Integration of Pharmaceutical Discovery and Development

by Borchardt, Ronald T.; Freidinger, Roger M.; Sawyer, Tomi K.; Smith, Philip L.

• ISBN13: 9780306457432
• ISBN10: 0306457431
• Format: Hardcover
• Copyright: 1998-09-01
• Publisher: Plenum Pub Corp

Summary

This volume provides case histories illustrating the types of interdisciplinary interactions necessary to design drug candidates with optimal pharmacological, pharmaceutical, biopharmaceutical, and metabolic/pharmacokinetic properties. Key features include an incisive discussion of HIV protease inhibitors and 287 illustrations.

Table of Contents

Chapter 1 Introduction	1	(6)
Ralph Hirschmann
Chapter 2 Renin Inhibitors	7	(22)
Saul H. Rosenberg
Hollis D. Kleinert
1. The Renin Angiotensin System (RAS)	7	(1)
2. In Vitro Assays	8	(2)
3. Renin Inhibitor Design	10	(14)
3.1 Novel Transition-State Analogues	10	(2)
3.2 Models to Evaluate Pharmacological Responses	12	(1)
3.3 Molecular Weight, Proteolytic Stability, and Aqueous Solubility	13	(4)
3.4 Renin Inhibitors with Oral Bioavailability	17	(7)
4. Conclusions	24	(1)
References	25	(4)
Chapter 3 The Discovery and Development of Angiotensin II Antagonists	29	(28)
David J. Carini
David D. Christ
John V. Duncia
Michael E. Pierce
1. Introduction	29	(1)
2. Development of a Tetrazole Derivative	30	(14)
2.1 Chemical Stability and Potential Toxicity of Tetrazoles	30	(2)
2.2 Metabolism of Tetrazoles	32	(1)
2.3 The Search for Tetrazole Replacements	33	(6)
2.4 Synthetic Availability of Biphenyltetrazoles	39	(5)
3. An Active Metabolite of Losartan	44	(3)
3.1 Identification of EXP3174	44	(1)
3.2 Should We Develop EXP3174?	45	(1)
3.3 The Search for a Superior EXP3174 Analogue	45	(2)
4. Early Evaluation of Losartan's Activity in Humans	47	(1)
5. Selective versus Balanced Angiotensin II Receptor Antagonists	48	(3)
6. Conclusion	51	(1)
References	52	(5)
Chapter 4 Development of an Orally Active Tripeptide Arginal Thrombin Inhibitor	57	(24)
Robert T. Shuman
Paul D. Gesellchen
1. Introduction	57	(3)
2. Identification of Lead Compounds	60	(9)
2.1 In Vitro Structure-Activity Relationships	61	(3)
2.2 In Vivo Structure-Activity Relationships	64	(5)
3. Development of Parenteral Clinical Candidate	69	(1)
3.1 Development of Licensed Compound (Efegatran)	69	(1)
3.2 Summary of Clinical Data on Efegatran	70	(1)
4. Development of an Oral Candidate	70	(7)
4.1 In Vivo Oral Bioavailability	71	(2)
4.2 Oral Dosing in Efficacy Models	73	(1)
4.3 Pharmacokinetics of Oral Candidate	73	(2)
4.4 Clinical Data for Oral Candidate	75	(2)
5. Conclusion	77	(1)
References	78	(3)
Chapter 5 Discovery and Development of an Endothelin A Receptor-Selective Antagonist PD 156707	81	(32)
Annette M. Doherty
Andrew C.G. Uprichard
1. Introduction	81	(3)
2. Discovery of PD 156707: Medicinal Chemistry, Pharmacology, and Pharmacokinetics	84	(12)
2.1 Identification of Lead Structures	84	(2)
2.2 Structure-Activity Relationships	86	(1)
