84559-70-6

Upstream product

• 1738-69-8 L-Leucine benzyl ester 
• 22838-58-0 Boc-D-Val-OH 
• 1738-77-8 L-leucine benzyl ester p-toluenesulfonate 

Downstream Products

• 136554-62-6 H-D-Val-Leu-OBzl 
• 1014985-85-3 C₁₈H₂₈N₂O₃*ClH 
• 84559-75-1 N-(D-valylleucyllysyl)-N',N'-bis(2-chloroethyl)-p-phenylenediamine bis(trifluoroacetate) 
• 84559-77-3 N-(D-valylleucyl-D-lysyl)-N',N'-bis(2-chloroethyl)-p-phenylenediamine bis(trifluoroacetate) 
• 84559-73-9 N-α-(tert-buthoxycarbonyl)-D-valylleucyl-N^ε-(tert-buthoxycarbonyl)lysyl>-N',N'-bis(2-chloroethyl)-p-phenylenediamine 
• 84559-74-0 N-α-(tert-buthoxycarbonyl)-D-valylleucyl-N^ε-(tert-buthoxycarbonyl)-D-lysyl>-N',N'-bis(2-chloroethyl)-p-phenylenediamine 
• 166761-01-9 Boc-Hyp-D-Val-Leu-D-Trp(Z)-D-Asp(OBzl)-O-t-Bu 
• 166761-02-0 cyclo(-D-Trp(Z)-D-Asp(OBzl)-Hyp-D-Val-Leu-) 
• 789458-70-4 Boc-D-Trp-D-Sal-Pro-D-Val-Leu-OBzl 
• 1027886-88-9 Boc-D-Sal-Pro-D-Val-Leu-OBzl 
• 166761-00-8 Boc-Hyp-D-Val-Leu-OBzl 
• 157569-04-5 Boc-Pro-D-Val-Leu-OBzl 
• 1025835-45-3 (S)-4-Methyl-2-{(R)-3-methyl-2-[((S)-pyrrolidine-2-carbonyl)-amino]-butyrylamino}-pentanoic acid benzyl ester 

Relevant academic research and scientific papers

MACROCYCLIC ANTAGONISTS OF THE MOTILIN RECEPTOR FOR TREATMENT OF GASTROINTESTINAL DYSMOTILITY DISORDERS

The present invention provides conformationally-defined macrocyclic compounds that bind to and/or are functional modulators of the motilin receptor including subtypes, isoforms and/or variants thereof. These macrocyclic compounds, at a minimum, possess adequate pharmacological properties to be useful as therapeutics for a range of disease indications. In particular, these compounds are useful for treatment and prevention of disorders characterized by hypermotilinemia and/or gastrointestinal hypermotility, including, but not limited to, diarrhea, cancer treatment-related diarrhea, cancer-induced diarrhea, chemotherapy-induced diarrhea, radiation enteritis, radiation-induced diarrhea, stress-induced diarrhea, chronic diarrhea, AIDS-related diarrhea, C. difficile associated diarrhea, traveller's diarrhea, diarrhea induced by graph versus host disease, other types of diarrhea, dyspepsia, irritable bowel syndrome, chemotherapy-induced nausea and vomiting (emesis) and post-operative nausea and vomiting and functional gastrointestinal disorders. In addition, the compounds possess utility for the treatment of diseases and disorders characterized by poor stomach or intestinal absorption, such as short bowel syndrome, celiac disease and cachexia. The compounds also have use for the treatment of inflammatory diseases and disorders of the gastrointestinal tract, such as inflammatory bowel disease, ulcerative colitis, Crohn's disease and pancreatitis. Accordingly, methods of treating such disorders and pharmaceutical compositions including compounds of the present invention are also provided.

Structure-activity relationships of cyclic pentapeptide endothelin A receptor antagonists

Analogues of the natural product endothelin A (ET(A)) receptor antagonists cyclo(-D-Trp1-D-Glu2-Ala3-D-Va14-Leu5-) (1) and cyclo(-D-Trp1-D-Glu2- Ala3-D-alloIle4-Leu5-) (2) were prepared and tested for inhibitory activity against [125I]endothelin (ET-1) binding to protein ET(A) receptors. The DDLDL chirality sequence of the natural products appeared to be critical for inhibitory activity because conversion of either D-Trp or D- Glu (or both) in 1 to the corresponding L-isomer(s) abolished this property. Systematic modifications at each position of the natural products clarified the structure-activity relationships and led to highly potent and selective ET(A) receptor antagonists. Most replacements of D-Trp1 and Leu5 with other amino acids caused a significant loss of inhibitory activity. In contrast, replacement of D-Glu2 with D-Asp2 enhanced the activity. With regard to the Ala3 position, all analogues with imino acids, independent of being cyclic or acyclic, showed higher affinities than did the amino acid analogues. In addition, most replacements with amino acids, which had various functional groups in their side chains, did not significantly modify ET(A) binding affinity. The D-Va14/D-alloIle4 position was very important for inhibitory activity, and a β-position branched D-amino acid or a D-heteroarylglycine was preferable at this position. Among synthesized cyclic pentapeptides, compound 36 (BQ-518) was the most potent ETA receptor antagonist, with a pA2 of 8.1 against ET-1-induced vasoconstriction in isolated porcine coronary arteries. This compound also showed the greatest selectivity between ET(A) and ET(B) receptors (IC50 for human ET(A) = 1.2 nM, IC50 for human ET(B) = 55 μM). In contrast, compound 8 (BQ-123) is a highly soluble, potent, and selective ET(A) receptor antagonist (pA2 = 7.4, IC50 for human ET(A) = 8.3 nM, IC50 for human ET(B) = 61 μM). The sodium salt of 8 is practically freely soluble in saline. These compounds are useful tools for not only in vitro but also in vivo pharmacological studies.