SMALL PEPTIDES CHEMISTRY, BIOLOGY AND CLINICAL STUDIES. .t. V A.S. DUTTA. PHARMACOCHEMISTRY LIBRARY Editor: H. Timmerman.

Transcription

1 .t. V 0 PHARMACOCHEMISTRY LIBRARY Editor: H. Timmerman Volume 19 SMALL PEPTIDES CHEMISTRY, BIOLOGY AND CLINICAL STUDIES A.S. DUTTA Company Research Associate ZENECA Pharmaceuticals Alder ley Park, Macclesfield Cheshire SKI0 4TG, U.K. ELSEVIER - Amsterdam - London - New York - Tokyo 1993

2 VII CONTENTS Acknowledgements Introduction 1 XVI CHAPTER 1 ANGIOTENSIN II 1. INTRODUCTION 9 2. RECEPTOR SUBTYPES OF ANGIOTENSIN II 9 3. AGONIST ANALOGUES OF ANGIOTENSIN II PEPTIDE ANTAGONISTS OF ANGIOTENSIN II Modifications of the C-Terminal Phe Residue Replacement of the Tyr 4 Residue N- orc-terminal Deletions Interchanging the Tyr 4 and Phe^ Residues NON-PEPTIDE ANTAGONISTS OF ANGIOTENSIN II Modifications of the Early Imidazole Leads lmidazole-5-acrylic acid Derivatives as Antagonists of Angiotensin II lmidazo[4,5-b]pyridine Derivatives as Antagonists of Angiotensin II Alkyl Benzimidazole Derivatives as Antagonists of Angiotensin II Alkyl-4-(biphenyl)methoxyquinoline and 2,6-Dialkyl-4-(biphenyl)- methoxy pyridine Derivatives as Antagonists of Angiotensin II Naphthalene, Tetrahydronaphthalene, Bromoindole and Bromobenzofuran Derivatives as Antagonists of Angiotensin II Angiotensin Antagonists Containing an Aminomethylene Bridge NON-PEPTIDE ANTAGONISTS OF ANGIOTENSIN II ACTING AT THE AT2 RECEPTOR SUMMARY REFERENCES 60 CHAPTER 2 BOMBESIN/GASTRIN-RELEASING PEPTIDE 1. INTRODUCTION ANTAGONISTS OF BOMBESIN/GRP Deletion of the C-Terminal Methionine Residue or the Dipeptide Leucylmethionine Modification of the Backbone Amide Groups 73

3 VIII 2.3 Amino Acid Substitutions in Position Substance P Antagonists as Bombesin Antagonists CONFORMATIONALLY RESTRICTED ANALOGUES OF BOMBESIN BOMBESIN/GRP ANTAGONISTS AND CANCER SUMMARY REFERENCES 80 CHAPTER 3 BRADYKININ ANALOGUES 1. INTRODUCTION RECEPTOR SUBTYPES OF BRADYKININ AGONIST ANALOGUES OF BRADYKININ ANTAGONISTS OF BRADYKININ Bi Receptor Antagonists Bi and B2 Receptor Antagonists Antagonists containing a D-Phe residue in position Antagonists of bradykinin containing conformationally restricted amino acid residues in positions 7 and BIOLOGICAL PROFILE OF HOE 140 AND RELATED ANTAGONISTS In Vitro Studies In Vivo Studies SIDE EFFECTS ASSOCIATED WITH BRADYKININ ANTAGONISTS SUMMARY REFERENCES 100 CHAPTER 4 CHOLECYSTOKININ ANALOGUES 1. INTRODUCTION DISTRIBUTION AND BIOLOGICAL FUNCTIONS OF CHOLECYSTOKININ CHOLECYSTOKININ RECEPTOR SUBTYPES AND RECEPTOR- SELECTIVE LIGANDS CCK-A Receptor Ligands CCK-B Receptor Ligands PEPTIDE ANTAGONISTS OF CHOLECYSTOKININ AND GASTRIN Cholecystokinin and Gastrin Antagonists Based on the CCK Sequence Antagonists Based on the Gastrin C-Terminal Sequence Antagonists Obtained by Peptide Bond Replacements Antagonists Containing a Homo Amino Acid Residue Other Approaches to Antagonists 124

4 IX 5. NON-PEPTIDE ANTAGONISTS OF CCK AND GASTRIN Amino Acid Derivatives as CCK and Gastrin Antagonists Substituted Benzodiazepines as CCK and Gastrin Antagonists Substituted-1,4-benzodiazepines as CCK Antagonists Alkyl series of analogues Amido series of analogues as CCK-A selective ligands Urea series of analogues as selective CCK-B/Gastrin receptor ligands CCK-A Receptor Ligands Based on Tifluadom Hybrid CCK Antagonists Based on Lorglumide and L-364,718 (MK-329) oc-methyltryptophan Derivatives as CCK Antagonists Quinazolinone derivatives as CCK-B receptor ligands SUMMARY REFERENCES 159 CHAPTER 5 ENKEPHALIN ANALOGUES 1. INTRODUCTION ENZYMIC INACT1VATION OF ENKEPHALINS EARLY STRUCTURE ACTIVITY RELATIONSHIP STUDIES AGONIST ANALOGUES DISPLAYING ANALGESIC ACTIVITY ANALOGUES WITH IMPROVED SELECTIVITY FOR THE \i and 5 RECEPTORS Selective Analogues Linear peptides Cyclic peptides ^.-Selective Analogues Linear peptides Cyclic peptides ANTAGONISTS OF ENKEPHALINS Selective Antagonists Based on the Enkephalin Sequence ^-Selective Antagonists of Enkephalin ^.-Selective antagonists based on the enkephalin sequence ^-Selective antagonists of enkephalin based on the somatostatin sequence SUMMARY REFERENCES 197