2.3 Pharmacokinetics/Selection	87	(2)
2.4 Chemistry/Chemical Development	89	(1)
2.5 Biological Evaluation of PD 156707	90	(2)
2.6 Metabolism	92	(1)
2.7 Assay Development	93	(3)
3. Efficacy Studies: Which Disease States?	96	(7)
3.1 Hypertension	96	(3)
3.2 Heart Failure	99	(1)
3.3 Pulmonary Hypertension	100	(3)
3.4. Stroke	103	(1)
4. Future Plans	103	(2)
5. Summary	105	(1)
References	105	(8)
Chapter 6 Endothelin Receptor Antagonists	113	(18)
John D. Elliott
Eliot H. Ohlstein
Catherine E. Peishoff
Harma M. Ellens
M. Amparo Lago
1. Introduction	113	(2)
2. Rational Design of SB 209670	115	(6)
3. Pharmacological, Drug Metabolism, and Pharmacokinetic Characterization of SB 209670	121	(1)
4. Selection of the Orally Bioavailable Candidate SB 217242	121	(6)
5. Conclusion	127	(1)
References	127	(4)
Chapter 7 LHRH Antagonists	131	(20)
Fortuna Haviv
Eugene N. Bush
Judith Knittle
Jonathan Greer
1. Mechanism of Action of LHRH Agonists and Antagonists	131	(2)
2. Structural Differences of LHRH Agonists and Antagonists	133	(4)
2.1 Reduction of Size of LHRH Analogues	135	(1)
2.2 Enzymatic Stability of LHRH Analogues and Effect of N-methyl Substitution on Enzymatic Stability of LHRH Agonists	136	(1)
2.3 Effect of N-methyl Substitution on Water Solubility of LHRH Antagonists. Discovery of A-75998	137	(1)
3. Biological Testing Strategy	137	(4)
3.1 In Vitro Testing of A-75998: Receptor Binding, Inhibition of LH Release, and Histamine Release	138	(1)
3.2 In Vivo Studies of A-75998 in Rat, Dog, and Monkey	138	(2)
3.3 Pharmacokinetics of A-75998 in Rat, Dog, and Monkey	140	(1)
4. Aggregation and Formulation of A-75998	141	(3)
5. LHRH Antagonists in Clinical Evaluation	144	(2)
5.1 Clinical Study of A-75998	144	(1)
5.2 Current LHRH Antagonists in Clinical Studies	144	(2)
6. Summary	146	(1)
References	146	(5)
Chapter 8 LHRH Agonists	151	(32)
Kenneth W. Funk
Jonathan Greer
Akwete L. Adjei
1. Introduction	151	(6)
1.1 Background	152	(1)
1.2. Drug Candidate Selection	153	(4)
2. Physical Chemistry and Chemical Characterization	157	(8)
2.1. Bulk Drug Synthesis	158	(2)
2.2. Manufacturing Controls	160	(1)
2.3. Physical Characteristics and Methods	161	(2)
2.4. Chemical Characterization and Methods	163	(1)
2.5. Moisture and Acetic Acid	163	(1)
2.6. Amino Acid Analysis	164	(1)
3. Formulation Chemistry of Leuprolide Acetate	165	(4)
3.1. In Vitro Studies	165	(1)
3.2. In Vivo Studies	166	(3)
4. Clinical Development	169	(9)
4.1 Standards and Controls	169	(2)
4.2. Physical and Chemical Characterization	171	(3)
4.3. Pathology and Toxicology	174	(3)
4.4. Clinical Pharmacokinetics and Pharmacodynamics	177	(1)
5. Conclusions	178	(1)
References	179	(4)
Chapter 9 Discovery and Development of Somatostatin Agonists	183	(28)
Peter Marbach
Wilfried Bauer
David Bodmer
Ulrich Briner
Christian Bruns
Andrea Kay
Ioana Lancranjan
Janos Pless
Friedrich Raulf
Rodney Robison
John Sharkey
Thomas Soranno
Barbara Stolz
Peter Vit
Gisbert Weckbecker
1. Introduction	183	(1)
