Solithromycin

Solithromycin

Systematic (IUPAC) name
(3aS,4R,7S,9R,10R,11R,13R,15R,15aR)-1-[4-[4-(3-aminophenyl)-1H-1,2,3-triazol-1-yl]butyl]-4-ethyl-7-fluorooctahydro-11-methoxy-3a,7,9,11,13,15-hexamethyl-10-{[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosyl]oxy}-2H-Oxacyclotetradecino[4,3-d]oxazole-2,6,8,14(1H,7H,9H)-tetrone
Clinical data
Routes of administration	oral, intravenous
Legal status	Phase III clinical trials, North America, South America, Europe, Asia, S. Africa
Identifiers
CAS Number	760981-83-7
ATC code	none
ChemSpider	25056854
UNII	9U1ETH79CK
ChEMBL	CHEMBL1240704
Synonyms	CEM-101; OP-1068
Chemical data
Formula	C43H65FN6O10
Molar mass	845.01 g/mol
SMILES CC[C@@H]1[C@@]2([C@@H]([C@H](C(=O)[C@@H](C[C@@]([C@@H]([C@H](C(=O)[C@](C(=O)O1)(C)F)C)O[C@H]3[C@@H]([C@H](C[C@H](O3)C)N(C)C)O)(C)OC)C)C)N(C(=O)O2)CCCCn4cc(nn4)c5cccc(c5)N)C
InChI InChI=1S/C43H65FN6O10/c1-12-32-43(8)35(50(40(55)60-43)19-14-13-18-49-23-30(46-47-49)28-16-15-17-29(45)21-28)26(4)33(51)24(2)22-41(6,56-11)37(27(5)36(53)42(7,44)39(54)58-32)59-38-34(52)31(48(9)10)20-25(3)57-38/h15-17,21,23-27,31-32,34-35,37-38,52H,12-14,18-20,22,45H2,1-11H3/t24-,25-,26+,27+,31+,32-,34-,35-,37-,38+,41-,42+,43-/m1/s1 Key:IXXFZUPTQVDPPK-ZAWHAJPISA-N
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Solithromycin (formerly known as CEM-101 and OP-1068) is a ketolide antibiotic undergoing clinical development for the treatment of community-acquired pneumonia (CAP)^[1] and other infections.^[2]

Solithromycin exhibits excellent in vitro activity against a broad spectrum of Gram-positive respiratory tract pathogens,^[3][4] including macrolide-resistant strains.^[5] Solithromycin has activity against most common respiratory Gram-(+) and fastidious Gram-(-) pathogens,^[6][7] and is being evaluated for its utility in treating gonorrhea.

• May 2011: Solithromycin is in a Phase 2 clinical trial for serious community-acquired bacterial pneumonia (CABP) and in a Phase 1 clinical trial with an intravenous formulation.^[8]

• September 2011 : Solithromycin demonstrated comparable efficacy to levofloxacin with reduced adverse events in Phase 2 trial in people with community-acquired pneumonia^[9]

• January 2015: In a Phase 3 clinical trial for community-acquired bacterial pneumonia (CABP), Solithromycin administered orally demonstrated statistical non-inferiority to the fluoroquinolone, Moxifloxacin.^[10]

• July 2015: Patient enrollment for the second Phase 3 clinical trial (Solitaire IV) for community-acquired bacterial pneumonia (CABP) was completed with results expected in Q4 2015. ^[11]

• Oct 2015: IV to oral solithromycin demonstrated statistical non-inferiority to IV to oral moxifloxacin in adults with CABP. ^[12]

Structure

X-ray crystallography studies have shown solithromycin, the first fluoroketolide in clinical development, has a third region of interactions with the bacterial ribosome,^[13] as compared with two binding sites for other ketolides.

The only currently marketed ketolide, telithromycin, suffers from rare, but serious side effects. Recent studies^[14] have shown this to be likely due to the presence of the pyridine-imidazole group of the telithromycin side chain acting as an antagonist towards various nicotinic acetylcholine receptors.

