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KAI-1678

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KAI-1678 is an inhibitor of epsilon protein kinase C.

Category

Peptide Inhibitors

Catalog number

BAT-009072

CAS number

1041004-14-1

Molecular Formula

C107H191N43O29S2

Molecular Weight

2522

Specification
Reference Reading

IUPAC Name

(4S)-4-acetamido-5-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-6-amino-1-[(2S)-2-[[(2S,3R)-1-[[2-[[2-[[(2S)-1-[[2-[[(2S)-1-[[(2S)-6-amino-1-[[(2S)-6-amino-1-[[(2S)-1-[[(2S)-1-[[(2S)-5-amino-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-amino-5-carbamimidamido-1-oxopentan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-1,5-dioxopentan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-1-oxohexan-2-yl]amino]-1-oxohexan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-2-oxoethyl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-2-oxoethyl]amino]-3-hydroxy-1-oxobutan-2-yl]carbamoyl]pyrrolidin-1-yl]-1-oxohexan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-1-oxopropan-2-yl]amino]-5-oxopentanoic acid

Synonyms

UNII-32P8I5VL5A; 32P8I5VL5A; KAI-1678; KP-1678; L-Argininamide, N-acetyl-L-alpha-glutamyl-L-alanyl-L-valyl-L-seryl-L-leucyl-L-lysyl-L-prolyl-L-threonylglycylglycyl-L-tyrosylglycyl-L-arginyl-L-lysyl-L-lysyl-L-arginyl-L-arginyl-L-glutaminyl-L-arginyl-L-arginyl-; 1041004-14-1

Sequence

CYGRKKRRERRRCEAVSLKPT

Storage

Store at -20°C

InChI

InChI=1S/C107H190N44O28/c1-55(2)49-73(147-97(175)75(54-152)148-100(178)82(56(3)4)149-85(163)57(5)134-87(165)70(135-59(7)154)36-38-81(160)161)96(174)146-72(23-10-13-41-110)101(179)151-48-20-30-76(151)98(176)150-83(58(6)153)99(177)133-51-78(157)131-52-79(158)137-74(50-60-31-33-61(155)34-32-60)86(164)132-53-80(159)136-63(25-15-43-126-103(115)116)88(166)139-64(21-8-11-39-108)90(168)140-65(22-9-12-40-109)91(169)142-67(27-17-45-128-105(119)120)92(170)143-69(29-19-47-130-107(123)124)94(172)145-71(35-37-77(111)156)95(173)144-68(28-18-46-129-106(121)122)93(171)141-66(26-16-44-127-104(117)118)89(167)138-62(84(112)162)24-14-42-125-102(113)114/h31-34,55-58,62-76,82-83,152-153,155H,8-30,35-54,108-110H2,1-7H3,(H2,111,156)(H2,112,162)(H,131,157)(H,132,164)(H,133,177)(H,134,165)(H,135,154)(H,136,159)(H,137,158)(H,138,167)(H,139,166)(H,140,168)(H,141,171)(H,142,169)(H,143,170)(H,144,173)(H,145,172)(H,146,174)(H,147,175)(H,148,178)(H,149,163)(H,150,176)(H,160,161)(H4,113,114,125)(H4,115,116,126)(H4,117,118,127)(H4,119,120,128)(H4,121,122,129)(H4,123,124,130)/t57-,58+,62-,63-,64-,65-,66-,67-,68-,69-,70-,71-,72-,73-,74-,75-,76-,82-,83-/m0/s1

InChI Key

UVKJMACBAZMKAL-IAPYPFBNSA-N

Canonical SMILES

CC(C)CC(C(=O)NC(CCCCN)C(=O)N1CCCC1C(=O)NC(C(C)O)C(=O)NCC(=O)NCC(=O)NC(CC2=CC=C(C=C2)O)C(=O)NCC(=O)NC(CCCNC(=N)N)C(=O)NC(CCCCN)C(=O)NC(CCCCN)C(=O)NC(CCCNC(=N)N)C(=O)NC(CCCNC(=N)N)C(=O)NC(CCC(=O)N)C(=O)NC(CCCNC(=N)N)C(=O)NC(CCCNC(=N)N)C(=O)NC(CCCNC(=N)N)C(=O)N)NC(=O)C(CO)NC(=O)C(C(C)C)NC(=O)C(C)NC(=O)C(CCC(=O)O)NC(=O)C

1. PKC delta and epsilon in drug targeting and therapeutics

Tomo Yonezawa, Riho Kurata, Minoru Kimura, Hidetoshi Inoko Recent Pat DNA Gene Seq. 2009;3(2):96-101. doi: 10.2174/187221509788654205.

