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Structure of 35180-01-9
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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
4.5
*For Research Use Only !
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Raithatha, Sheetal A. ; Hagel, Jillian M. ; Matinkhoo, Kaveh ; Yu, Lisa ; Press, David ; Cook, Sarah G. , et al.
Abstract: The psychedelic prodrug psilocybin has shown therapeutic benefits for the treatment of numerous psychiatric conditions. Despite pos. clin. end points targeting depression and anxiety, concerns regarding the duration of the psychedelic experience produced by psilocybin, associated with enduring systemic exposure to the active metabolite psilocin, pose a barrier to its therapeutic application. Our objective was to create a novel prodrug of psilocin with similar therapeutic benefits but a reduced duration of psychedelic effects compared with psilocybin. Here, we report the synthesis and functional screening of 28 new chem. entities. Our strategy was to introduce a diversity of cleavable groups at the 4-hydroxy position of the core indole moiety to modulate metabolic processing. We identified several novel prodrugs of psilocin with altered pharmacokinetic profiles and reduced pharmacol. exposure compared with psilocybin. These candidate prodrugs have the potential to maintain the long term benefits of psilocybin therapy while attenuating the duration of psychedelic effects.
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Purchased from AmBeed: 77877-94-2 ; 7693-46-1 ; 33657-49-7 ; 38871-41-9 ; 20289-26-3 ; 7693-46-1 ; 2251-50-5 ; 35180-01-9 ; 4090-55-5 ; 54322-65-5 ; 52061-51-5 ; 63881-16-3 ; 5402-53-9
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Pooja V. Hegde ; Michael D. Howe ; Matthew D. Zimmerman ; Helena I.M. Boshoff ; Sachin Sharma ; Brianna Remache , et al.
Abstract: Tuberculosis (TB) is one of the world's most deadly infectious diseases resulting in nearly 1.3 million deaths annually and infecting nearly one-quarter of the population. para-Aminosalicylic acid (PAS), an important second-line agent for treating drug-resistant Mycobacterium tuberculosis, has moderate bioavailability and rapid clearance that necessitate high daily doses of up to 12 g per day, which in turn causes severe gastrointestinal disturbances presumably by disruption of gut microbiota and host epithelial cells. We first synthesized a series of alkyl, acyloxy and alkyloxycarbonyloxyalkyl ester prodrugs to increase the oral bioavailability and thereby prevent intestinal accumulation as well as undesirable bioactivation by the gut microbiome to non-natural folate species that exhibit cytotoxicity. The pivoxyl prodrug of PAS was superior to all of the prodrugs examined and showed nearly quantitative absorption. While the conceptually simple prodrug approach improved the oral bioavailability of PAS, it did not address the intrinsic rapid clearance of PAS mediated by N-acetyltransferase-1 (NAT-1). Thus, we next modified the PAS scaffold to reduce NAT-1 catalyzed inactivation by introduction of groups to sterically block N-acetylation and fluorination of the aryl ring of PAS to attenuate N-acetylation by electronically deactivating the para-amino group. Among the mono-fluorinated analogs prepared, 5-fluoro-PAS, exhibited the best activity and an 11-fold decreased rate of inactivation by NAT-1 that translated to a 5-fold improved exposure as measured by area-under-the-curve (AUC) following oral dosing to CD-1 mice. The pivoxyl prodrug and fluorination at the 5-position of PAS address the primary limitations of PAS and have the potential to revitalize this second-line TB drug.
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Keywords: Tuberculosis ; para-Aminosalicylic acid (PAS) ; Prodrug ; Fluorination ; Metabolism ; N-acetyltransferase
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Purchased from AmBeed: 65-49-6 ; 17455-13-9 ; 80841-78-7 ; 4136-97-4 ; 98298-66-9 ; 4093-28-1 ; 35180-01-9 ; 184033-42-9 ; 75-07-0 ; 40258-80-8 ; 6059-17-2 ; 66761-27-1 ; 475150-68-6 ; 75-30-9 ; 3282-30-2 ; 80841-79-8 ; 84089-73-6 ; 6952-12-1
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CAS No. : | 35180-01-9 |
Formula : | C5H9ClO3 |
M.W : | 152.58 |
SMILES Code : | O=C(OCCl)OC(C)C |
MDL No. : | MFCD07375443 |
InChI Key : | JHYNXXBAHWPABC-UHFFFAOYSA-N |
Pubchem ID : | 14787051 |
GHS Pictogram: |
![]() ![]() |
Signal Word: | Danger |
Hazard Statements: | H226-H314 |
Precautionary Statements: | P501-P240-P210-P233-P243-P241-P242-P264-P280-P370+P378-P303+P361+P353-P301+P330+P331-P363-P304+P340+P310-P305+P351+P338+P310-P403+P235-P405 |
Class: | 3(8) |
UN#: | 2924 |
Packing Group: | Ⅲ |
Num. heavy atoms | 9 |
Num. arom. heavy atoms | 0 |
Fraction Csp3 | 0.8 |
Num. rotatable bonds | 4 |
Num. H-bond acceptors | 3.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 33.7 |
TPSA ? Topological Polar Surface Area: Calculated from |
35.53 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.22 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
2.01 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.74 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.8 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
0.8 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.52 |
Log S (ESOL):? ESOL: Topological method implemented from |
-1.79 |
Solubility | 2.48 mg/ml ; 0.0163 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.38 |
Solubility | 0.632 mg/ml ; 0.00414 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-1.14 |
Solubility | 11.1 mg/ml ; 0.0729 mol/l |
Class? Solubility class: Log S scale |
Soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
High |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
Yes |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
No |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-5.8 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
Muegge? Muegge (Bayer) filter: implemented from |
1.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
1.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
2.26 |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | EXAMPLE IB - Synthesis of (6b/f,10a5)-8-[4-(4-fluoro-phenyl)-4-oxo-butyl]-8- isopropoxycarbonyloxymethyl-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-lH- pyrido[3',4':4,5]pyrrolo[l,2,3-de]quinoxalin-8-ium formate [0099] To a solution of the 4-((6b,10a5')-3-methyl-2,3,6b,9,10,10a-hexahydro-lH,7H- pyrido[3',4':4,5]pyrrolo[l,2,3-(ie]quinoxalin-8-yl)-l-(4-fluorophenyl)-butan-l-one (48.0 mg, 0.12 mmol) in acetonitrile (2.0 mL) is added chloromethyl isopropyl carbonate (25.0 mg, 0.16 mmol), followed by adding Nal (60.0 mg, 0.40 mmol). The reaction mixture is stirred at room temperature over a weekend, and then filtered. The obtained filtrate is purified with a semi-preparative HPLC using a gradient of 0 - 35% B (gradient curve 4) to give (6b/?,10a5)- 8-[4-(4-fluoro-phenyl)-4-oxo-butyl]-8-isopropoxycarbonyloxymethyl-3-methyl- 2,3,6b ,8,9J0J0a-octahydro-lH-pyrido[3',4':4,5]pyrrolo[l ,2,3-(ie]quinoxalin-8-ium formate (50 mg, 75% yield). UPLC retention time: 2.49 min. ESI-MS (m/z, positive mode): 510.3. |
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