13 was removed under basic conditions to give 14 (Aβ42 IC50 = 3100 nM), which was 50-fold less potent. When both the xylose and acetyl groups were removed the loss of potency was additive (Aβ42 IC50 > 10,000 nM). Since potency loss upon xylosyl removal was less significant, we chose to focus our initial efforts on finding a replacement of this group that would retain the potency found in 13 while improving the chances the compound would be a successful CNS drug. One strategy we pursued was to modify the sugar (8). This was accomplished by double oxidative cleavage with sodium periodate or lead tetraacetate to give dialdehyde 17, which was used without purification (Scheme 4). Dialdehyde 17 could be converted to the corresponding diol 18 (Aβ42 IC50 = 100 nM ) with sodium borohydride, diamine 19 (Aβ42 IC50 = 2400 nM) with dimethylamine and sodium cyanoborohydride, or to morpholine 20 (Aβ42 IC50 = 130 nM) by 258

Abdel-Magid et al.; Comprehensive Accounts of Pharmaceutical Research and Development: From Discovery to Late-Stage ... ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


treatment with methylamine and sodium cyanoborohydride. We believed that morpholine 20 was quite promising for further optimization because it had a significantly lower PSA (98 Å2) than 18 and 19

Scheme 3. Acetate and Xylose Removal of 13

Scheme 4. Oxidative Cleavage of 13 and Further Reactions We replaced the methyl group on the nitrogen of the morpholine ring of compound 20 with H as well as a number of other substituents and examined their effects on its potency and whether they would improve its pharmaceutical properties. Examples of morpholine substituents tested are shown in Table 3. The unsubstituted morpholine 21 (Aβ42 IC50 = 70 nM) showed slightly improved potency relative to the methyl-substituted morpholine 20 (Aβ42 IC50 = 130 nM). An inductively electron withdrawing oxetanyl group resulted in a 259 Abdel-Magid et al.; Comprehensive Accounts of Pharmaceutical Research and Development: From Discovery to Late-Stage ... ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

neutral compound at physiological pH and modestly decreased potency (22, Aβ42 IC50 = 170 nM). Amine or carboxylic acid substituents were also tolerated (23, Aβ42 IC50 = 110 nM; 24, Aβ42 IC50 = 370 nM), as were sulfonamides (25, Aβ42 IC50 = 80 nM) and amides (Aβ42 IC50 = 90 nM). In summary, we found that Aβ42 lowering potency was retained with a variety of substituents on the morpholine nitrogen atom, which allowed us to use this position to later fine-tune the physicochemical properties of our compounds or optimize other paramaters such as off-target pharmacology.


Table 3. SAR of Representative N-Substituted Morpholine Derivatives

In addition to replacing the sugar moiety on C3 with a morpholine ring, we examined other possible xyloside replacements (9). We primarily focused on esters (Table 4, 27-31) and carbamates (32-36) since introduction of other groups such as ethers at the sterically encumbered neopentylic alcohol proved very challenging. The range of substituents affording potent Aβ42-lowering compounds was significantly narrower than with morpholines. For example, esters with basic substituents were generally potent (28, Aβ42 IC50 = 95 nM and 31, Aβ42 IC50 = 55 nM), but those with neutral (27, Aβ42 IC50 = 760 nM) and acidic (29, Aβ42 IC50 = 1600 nM) substituents showed only modest potency. In addition, the specific pyridyl ester 30 (Aβ42 IC50 = 260 nM) showed moderately 260 Abdel-Magid et al.; Comprehensive Accounts of Pharmaceutical Research and Development: From Discovery to Late-Stage ... ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

good potency. Carbamates showed a similar trend where basic substituents resulted in potent compounds (34, Aβ42 IC50 = 85 nM and 35, Aβ42 IC50 = 47 nM). Other substituents were better tolerated than with esters. For example, carbamates 33 (Aβ42 IC50 = 340 nM) and 36 (Aβ42 IC50 = 450 nM) showed moderately good potency.