Protein kinase C (PKC) belongs to the serine and threonine kinase family. At least ten PKC isoforms have been identified and subdivided into three groups: classical (alpha, beta I, beta II and gamma), novel (delta, epsilon, theta and eta), and atypical (zeta and iota/lambda). Two calcium-insensitive isoforms of novel PKC, PKC delta and epsilon, have received particular attention as promising targets for new drugs. PKCs play a multifaceted role in cellular responses in a range of tissues. Professor Mochly-Rosen's group and KAI Pharmaceuticals Inc. have developed drugs targeted against PKC delta (KAI-9803) and epsilon (KAI-1678). These drugs ameliorate pathological conditions in acute myocardial infarction and reduce pain via specific modulation of membrane-translocation of PKC delta or epsilon. Another research group has recently used the KinAce() approach to produce PKC epsilon-abrogating peptides (KCe-12 and KCe-16) that are based on the catalytic domain of PKC. These peptides specifically inhibit PKC epsilon and ameliorate pathological conditions in a rodent insulin resistance model. This review describes the development of these therapeutic drugs targeting PKC delta and epsilon by two independent groups in the light of recent patents.

2. A single-center, randomized, double-blind, active, and placebo-controlled study of KAI-1678, a novel PKC-epsilon inhibitor, in the treatment of acute postoperative orthopedic pain

John E Moodie, Eileen J Bisley, Saling Huang, Karen Pickthorn, Gregory Bell Pain Med. 2013 Jun;14(6):916-24. doi: 10.1111/pme.12088. Epub 2013 Apr 8.

Objective: KAI-1678, a novel inhibitor of the interaction of the epsilon isoform of protein kinase C (εPKC) with its intracellular receptor, has demonstrated activity in countering hyperalgesia in several models of pain. In this controlled randomized trial, KAI-1678 was tested for analgesic activity in an orthopedic acute postoperative pain setting. Design: Following hip or knee replacement surgery, subjects were treated with KAI-1678, ketorolac, or saline. Subjects recorded their pain intensity on a visual analog scale and rated their quality of analgesia. The pain intensity differences between baseline and the evaluations were summed over the first 4 hours. Results: The analysis revealed that, while ketorolac displayed good analgesic activity, KAI-1678 was not significantly different than placebo. Analgesia quality ratings similarly did not show a difference between KAI-1678 and placebo in this pain model. A small excess of infusion site erythema was seen with KAI-1678, but otherwise the drug was safe and well tolerated. Conclusions: We investigated the safety and efficacy of a novel inhibitor of εPKC and provide clinical evidence that inhibition of εPKC with KAI-1678 is not effective in the treatment of acute postoperative orthopedic pain.

3. The safety and efficacy of KAI-1678- an inhibitor of epsilon protein kinase C (εPKC)-versus lidocaine and placebo for the treatment of postherpetic neuralgia: a crossover study design

Michael J Cousins, Karen Pickthorn, Saling Huang, Linda Critchley, Gregory Bell Pain Med. 2013 Apr;14(4):533-40. doi: 10.1111/pme.12058. Epub 2013 Feb 25.

Objective: Postherpetic neuralgia (PHN) occurs in approximately 10-20% of patients with herpes zoster, and the risk increases with age. In this clinical trial, we evaluated the analgesic properties of KAI-1678-an inhibitor of epsilon protein kinase C-in the treatment of neuropathic pain in patients with PHN. Design: The study was a three-treatment period, double-blind, randomized, placebo and active comparator crossover trial evaluating subcutaneous infusions of KAI-1678 (25 mg), placebo, and lidocaine hydrochloride (700 mg; active comparator). Patients: A total of 17 men and 6 women (N = 23) were enrolled after fulfilling diagnosis of PHN with pain persisting for ≥3 months after a segmental herpes zoster eruption. Patients had to have a mean average pain score of ≥4 points on an 11-point numerical rating scale (NRS; ranging from 0 to 10) based on at least three daily entries prior to participation in the subsequent treatment period. Results: Overall, administration of KAI-1678 was generally safe and well tolerated. However, compared with placebo, KAI-1678 did not improve clinical pain scores as recorded using the NRS (0-10). In contrast, subcutaneous infusions of lidocaine were associated with a significant reduction in pain intensity at the end of the infusion. Conclusions: We conclude that KAI-1678 is not efficacious as an acute analgesic for chronic neuropathic pain because of PHN. However, for the first time, the results demonstrate that subcutaneous infusions of lidocaine are effective in treating neuropathic pain. The results of lidocaine treatment also indicate that the crossover study design was adequate to detect a clinically meaningful response in this analgesia study.