2. Somatostatin Receptors	184	(2)
2.1. Heterogeneity of Somatostatin Receptors	184	(1)
2.2. The Somatostatin Receptor Gene Family	184	(1)
2.3. Tissue Distribution	185	(1)
2.4. Pharmacology	186	(1)
3. Discovery and Development of Sandostatin(R)	186	(7)
3.1. Synthesis of Octreotide	189	(1)
3.2. Pharmacodynamic Tests	190	(1)
3.3. Pharmacokinetic Studies	191	(1)
3.4. Toxicology	191	(1)
3.5. Clinical Development	192	(1)
4. Development of Sandostatin(R) LAR(R)	193	(3)
4.1. Manufacture	194	(1)
4.2. Preclinical Studies	194	(1)
4.3. Clinical Studies	195	(1)
5. Oncolar(TM): Technical Development of a New LAR Formulation of Octreotide	196	(1)
5.1. Manufacture	196	(1)
5.2. Preclinical Studies	196	(1)
6. Antiproliferative Effects of Single-Agent Octreotide	197	(4)
6.1. Mechanism of Antiproliferative Action	198	(1)
6.2. Route of Administration and Plasma Levels	199	(1)
6.3. Octreotide as a Potentiator of Standard Anticancer Regimens	199	(2)
7. Development of Octreotide for Oncological Uses beyond the Control of Disease-Related Symptoms in GEP Tumors	201	(1)
7.1. Somatostatin Receptor Binding and Growth Factor Suppression	201	(1)
7.2. Clinical Trials	202	(1)
8. Radiolabeled Octreotide Analogues	202	(2)
8.1. Imaging of Tumors with OctreoScan(R)	203	(1)
8.2. Tumor Radiotherapy with SMT 487	203	(1)
9. Summary and Outlook	204	(1)
References	205	(6)
Chapter 10 Factors Impacting the Delivery of Therapeutic Levels of Pyrone-Based HIV Protease Inhibitors	211	(22)
Guy E. Padbury
Gail L. Zipp
Francis J. Schwende
Zhiyang Zhao
Kenneth A. Koeplinger
Kong Teck Chong
Thomas J. Raub
Suvit Thaisrivongs
1. Introduction	211	(5)
1.1. HIV Protease as a Therapeutic Target	211	(2)
1.2. Pyrone-Based Inhibitors	213	(2)
1.3. Factors that Affect Drug Delivery	215	(1)
1.4. Life in a Perfect World	215	(1)
2. Efficacy	216	(4)
2.1. Effect/Importance of Protein Binding	216	(3)
2.2. Clinical Targets	219	(1)
3. Pharmacokinetics	220	(5)
3.1. Total versus Unbound Intrinsic Clearance	220	(1)
3.2. Factors Affecting Clearance	221	(3)
3.3. Absolute Oral Bioavailability versus Systemic Exposure	224	(1)
4. Life in the Real World	225	(4)
4.1. Selection of a Viable Chemical Template	225	(2)
4.2. Identification of a Final Clinical Candidate	227	(2)
References	229	(4)
Chapter 11 The Integration of Medicinal Chemistry, Drug Metabolism, and Pharmaceutical Research and Development in Drug Discovery and Development: The Story of Crixivan(R), an HIV Protease Inhibitor	233	(24)
Jiunn H. Lin
Drazen Ostovic
Joseph P. Vacca
1. Introduction	233	(1)
2. Discovery of L-735,524 (Crixivan(R))	234	(4)
3. Improvement of Solubility	238	(3)
4. Physicochemical Properties of MK-639 (Indinavir)	241	(5)
5. pH-Dependent Oral Absorption	246	(2)
6. In Vitro/In Vivo Metabolism	248	(1)
7. Backup Compounds	249	(3)
8. Conclusion	252	(2)
References	254	(3)
Chapter 12 De Novo Design and Discovery of Cyclic HIV Protease Inhibitors Capable of Displacing the Active-Site Structural Water Molecule	257	(28)