Table 4. SAR of Representative Ester and Carbamate Substituted Analogs

Replacement of the C24 Acetyl Group To Improve Liver Metabolic Stability Now that we had established trends in SAR at the C3 position we turned our attention to replacing the acetyl group at the C24, which we believed was resulting in poor metabolic stability (10). Our hypothesis was that liver mediated carboxylesterase hydrolysis was responsible for this poor stability and turned to testing compounds in human liver microsome (HLM) stability assays to probe stability. The HLM assays were run in the absence of added NADPH to eliminate the effects of cytochrome P450-mediated metabolism. 261 Abdel-Magid et al.; Comprehensive Accounts of Pharmaceutical Research and Development: From Discovery to Late-Stage ... ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


Removal of the C25 hydroxyl group from tetraol 16 gave a compound with similar potency (Table 5, 37, Aβ42 IC50 = 780 nM) and as expected, HLM stability was poor (0% remaining at 60 min). When the ester was replaced with a dimethylamino carbamate, the Aβ42 IC50 was dramatically reduced (~20,000 nM) however the microsomal stability was now good (>100%) remaining at 60 min). We were surprised to find that removal of the hydroxyl group from 38 to give analog 39 restored most of the potency relative to the acetate (Aβ42 IC50 = 1000 nM) since the presence or absence of this group was inconsequential for the acetate analog (Table 5, 16 vs. 37). Compound 39 also maintained most of the HLM stability (81% remaining at 60 min).

Table 5. Aβ Lowering Activity and HLM Stability of C24-C25 Analogs

Finally, we examined C24 ether analogs. Replacement of the acetate in tetraol 16 with an ethyl ether gave ether 40 that was more potent (Aβ42 IC50 = 350) and which had excellent microsomal stability (100% remaining at 60 min). We were also surprised to find that removal of the hydroxyl group from 40 gave dramatically decreased Aβ42 lowering potency (41, Aβ42 IC50 = 4400 nM). Other ester and carbamate analogs were tested and the ethyl ether (40, Aβ42 IC50 = 350) and 262 Abdel-Magid et al.; Comprehensive Accounts of Pharmaceutical Research and Development: From Discovery to Late-Stage ... ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

azetidinyl carbamate (data not shown) proved optimal and were utilized in further optimization.


Analogs with Improved CNS Penetration With potency and metabolic stability optimized, we turned our attention to testing our compounds for their ability to enter the central nervous system. Our approach towards this was to examine combinations of C3 and C24 groups that afforded potent analogs. A subset of the compounds tested is shown in Table 6. These data demonstrated that a combination of a morpholine at C3 and an ether at C24 were necessary to get acceptable (>0.5) brain:plasma (B:P) ratios. For example, morpholine 42 with an unsubstituted morpholine and ethyl ether had B:P = 1.67. Carbamates at the C3 position (44-47) and at the C24 position (compounds 43, 45 and 47) all had poor B:P (≤0.13).

Table 6. Examination of C3 and C24 Substitution on Activity

263 Abdel-Magid et al.; Comprehensive Accounts of Pharmaceutical Research and Development: From Discovery to Late-Stage ... ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


With confidence that we could achieve good brain exposure levels with our compounds, we prepared a set of C24 ether and C3 morpholine analogs with a variety of substituents on the morpholine nitrogen. A subset of these compounds is listed in Table 7. In preparing these analogs, our goal was to prepare analogs with diverse properties that may be suitable for selection as development candidates after further profiling. As shown, compounds with the most basic nitrogen atoms were the most potent (42, Aβ42 IC50 = 91 nM; 52, Aβ42 IC50 = 100 nM), while those with attenuated bacisity were approximately 2- to 3-fold less potent (48, Aβ42 IC50 = 250 nM ; 49, Aβ42 IC50 = 270 nM; 50, Aβ42 IC50 = 260 nM; 51, 270 nM).

Table 7. Potency of C24 Ether and C3 Morpholine Analogs with a Variety of Substituents on the Morpholine Nitrogen

While greater Aβ42-lowering was desirable, we thought that this might be counterbalanced by an increased toxicology risk associated with the more basic compounds. We found that both 49 and 52 lowered Aβ42 in mouse. At 100 mg/kg IP (single dose) methoxyethyl morpholine 49 lowered Aβ42 by 46% (±5%) at a brain exposure of 23 µM and plasma exposure of 12 µM. At 100 mg/kg PO (single


dose) methylazetidinyl 52 lowered Aβ42 by 26% (±11%) at a brain exposure level of 20 µM and a plasma exposure level of 15 µM. Further characterization of 49, 52 and others revealed that several compounds were moderate to strong inhibitors of CYP3A4 and other cytochrome P450 isoforms (11). For example, 49 had a CYP3A4 IC50 = 1.1 µM and 52 had a CYP3A4 IC50 = 12 µM. Unsubstituted morpholine 42 was the strongest CYP3A4 inhibitor with 99% inhibition at 10 µM.


