Source: https://patents.google.com/patent/US8057822?oq=6188988
Timestamp: 2018-03-23 00:06:13
Document Index: 428640579

Matched Legal Cases: ['Application No. 2', 'Application No. 2', 'Application No. 00', 'Application No. 00', 'Application No. 00', 'Application No. 00', 'Application No. 00', '§1']

US8057822B2 - Modified exendins and exendin agonists - Google Patents
Modified exendins and exendin agonists Download PDF
US8057822B2
US8057822B2 US11174089 US17408905A US8057822B2 US 8057822 B2 US8057822 B2 US 8057822B2 US 11174089 US11174089 US 11174089 US 17408905 A US17408905 A US 17408905A US 8057822 B2 US8057822 B2 US 8057822B2
US11174089
US20050267034A1 (en )
The exendins have some sequence similarity to several members of the glucagon-like peptide family, with the highest homology, 53%, being to GLP-1 [7-36]NH2 [SEQ. ID. NO. 3] (Goke, et al., J. Biol. Chem., 268:19650-55, 1993). GLP-1 [7-36]NH2, also sometimes referred to as proglucagon [78-107] or simply “GLP-1”, has an insulinotropic effect, stimulating insulin secretion from pancreatic beta-cells; GLP-1 has also been reported to inhibit glucagon secretion from pancreatic alpha-cells (Ørsov, et al., Diabetes, 42:658-61, 1993; D'Alessio, et al., J. Clin. Invest., 97:133-38, 1996). GLP-1 has been reported to inhibit gastric emptying (Willms B, et al., J. Clin. Endocrinol. Metab. 81 (1): 327-32, 1996; Wettergren A, et al., Dig. Dis. Sci. 38 (4): 665-73, 1993), and gastric acid secretion (Schjoldager B T, et al., Dig. Dis. Sci. 34 (5): 703-8, 1989; O'Halloran D J, et al., J. Endocrinol. 126 (1): 169-73, 1990; Wettergren A, et al., Dig. Dis. Sci. 38 (4): 665-73, 1993)). GLP-1 [7-37], which has an additional glycine residue at its carboxy terminus, is reported to stimulate insulin secretion in humans (Ørsov, et al., Diabetes, 42:658-61, 1993). Other reports relate to the inhibition of glucagon secretion (Creutzfeldt W O C, et al., Glucagonostatic actions and reduction of fasting hyperglycemia by exogenous glucagon-like peptide I (7-36) amide in Type 1 diabetic patients, Diabetes Care 1996; 19(6):580-6), and a purported role in appetite control (Turton M D, et al., A role for glucagon-like peptide-1 in the central regulation of feeding, Nature 1996 January; 379(6560):69-72). A transmembrane G-protein adenylate-cyclase-coupled receptor, said to be responsible at least in part for the insulinotropic effect of GLP-1, has reportedly been cloned from a beta-cell line (Thorens, Proc. Natl. Acad. Sci. USA 89:8641-45, 1992). GLP-1 has been the focus of significant investigation in recent years due to its reported action on the amplification of stimulated insulin production (Byrne M M, Goke B. Lessons from human studies with glucagon-like peptide-1: Potential of the gut hormone for clinical use. In: Fehmann H C, Goke B. Insulinotropic Gut Hormone Glucagon-Like Peptide 1. Basel, Switzerland: Karger, 1997:219-33).