5 CHAPTER 6 LUTEINISING HORMONE RELEASING HORMONE 1. INTRODUCTION ENZYMIC DEGRADATION OF LHRH SAR OF LHRH AGONISTS Biologically Active Analogues of LHRH Smaller than a Decapeptide Potent Analogues of LHRH Incorporating Changes in Positions 6, 7 and Potent Analogues of LHRH Incorporating cc-aza-amino-acid Residues Potent Analogues of LHRH with Hydrophilic Residues in Position Analogues of LHRH Containing Nitrogen Mustard Derivatives or Cytotoxic Metal Complexes SAR OF LHRH ANTAGONISTS Summary of the Earlier Work Recent Work on LHRH Antagonists Effects of changes in position Effects of changes in position Effects of changes in positions 3 and Effects of changes in position Effects of changes in position Effects of changes in position Effects of changes in position Effects of changes in position Cyclic analogues LHRH ANTAGONISTS AND HISTAMINE RELEASE HEXAPEPTIDE DERIVATIVES AS LHRH ANTAGONISTS KETACONAZOLE DERIVATIVES AS LHRH ANTAGONISTS FORMULATIONS OF LHRH AND THE ANALOGUES PHARMACOLOGICAL AND CLINICAL STUDIES WITH LHRH AGONISTS AND ANTAGONISTS Use of LHRH Agonists for the Treatment of Prostate Cancer Use of LHRH Antagonists for the Treatment of Prostate Cancer Use of LHRH Agonists for the Treatment of Breast Cancer Use of LHRH Antagonists for the Treatment of Breast Cancer Use of LHRH Agonists and Antagonists in Endometriosis LHRH Agonists for the Treatment of Uterine Fibroids (Leiomyomata) LHRH Agonists as Male Contraceptives LHRH Antagonists as Male Contraceptives 268

6 XI 9.9 LHRH Agonists as Female Contraceptives LHRH Antagonists as Female Contraceptives SUMMARY REFERENCES 281 CHAPTER 7 SOMATOSTATIN 1. INTRODUCTION ENZYMIC DEGRADATION OF SOMATOSTATIN AND ANALOGUES AGONIST ANALOGUES OF SOMATOSTATIN. SAR STUDIES Role of the Disulphide Bridge and the N-Terminal Ala-Gly Residues Effects of Single Amino Acid Substitutions on the Biological Activity of Somatostatin Effects of N-Terminal Extension and Multiple Substitutions on the Biological Activity of Somatostatin Cyclic Dodecapeptide Analogues with Amino Acid Deletions and Disulphide Bridge Modifications Bicyclic Decapeptide and Cyclic Hexapeptide Analogues Linear and Cyclic Octapeptide Analogues Somatostatin Analogues as Opiate (^-Receptor) Antagonists CLINICAL APPLICATIONS OF SOMATOSTATIN ANALOGUES Pituitary Tumours Pancreatic Tumours Breast Cancer Prostate Cancer Lung Cancer Mechanism of Tumour Growth Inhibition Existence of somatostatin receptors in tumour cells Role of somatostatin in dephosphorylation of the growth factor (EGF) induced phosphorylated tyrosine kinase SUMMARY REFERENCES 350 CHAPTER 8 TACHYKININS SUBSTANCE P, NEUROKININ A AND NEUROKININ B 1. INTRODUCTION RECEPTOR SUBTYPES OF TACHYKININS 357