George V. De Lucca
Prabhakar K. Jadhav
Robert E. Waltermire
Bruce J. Aungst
Susan Erickson-Viitanen
Patrick Y.S. Lam
1. Introduction	257	(1)
2. Initiation of Program at DMPC	258	(1)
3. Design of Cyclic Ureas	259	(7)
3.1. De Novo Design	259	(3)
3.2. Confirmation of Design	262	(3)
3.3. Molecular Recognition	265	(1)
4. First Clinical Candidate DMP 323	266	(4)
4.1. Discovery and Optimization	266	(1)
4.2. Chemistry and Process Development	267	(3)
4.3. Clinical Study	270	(1)
5. Second Clinical Candidate DMP 450	270	(4)
5.1. Discovery and Optimization	270	(1)
5.2. Safety and Pharmacokinetics	271	(1)
5.3. Chemistry and Process Development	272	(1)
5.4. Clinical Study	273	(1)
6. Future Cyclic Ureas	274	(6)
6.1. Potency	275	(1)
6.2. Resistance Profile	276	(2)
6.3. Pharmacokinetics	278	(2)
6.4. Design and Physicochemical Properties	280	(1)
7. Conclusion	280	(1)
References	281	(4)
Chapter 13 Discovery and Development of the BHAP Nonnucleoside Reverse Transcriptase Inhibitor Delavirdine Mesylate	285	(28)
Wade J. Adams
Paul A. Aristoff
Richard K. Jensen
Walter Morozowich
Donna L. Romero
William C. Schinzer
W. Gary Tarpley
Richard C. Thomas
1. Introduction, Goals, and Strategy	285	(2)
2. Discovery of Initial Lead (PNU-80493E)	287	(1)
3. Selection of First-Generation Candidate (PNU-87201)	288	(4)
4. Development of PNU-87201E (Atevirdine Mesylate)	292	(1)
5. Goals for Second-Generation Candidate	292	(1)
6. Selection Process	293	(1)
7. Water-Soluble Compounds	294	(6)
8. Development of PNU-90152T (Delavirdine Mesylate)	300	(10)
8.1. Pharmacology	300	(1)
8.2. Formulation/Salt Selection/Crystal Form	301	(4)
8.3. Absorption, Distribution, Metabolism, and Excretion	305	(3)
8.4. Safety/Toxicokinetics	308	(1)
8.5 Clinical Summary	309	(1)
9. Conclusions	310	(1)
References	310	(3)
Chapter 14 Famciclovir: Discovery and Development of a Novel Antiherpesvirus Agent	313	(32)
Richard L. Jarvest
David Sutton
R. Anthony Vere Hodge
1. Introduction	313	(8)
1.1. Identification of Penciclovir as an Antiherpesvirus Agent	314	(1)
1.2. Antiviral Activity and Spectrum of Activity	315	(1)
1.3. Mechanism of Action	316	(5)
1.4. Oral Bioavailability	321	(1)
2. Prodrug Forms of Penciclovir	321	(8)
2.1. Strategy and Evaluation of Oral Bioavailability	321	(5)
2.2. Evaluation of Metabolic Conversion in Human Body Fluids and Tissues	326	(1)
2.3. Selection of Preferred Oral Candidate: Famciclovir	327	(1)
2.4. Other Routes of Administration	327	(2)
3. Preclinical Evaluation of Famciclovir	329	(2)
3.1. Animal Models of Infection	329	(1)
3.2. Chirality of Metabolic Products from Famciclovir	330	(1)
3.3. Identification of Enzymatic Oxidation in Humans	331	(1)
4. Clinical Evaluation	331	(6)
4.1. Metabolism and Pharmacokinetics	331	(2)
4.2. Efficacy	333	(4)
5. Conclusion	337	(1)
References	338	(7)
Chapter 15 The Use of Esters as Prodrugs for Oral Delivery of Beta-Lactam Antibiotics	345	(22)
Linda Mizen
George Burton