Modeing CYP3A4 Inhibition In order to understand the reason for this strong inhibition, we turned to modeling. Using the structure of CYP3A4 bound to ketoconazole as a starting point (12), we found that the strong inhibition was likely due to coordination of the morpholine nitrogen atom to the iron atom in the heme moiety. Docking studies with other molecules suggested that additional steric bulk and a positive charge on the morpholine substituent would likely reduce CYP3A4 binding and inhibition.

Figure 2. Model of compound 42 bound to CYP3A4.

Based on these results we prepared a series of additional morpholine analogs with azetidine substituents either directly attached to the morpholine or attached through a methylene linker (Table 8). The least potent CYP3A4 inhibitors carried a bulky group on an azetidine moiety directly attached to the morpholine group (53, CYP3A4 IC50= 37 µM; 54, CYP3A4 IC50= >100 µM). The most potent CYP inhibitors bore an inductively electron withdrawing group on the azetidine group attached to the morpholine moiety (55, CYP3A4 IC50= 5.3 µM; 56, CYP3A4 IC50= 3.0 µM). Analogs with a methylene-linked azetidine group (57-60) had similar potencies (CYP3A4IC50= 13-22 µM). We ruled out 55 and 56 as potential preclinical development candidates based on their CYP3A4 inhibition, and 59 based on time dependent inhibition (CYP3A4IC50= 7.8 µM after preincubation with NADPH). 265 Abdel-Magid et al.; Comprehensive Accounts of Pharmaceutical Research and Development: From Discovery to Late-Stage ... ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


Table 8. CYP3A4 Inhibition for Several Azetidinyl Morpholine Analogs

As a next step in candidate selection, 53, 54, and 60 were selected for testing in rat PK/PD experiments at dose levels expected to give similar plasma exposure based on their individual rat PK profiles (Table 9). Consistent with our expectations, all compounds gave good brain exposure (B:P = 0.69 to 2.4; 6.3 to 33 µM) and statistically significant lowering of Aβ42 (23 to 50%). The compounds were examined in a 14-day exploratory safety study in the same strain of rats. Compound 53 (SPI-1865) provided the best therapeutic window based on amaximum tolerated dose of >90 mg/kg and >40µM average plasma concentration, and from this assessment and was chosen as a candidate for preclinical development. 266 Abdel-Magid et al.; Comprehensive Accounts of Pharmaceutical Research and Development: From Discovery to Late-Stage ... ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


Table 9. PK/PD Experiments with Compounds 53, 54, and 60

Figure 3. SPI-1865 mult-dose oral PK/PD experiment in Sprague Dawley rats. 267 Abdel-Magid et al.; Comprehensive Accounts of Pharmaceutical Research and Development: From Discovery to Late-Stage ... ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


SPI-1865 was further profiled in PK/PD experiments to confirm it has sufficient gamma secretase modulating properties to justify further development (13). These studies included wild-type mouse and rat studies, and studies in Tg2576 mice that overexpress human amyloid precursor protein (APP). Figure 3 shows the results form a multi-dose PK/PD experiment in wild type rats. SPI-1865 shows a clear decrease in Aβ42 at 10, 30 and 60 mg/kg. The 10 mg/kg dose lowered Aβ42 by approximately 25% with 4.4 µM brain exposure and 8.0 µM plasma exposure. At 30 mg/kg, Aβ42 was lowered by approximately 49% with 16 µM brain exposure and 13 µM plasma exposure. The 60 mg/kg dose lowered Aβ42 by 61% at exposure levels of 45 µM in brain and 19 µM in plasma.

Conclusions Our discovery effort and lead optimization program took us from an active and Aβ42-selective extract to a CNS development candidate. Along the way challenges were encountered with chemistry, poor metabolic stability, CNS penetration, and cytochrome P450 inhibition. The following chapter will describe our company’s success in crafting a process to prepare SPI-1865 on large scale.

Acknowledgments The authors sincerely thank all coworkers at former Satori Pharmaceuticals, and colleagues at Carbogen-Amcis and WuXi AppTec for their contributions in this project.

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Discovery and Development of the Natural Product Derivative SPI

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