Gly Gly Xaa31 Ser-Z21
Gly Gly Xaa31 Ser Ser Gly-Z21
Gly Gly Xaa31 Ser Ser Gly Ala Xaa36 Xaa37 Xaa38 Xaa39-Z2; [SEQ ID NO. 203] wherein
Gly Gly Xaa31 Ser Ser Gly Ala Xaa36 Xaa37-Z2 or Gly Gly Xaa31
Ser Ser Gly Ala Xaa36 Xaa37 Xaa38-Z2;
Gly Gly Xaa31-Z21
Gly Gly Xaa31 Ser Ser Gly Ala Xaa36 Xaa37 Xaa38 Ser-Z2; [SEQ ID NO. 206]:
Xaa1 Xaa2 Xaa3 Gly Xaa5 Xaa6 Xaa7 Xaa8 Xaa9 Xaa10
Xaa11 Xaa12 Xaa13 Xaa14 Xaa15 Xaa16 Xaa17 Ala Xaa19
Xaa20 Xaa21 Xaa22 Xaa23 Xaa24 Xaa25 Xaa26 X1 -Z1;
Xaa1 Xaa2 Xaa3 Xaa4 Xaa5 Xaa6 Xaa7 Xaa8 Xaa9 Xaa10
Xaa11 Xaa12 Xaa13 Xaa14 Xaa15 Xaa16 Xaa17 Ala
Xaa1 Xaa2 Xaa3 Gly Thr Xaa4 Xaa5 Xaa6 Xaa7 Xaa8
Ser Lys Gln Xaa9 Glu Glu Glu Ala Val Arg Leu
Xaa10 Xaa11 Xaa12 Xaa13 Leu Lys Asn Gly Gly Xaa14
Ser Ser Gly Ala Xaa15 Xaa16 Xaa17 Xaa18-Z
Xaa10 Xaa11 Xaa12 Xaa13 Leu X1 Gly Gly Xaa14
wherein Xaa1 is His, Arg, Tyr or 4-imidazopropionyl; Xaa2 is Ser, Gly, Ala or Thr; Xaa3 is Asp or Glu; Xaa4 is Phe, Tyr or naphthylalanine; Xaa5 is Thr or Ser; Xaa6 is Ser or Thr; Xaa7 is Asp or Glu; Xaa8 is Leu, Ile, Val, pentylglycine or Met; Xaa9 is Leu, Ile, pentylglycine, Val or Met; Xaa10 is Phe, Tyr or naphthylalanine; Xaa11 is Ile, Val, Leu, pentylglycine, tert-butylglycine or Met; Xaa12 is Glu or Asp; Xaa13 is Trp, Phe, Tyr, or naphthylalanine; X1 is Lys Asn, Asn Lys, Lys-NHε—R Asn, Asn Lys-NHε—R where R is Lys, Arg, C1-C10 straight chain or branched alkanoyl or cycloalkylalkanoyl; Xaa14, Xaa15, Xaa16 and Xaa17 are independently Pro, homoproline, 3Hyp, 4Hyp, thioproline, N-alkylglycine, N-alkylpentylglycine or N-alkylalanine; Xaa18 is Ser, Thr or Tyr; and Z is —OH or —NH2; with the proviso that the compound does not have the formula of either SEQ. ID. NOS. 1 or 2. Suitable compounds of formula (VIII) include compounds described in PCT Application Serial No. PCT/US98/16387, filed Aug. 6, 1998, entitled “Novel Exendin Agonist Compounds” having the amino acid sequences of SEQ. ID. NOS. 37-40 therein.