1. Introduction	345	(2)
2. Chemical Overview	347	(3)
3. Animal Bioavailability Studies and Selection	350	(7)
3.1. Penicillins, Penems, Trinem	351	(2)
3.2. Cephalosporins	353	(4)
4. Hydrolysis Rates and Physicochemical Properties	357	(4)
4.1. Hydrolysis by Liver	357	(1)
4.2. Hydrolysis by Small Intestine	358	(1)
4.3. Hydrolysis by Blood	358	(2)
4.4. Physicochemical Properties	360	(1)
5. Dosing Vehicles and Formulations	361	(1)
6. Summary and Conclusions	361	(1)
References	362	(5)
Chapter 16 Hematoregulators: A Case History of a Novel Hematoregulatory Peptide, SK&F 107647	367	(26)
Pradip K. Bhatnagar
William F. Huffman
Andrew G. King
Dagfinn Lovhaug
Louis M. Pelus
William M. Potts
Philip L. Smith
1. Introduction	367	(1)
2. Hematopoiesis, Endogenous Regulators, and Host Defense Mechanism	368	(1)
3. Unmet Needs	369	(2)
4. Nonproteinaceous Hematoregulators	371	(4)
4.1. Polymeric Carbohydrate: Betafectin	371	(1)
4.2. Low-Molecular-Weight Hematoregulators	371	(4)
5. SK&F 107647 and Analogues	375	(8)
5.1. Structure-Activity Relationships of SK&F 107647	376	(3)
5.2. Mechanism of Action	379	(1)
5.3. Colony Stimulating Activity Induction Assay	379	(1)
5.4. Hematopoietic Synergistic Factor Assay	379	(1)
5.5. Preclinical Studies	380	(3)
6. Conclusions	383	(1)
References	384	(9)
Chapter 17 Discovery and Development of GG745, a Potent Inhibitor of Both Isozymes of 5 Alpha-Reductase	393	(30)
Stephen V. Frye
H. Neal Bramson
David J. Hermann
Frank W. Lee
Achintya K. Sinhababu
Gaochao Tian
1. Introduction	393	(6)
1.1. 5 Alpha-Reductases	393	(4)
1.2. Pathophysiology of DHT	397	(1)
1.3. Finasteride: Clinical Effects of a Type 2-Selective 5Alpha-Reductase Inhibitor	398	(1)
1.4. Potential Utility of a Dual 5Alpha-Reductase Inhibitor	399	(1)
2. Enzymology of 5Alpha-Reductases	399	(6)
2.1. Time Dependence of Inhibition by Delta(1) 4-Azasteroids	399	(5)
2.2. Modeling of the Clinical Effect of Finasteride	404	(1)
3. Discovery of Dual 5Alpha-Reductase Inhibitors: 6-Azasteroids	405	(5)
3.1. Medicinal Chemistry	405	(3)
3.2. Pharmacokinetic Studies: In Vivo and in Vitro Correlations	408	(2)
4. Discovery of GG745	410	(3)
5. Initial Clinical Studies with GG745	413	(4)
5.1. Interspecies Scaling/Dose Selection	413	(1)
5.2. Pharmacokinetic and Pharmacodynamic Results in Man	414	(3)
References	417	(6)
Chapter 18 Discovery of a Potent and Selective Alpha(1A) Antagonist: Utilization of a Rapid Screening Method to Obtain Pharmacokinetic Parameters	423	(22)
Kimberly K. Adkison
Kathy A. Halm
Joel E. Shaffer
David Drewry
Achintya K. Sinhababu
Judd Berman
1. Introduction	423	(2)
1.1. Benign Prostatic Hyperplasia	423	(1)
1.2. Therapeutic Use of Alpha(1A)-Selective Antagonists	424	(1)
1.3. Project Goal	425	(1)
2. Research Strategy	425	(8)
2.1. Compound Progression and Critical Path	425	(1)
2.2. Discovery of Alpha(1A)-Selective Oxazole-Containing Antagonists	426	(7)
3. Pharmacokinetic/Pharmacodynamic Strategy	433	(9)