7 XII 2.1 Receptor Classification Based on Tachykinins Receptor Classification Based on Tachykinin Fragments Receptor Classification Based on Tachykinin Antagonists SAR OF THE MAMMALIAN TACHYKININS SAR of the C-Terminal Fragments Effects of Amino Acid Substitutions in Substance P Analogues of Substance P More Selective at the NK-1 Receptor Agonist Analogues of Neurokinin A and Neurokinin B NKA Analogues NKB Analogues ANTAGONISTS OF SUBSTANCE P Antagonists Based on the Undecapeptide Sequence Antagonists Based on the C-Terminal Fragments Tripeptide Derivatives as Antagonists of SP ANTAGONISTS OF NEUROKININ A AND NEUROKININ B NON-PEPTIDE ANTAGONISTS OF THE TACHYKININS CP-96,345 Series of Substance P Antagonists lmidazo[4,5-b]quinoxaline Series of Tachykinin Antagonists Naphthimidazolium Derivatives as Tachykinin Antagonists Perhydroisoindole and Androstano[3,2-b]pyrimido[1,2-a]benzimidazoles as Tachykinin Antagonists SR 48968, an NK-2 Receptor Antagonist NK-1 and NK-2 Selective Antagonists Obtained from Natural Products BIOLOGICAL STUDIES USING SP ANALOGUES SP Antagonists as Analgesics SP Antagonists in Neurogenic Inflammation SP Antagonists in Neurogenic Bronchoconstriction SP and Salivary Secretion SP Antagonists in Small-Cell Carcinoma of the Lung SP and Histamine Release Other Biological Effects Associated with SP Antagonists. Side-Effects? SUMMARY REFERENCES 406 CHAPTER 9 INHIBITORS OF ASPARTYL PROTEASES. 1. RENIN 1. INTRODUCTION INHIBITORS OF RENIN Inhibitors Based on the Renin Substrate Substrate Based Inhibitors of Renin Containing a Modified Scissile Peptide Bond 418

8 XIII Replacement of the scissile peptide bond by a > P(CH2-NH) group Replacement of the scissile peptide bond by a Y(CH0H-CH2) group Replacement of the scissile peptide bond by a X F(P(O)(OH)-CH2) group Inhibitors Containing a Statine Residue in the Pi Position Approaches Designed to Improve Potency, Stability, Oral Activity and Duration of Action of the Renin Inhibitors C-Terminal modifications in peptides containing a modified scissile peptide bond N- and C-Terminal modifications in peptides containing a modified scissile peptide bond Incorporation of unnatural amino acids Changes in the Phe-His (P3-P2) residues Multiple substitutions in renin inhibitors Conformationally restricted inhibitors of renin Inhibitors of Renin Unrelated to the Angiotensinogen Sequence Inhibitors of Renin Isolated From Natural Products SUMMARY REFERENCES 475 CHAPTER 10 INHIBITORS OF ASPARTYL PROTEASES. 2. HIV PROTEASE 1. INTRODUCTION NATURE OF THE ENZYME CHEMICAL APPROACHES USED IN THE DESIGN OF INHIBITORS Substrate Analogues Containing a Modified Scissile Peptide Bond Inhibitors of HIV Protease Containing a Hydroxymethylcarbonyl Isostere Inhibitors of HIV Protease Containing a Hydroxyethylamine Group Inhibitors of HIV Protease Containing a Hydroxyethylene Isostere Inhibitors of HIV Protease Containing a Dihydroxyethylene Isostere Dimeric Inhibitors of HIV Protease NON-PEPTIDE INHIBITORS OF HIV PROTEASE SUMMARY REFERENCES 520

9 XIV CHAPTER 11 METALLOPEPTIDASE (ACE, ENKEPHALINASE AND ATRIOPEPTIDASE) INHIBITORS 1. INTRODUCTION INHIBITORS OF ANGIOTENSIN CONVERTING ENZYME ACE Inhibitors with a Thiol Function as a Chelating Group ACE Inhibitors Containing a Carboxyl Function Phosphorus Containing Inhibitors of ACE Glutamic Acid Derivatives as Inhibitors of ACE Inhibitors of ACE Isolated from Natural Products INHIBITORS OF ENKEPHALIN DEGRADING DIPEPTIDYL- CARBOXYPEPTIDASE (ENKEPHALINASE) Properties of Enkephalinase Design of Enkephalinase Inhibitors Thiol-containing inhibitors of enkephalinase Carboxyalkyl derivatives as enkephalinase inhibitors Hydroxamic acid derivatives as enkephalinase inhibitors Other inhibitors of enkephalinase Analgesic Effects of the Enkephalinase Inhibitors INHIBITORS OF ATRIAL NATR1URETIC FACTOR (ANF) DEGRADING ENZYME Design of the Inhibitors Biological and Clinical Evaluations of the ANF Degrading Metallo-endopeptidase Inhibitors SUMMARY REFERENCES 575 CHAPTER 12 FORMULATION OF PEPTIDES 1. INTRODUCTION POLYMERIC CONTROLLED DRUG DELIVERY SYSTEMS (DEPOT FORMULATIONS) Depot Formulations of LHRH Analogues Depot Formulations of Insulin Depot Formulations of Oxytocin and Vasopressin Depot Formulations of Growth Hormone Releasing Factor and Calcitonin IMPROVEMENTS IN THE ORAL DELIVERY OF PEPTIDES 588

10 XV 4. INTRANASAL ADMINISTRATION OF PEPTIDES Intranasal Formulations of LHRH Analogues Intranasal Formulations of Insulin and Calcitonin Intranasal Formulations of ACTH, Growth Hormone and Desmopressin TRANSDERMAL lontophoretic DRUG DELIVERY OF PEPTIDES ADMINISTRATION OF PEPTIDES BY OCULAR, VAGINAL AND RECTAL ROUTES Ocular Absorption of Peptides Vaginal Absorption of Peptides Rectal Absorption of Peptides REFERENCES 596 SUBJECT INDEX 602