References

1. Reinert RR (June 2004). "Clinical efficacy of ketolides in the treatment of respiratory tract infections". The Journal of Antimicrobial Chemotherapy 53 (6): 918–27. doi:10.1093/jac/dkh169. PMID 15117934.
2. http://www.cempra.com/research/antibacterials/
3. Woolsey LN, Castaneira M, Jones RN. (May 2010). "CEM-101 activity against Gram-positive organisms". Antimicrobial Agents and Chemotherapy 54 (5): 2182–2187. doi:10.1128/AAC.01662-09. PMID 2017690.
4. Farrell DJ, Sader HS, Castanheira M, Biedenbach DJ, Rhomberg PR, Jones RN. (June 2010). "Antimicrobial characterization of CEM-101 activity against respiratory tract pathogens including multidrug-resistant pneumococcal serogroup 19A isolates". International Journal of Antimicrobial Agents 35 (6): 537–543. doi:10.1016/j.ijantimicag.2010.01.026. PMID 20211548.
5. McGhee P, Clark C, Kosowska-Shick K, Nagai K, Dewasse B, Beachel L, Appelbaum PC. (January 2010). "In Vitro Activity of Solithromycin against Streptococcus pneumoniae and Streptococcus pyogenes with Defined Macrolide Resistance Mechanisms". Antimicrobial Agents and Chemotherapy 54 (1): 230–238. doi:10.1128/AAC.01123-09. PMC 2798494. PMID 19884376. Retrieved 2011-02-28.
6. Putnam, Shannon D.; Castanheira, Mariana; Moet, Gary J.; Farrell, David J.; Jones, Ronald N. (2010). "CEM-101, a novel fluoroketolide: antimicrobial activity against a diverse collection of Gram-positive and Gram-negative bacteria". Diagnostic Microbiology and Infectious Disease 66 (4): 393–401. doi:10.1016/j.diagmicrobio.2009.10.013. PMID 20022192.
7. Putnam, Shannon D.; Sader, Helio S.; Farrell, David J.; Biedenbach, Douglas J.; Castanheira, Mariana (2011). "Antimicrobial characterisation of solithromycin (CEM-101), a novel fluoroketolide: activity against staphylococci and enterococci". International Journal of Antimicrobial Agents 37 (1): 39–45. doi:10.1016/j.ijantimicag.2010.08.021. PMID 21075602.
8. "Intravenous (IV) Administration of Cempra Pharmaceutical's Solithromycin (CEM-101) Demonstrates Excellent Systemic Tolerability in a Phase 1 Clinical Trial". 7 May 2011.
9. "Cempra antibiotic compound as effective, safer than levofloxacin". 15 Sep 2011.
10. http://investor.cempra.com/releasedetail.cfm?ReleaseID=889300. 4 Jan 2015
11. http://investor.cempra.com/releasedetail.cfm?ReleaseID=920866. 7 July 2015
12. http://investor.cempra.com/releasedetail.cfm?ReleaseID=936994
13. Llano-Sotelo B, Dunkle J, Klepacki D, Zhang W, Fernandes P, Cate JH, Mankin AS. (2010). "Binding and Action of CEM-101, a New Fluoroketolide Antibiotic That Inhibits Protein Synthesis". Antimicrobial Agents and Chemotherapy 54 (12): 4961–4970. doi:10.1128/AAC.00860-10. PMC 2981243. PMID 20855725.
14. Bertrand D, Bertrand S, Neveu E, Fernandes P. (2010). "Molecular characterization of off-target activities of telithromycin: a potential role for nicotinic acetylcholine receptors". Antimicrobial Agents and Chemotherapy 54 (12): 599–5402. doi:10.1128/AAC.00840-10. PMC 2981250. PMID 20855733.

Further reading

• Profile of and Research on Solithromycin