Admilparant, (BMS-986278)

CAS 2170126-74-4

MF C22H31N5O5 MW 445.5 g/mol

(1S,3S)-3-({2-methyl-6-[1-methyl-5-({[methyl(propyl)carbamoyl]oxy}methyl)-1H-1,2,3-triazol-4-l]pyridin-3-yl}oxy)cyclohexane-1-carboxylic acid
lysophosphatidic acid receptor 1 (LPA1) antagonist

• 4UN9AOU6G8
• BMS986278
• (1S,3S)-3-((2-Methyl-6-(1-methyl-5-(((methyl(propyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid

Admilparant is an investigational new drug being developed by Bristol-Myers Squibb for the treatment of idiopathic pulmonary fibrosis (IPF) and progressive pulmonary fibrosis (PPF). It is a first-in-class lysophosphatidic acid receptor 1 (LPA1) antagonist.^[1][2]

As of 2024, admilparant is in Phase III clinical trials for both IPF and PPF.^[2][3]

SYN

Discovery of an Oxycyclohexyl Acid Lysophosphatidic Acid Receptor 1 (LPA1) Antagonist BMS-986278 for the Treatment of Pulmonary Fibrotic Diseases

Publication Name: Journal of Medicinal Chemistry, Publication Date: 2021-10-28, PMID: 34709814

DOI: 10.1021/acs.jmedchem.1c01256

(1S,3S)-3-((2-Methyl-6-(1-methyl-5-(((methyl(propyl)carbamoyl)-oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic Acid (33). Compound 33 was prepared using the same
synthetic sequence as 25, except that intermediate 42 was reacted with
N-methylpropan-1-amine instead of 1-cyclobutyl-N-methylmethanamine. 1H NMR (500 MHz, DMSO-d6, 100 °C) δ 11.99−11.46 (m,1H), 7.82 (d, J = 8.3 Hz, 1H), 7.43 (d, J = 8.8 Hz, 1H), 5.65 (s, 2H),
4.89−4.62 (m, 1H), 4.10 (s, 3H), 3.12 (br t, J = 7.2 Hz, 2H), 2.79 (s,3H), 2.69 (tt, J = 9.4, 4.4 Hz, 1H), 2.44 (s, 3H), 2.03 (dt, J = 13.8, 4.5Hz, 1H), 1.92−1.86 (m, 1H), 1.86−1.79 (m, 2H), 1.74−1.68 (m, 1H),
1.68−1.58 (m, 2H), 1.58−1.51 (m, 1H), 1.43 (dq, J = 14.4, 7.1 Hz,2H), 0.76 (br t, J = 7.3 Hz, 3H). 13C NMR (126 MHz, DMSO-d6, 100°C) δ 175.4, 154.7, 150.1, 147.7, 143.9, 141.4, 129.6, 120.0, 118.6, 71.8,
54.5, 49.5, 37.4, 34.4, 33.4, 31.6, 28.7, 27.2, 19.8, 19.4, 18.6, 10.1. m/z446 [M + H]+
. HPLC/UV purity: 99.9% using the following reverse phase chromatographic conditions: Agilent HPLC; Phenomenex Kinetex-C-18; 100 (L) × 4.6 mm2 (i.d.) column; 2.6 μm particle size; wavelength, 220−380 nm; flow rate, 1.0 mL/min; temperature, 35°C; injection volume, 4 μL of 0.25 mg/mL in 1:1 MeCN:H2O; mobilephase A, H2O−0.05% TFA; mobile phase B, MeCN−0.05% TFA; gradient elution, starting at 10−80% B over 10 min and ending at 95% Bafter an additional 4 min; retention time = 8.28 min. Stereoisomeric purity was >99.5% using the following chiral chromatographic conditions: UPC2 Analytical SFC, ChromegaChiral CC4; 250 (L) ×4.6 mm2 (i.d.); 5 μm column; flow rate, 3 mL/min; temperature, 40 °C;injection volume, 10 μL of 0.25 mg/mL in MeCN:MeOH (1:1);mobile phase, 30% MeOH and 70% CO2 at 120 bar retention time =6.05 min. Accurate mass, [M + H]+ at m/z = 446.2398 (−2.03 ppmfrom theoretical for C22H32N5O5). [α]20D = +28.24° (MeOH, c = 0.51).
Elem. Anal. (theoretical): C, 59.31; H, 7.01; N, 15.72. Found: C, 59.35;H, 6.78; N, 15.69. UV (MeOH) at 254 nm (ε = 17,856), 290 nm (ε =7,519), and 296 nm (ε = 8,288). Concentration: adjusted for purity,
0.05154840 g/L or 0.0001157047 mol/L. Melting point = 152−154°C. Accurate mass, [M + H]+ at m/z 466.2398 (−2.03 ppm fromtheoretical for C22H32N5O5).