HGEGTFTSDLSK (PEG) QMEEEAVRLFIEWLKNGGPSSGAPPPS-NH2
HGEGTFTSDLSKQMEEEAVRLFIEWLK (PEG) NGGPSSGAPPPS-NH2
HK (PEG) EGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS-NH2
HGEGK (PEG) FTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS-NH2
HGEGTFTK (PEG) DLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS-NH2
HGEGTFTSDK (PEG) SKQMEEEAVRLFIEWLKNGGPSSGAPPPS-NH2
HGEGTFTSDLK (PEG) KQMEEEAVRLFIEWLKNGGPSSGAPPPS-NH2
HGEGTFTSDLSKK (PEG) MEEEAVRLFIEWLKNGGPSSGAPPPS-NH2
(209):*
HGEGTFTSDLSKQMEK (PEG) EAVRLFIEWLKNGGPSSGAPPPS-NH2
(210):*
HGEGTFTSDLSKQMEEK (PEG) AVRLFIEWLKNGGPSSGAPPPS-NH2
HGEGTFTSDLSKQMEEEAK (PEG) RLFIEWLKNGGPSSGAPPPS-NH2
HGEGTFTSDLSKQMEEEAVRK (PEG) FIEWLKNGGPSSGAPPPS-NH2
(213):*
HGEGTFTSDLSKQMEEEAVRLFIK (PEG) WLKNGGPSSGAPPPS-NH2
HGEGTFTSDLSKQMEEEAVRLFIEK (PEG) LKNGGPSSGAPPPS-NH2
HGEGTFTSDLSKQMEEEAVRLFIEWLKK (PEG) GGPSSGAPPPS-NH2
HGEGTFTSDLSKQMEEEAVRLFIEWLKNK (PEG) GPSSGAPPPS-NH2
HGEGTFTSDLSKQMEEEAVRLFIEWLKNGK (PEG) PSSGAPPPS-NH2
exendin-4 HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS-NH2 [SEQ ID NO. 2]
(218) (CH3) -COHGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS-NH2 [SEQ ID NO. 228]
(219) (CH3) -CH2HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS-NH2 [SEQ ID NO. 229]
(220) HGEGTFTSDLSRQMEEEAVRLFIEWLK (PEG) NGGPSSGAPPPS-NH2 [SEQ ID NO. 230]
(221) HGEGTFTSDLSK (PEG) QMEEEAVRLFIEWLRNGGPSSGAPPPS-NH2 [SEQ ID NO. 231]
(222) HGEGTFTSDLSRQMEEEAVRLFIEWLRNGGPSSGAPPPS-NH2 [SEQ ID NO. 232]
(223) HGEGTFTSDLSRQMEEEAVRLFIEWLRNGGPSSGAPPPK (PEG) -NH2 [SEQ ID NO. 233]
(224) HGEGTFTSDLSRQMEEEAVRLFIEWLRNGK (PEG) PSSGAPPPS-NH2 [SEQ ID NO. 234]
(225) HGEGTFTSDLSRQMEEEAVRLFIEWLK (PEG) NGGPSSGAPPPS-NH2 [SEQ ID NO. 235]
(226) HGEGTFTSDLSK (PEG) QMEEEAVRLFIEWLRNGGPSSGAPPPS-NH2 [SEQ ID NO. 236]
(227) (PEG) COHGEGTFTSDLSRQMEEEAVRLFIEWLRNGGPSSGAPPPS-NH2 [SEQ ID NO. 237]
(228) (PEG) CH2HGEGTFTSDLSRQMEEEAVRLFIEWLRNGGPSSGAPPPS-NH2 [SEQ ID NO. 238]
(229) HGEGTFTSDLSRQMEEEAVRLFIEWLRNGGPSSGAPPPK (PEG) -NH2 [SEQ ID NO. 239]
(230) HGEGTFTSDLSRQMEEEAVRLFIEWLRNGK (PEG) PSSGAPPPS-NH2 [SEQ ID NO. 240]
The various PEG modified exendins used in Examples 5-10, below, are provided in Table I, with the corresponding results being provided in Table II (see the end of Example 9). GLP-1 [7-36]NH2 (GLP-1) was purchased from Bachem (Torrance, Calif.). All other peptides were prepared using synthesis methods such as those described herein. All chemicals were of the highest commercial grade. The cAMP SPA immunoassay was purchased from Amersham. The radioligands were purchased from New England Nuclear (Boston, Mass.). RINm5f cells (American Type Tissue Collection, Rockville, Md.) were grown in DME/F12 medium containing 10% fetal bovine serum and 2 mM L-glutamine. Cells were grown at 37° C. and 5% CO2/95% humidified air and medium was replaced every 2 to 3 days. Cells were grown to confluence then harvested and homogenized using on a Polytron homogenizer. Cell homogenates were stored frozen at −70° C. until used.
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US13296120 Continuation US8445647B2 (en) 1999-04-30 2011-11-14 Modified exendins and exendin agonists
US20050267034A1 true US20050267034A1 (en) 2005-12-01
US8057822B2 true US8057822B2 (en) 2011-11-15
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