synthetic sequence as 25, except that intermediate 42 was reacted with N-methylpropan-1-amine instead of 1-cyclobutyl-N-methylmethanamine

a
Reagents and conditions: (a) I2 (1.1 equiv)/KI (2.5 equiv)/NaHCO3 (3 equiv)/water (96%); (b) H2 (50 psi)/ Pd/C (cat)/Et3N (2 equiv)/EtOAc (68%); (c) CH3COCl (2.5 equiv)/iPrOH (87−95%); d) (Ph3P)2PdCl2 (5%)/ Et3N/CuI (5%)/RT (75−94%); (e) Ru(II)-(Ph3P)2(Me5Cyp)Cl (5%)/TMSCH2N3/dioxane 50 °C/15 h; (f) Bu4NF/0 °C to RT (51−65% over 2 steps; 3:1 desired:undesired regioisomer); (g) 4-nitrophenyl chloroformate/pyridine/CH2Cl2 (86%); (h) N-cyclobutyl N-methylamine/iPr2NEt/CH2Cl2 (100%); (i) B2(pin)2/KOAc/PdCl2(dppf)/THF/80 °C; (j) NaH2BO4/H2O/RT (76% over 2 steps); (k) 38; 1,1′-(azodicarbonyl)dipiperidine/Bu3P/toluene/50 °C (45%); (l)LiOH/H2O/MeOH (76%).

PAT

https://patentscope.wipo.int/search/en/detail.jsf?docId=US208146892&_cid=P20-MFS2PF-83792-1

PATENT

• Carbamoyloxymethyl triazole cyclohexyl acids as lpa antagonistsPublication Number: US-2022249443-A1Priority Date: 2016-06-21
• Carbamoyloxymethyl triazole cyclohexyl acids as LPA antagonistsPublication Number: US-RE49352-EPriority Date: 2016-06-21Grant Date: 2023-01-03
• Carbamoyloxymethyl triazole cyclohexyl acids as LPA antagonistsPublication Number: AU-2021209334-B2Priority Date: 2016-06-21Grant Date: 2023-06-01
• Carbamoyloxymethyltriazole cyclohexylates as LPA antagonistsPublication Number: JP-7312295-B2Priority Date: 2016-06-21Grant Date: 2023-07-20
• Carbamoyloxymethyl triazole cyclohexyl acids as lpa antagonistsPublication Number: US-2023390249-A1Priority Date: 2016-06-21

• Carbamoyloxymethyltriazolylcyclohexanes as LPA antagonistsPublication Number: CN-109963843-BPriority Date: 2016-06-21Grant Date: 2022-03-11
• Carbamoyloxymethyltriazole cyclohexyl acid as LPA antagonistPublication Number: CN-114601830-APriority Date: 2016-06-21
• Carbamoyloxymethyl triazole cyclohexyl acid as an LPA antagonistPublication Number: KR-102377340-B1Priority Date: 2016-06-21Grant Date: 2022-03-21
• Carbamoyloxymethyl triazole cyclohexyl acids as lpa antagonistsPublication Number: KR-20220038537-APriority Date: 2016-06-21
• Carbamoyloxymethyl triazole cyclohexyl acids as lpa antagonistsPublication Number: KR-102463621-B1Priority Date: 2016-06-21Grant Date: 2022-11-03

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References

1.  “Admilparant (BMS-986278): Idiopathic Pulmonary Fibrosis Likelihood of Approval”. Pharmaceutical Technology. 25 December 2023. Retrieved 2024-11-23.
2.  Corte TJ, Behr J, Cottin V, Glassberg MK, Kreuter M, Martinez FJ, et al. (October 2024). “Efficacy and Safety of Admilparant, an LPA1 Antagonist in Pulmonary Fibrosis: A Phase 2 Randomized Clinical Trial”. American Journal of Respiratory and Critical Care Medicine. 211 (2): 230–238. doi:10.1164/rccm.202405-0977OC. PMID 39393084.
3.  Splete H (16 September 2024). “Admilparant Affects Biomarkers in Pulmonary Fibrosis”. Medscape. Retrieved 2024-11-23.

References

1. Zhou Y, Zhang Y, Zhao D, Yu X, Shen X, Zhou Y, Wang S, Qiu Y, Chen Y, Zhu F: TTD: Therapeutic Target Database describing target druggability information. Nucleic Acids Res. 2024 Jan 5;52(D1):D1465-D1477. doi: 10.1093/nar/gkad751. [Article]

/////////Admilparant, BMS 986278, PHASE 3, Bristol-Myers Squibb,  idiopathic pulmonary fibrosis, 4UN9AOU6G8