3.1. In Vitro Metabolism Screening Prior to Pharmacokinetic Studies	433	(1)
3.2. Improved Pharmacokinetic Throughput: Mixture Dosing Coupled with LC/MS Analysis	434	(5)
3.3. Pharmacokinetic Evaluation of Other Leads	439	(1)
3.4. Pharmacodynamics of the Lead Compound	440	(2)
4. Advancement of Compound 18 to Exploratory Development	442	(1)
References	442	(3)
Chapter 19 Discovery of Bioavailable Inhibitors of Secretory Phospholipase A(2)	445	(20)
Steven G. Blanchard
Robert C. Andrews
Peter J. Brown
Liang-Shang L. Gan
Frank W. Lee
Achintya K. Sinhababu
Thomas N. Wheeler
1. Introduction	445	(1)
1.1. Therapeutic Target	445	(1)
1.2. Program Objective	446	(1)
2. In Vitro Identification of Active-Site Inhibitors of sPLA(2)	446	(2)
2.1. "Dual Substrate" Strategy for Inhibitor Discovery	446	(1)
2.2. In Vitro Profile of Substrate Analogue PLA(2) Inhibitors	447	(1)
3. In Vivo Anti-inflammatory Activity of Initial Candidates	448	(4)
3.1. Choice of Animal Model	448	(1)
3.2. In Vivo Activity Is Dependent on Formulation of the Test Compound	449	(1)
3.3. Activity in the Rat Carrageenan Paw Edema Model	450	(2)
4. Pharmacokinetic and Metabolic Fate of Candidate Inhibitors	452	(6)
4.1. Plasma Levels and Metabolic Profiles after i.v. and p.o. Dosing	452	(1)
4.2. In Vitro Studies	453	(4)
4.3. Conclusions Based on Metabolism Studies	457	(1)
5. Preparation of Inhibitors Designed to Address the Observed Metabolic Instability	458	(3)
5.1. Synthesis and in Vitro Evaluation of Inhibitory Activity	458	(2)
5.2. Evaluation of in Vitro Stability	460	(1)
5.3. Pharmacokinetic Studies	460	(1)
5.4. In Vivo Activity of Inhibitors with Improved Metabolism and Pharmacokinetics	460	(1)
6. Summary and Conclusions	461	(1)
References	462	(3)
Chapter 20 The Anxieties of Drug Discovery and Development: CCK-B Receptor Antagonists	465	(16)
Franco Lombardo
Steven M. Winter
Larry Tremaine
John A. Lowe III
1. Introduction	465	(1)
2. Chemistry	466	(2)
3. Initial Drug Metabolism Studies	468	(3)
4. Formulation Studies	471	(5)
5. A New Analogue with Improved Aqueous Solubility: CP-310, 713	476	(1)
6. Lessons Learned	477	(1)
References	478	(3)
Chapter 21 CI-1015: An Orally Active CCK-B Receptor Antagonist with an Improved Pharmacokinetic Profile	481	(26)
Bharat K. Trivedi
Joanna P. Hinton
1. Introduction	481	(7)
1.1. First-Generation CCK-B Antagonists	482	(1)
1.2. CI-988 Pharmacokinetic Retrospective	483	(5)
1.3. Objectives of the Discovery Team	488	(1)
2. Discovery of CI-1015	488	(6)
2.1. Design Strategy	488	(1)
2.2. Structure-Activity Relationship Study	488	(6)
3. Preclinical Characterization of Backup Candidates	494	(6)
3.1. In Vitro and in Vivo Comparison	494	(1)
3.2. Pharmacokinetic Evaluations in Rat	494	(4)
3.3. Brain Penetration Studies	498	(1)
3.4. Evaluation of Potential for Gastric Acid Secretion	499	(1)
3.5. Pharmacokinetic Evaluation in Monkey	500	(1)
4. Conclusion	500	(3)
References	503	(4)
Chapter 22 Orally Active Nonpeptide CCK-A Agonists	507	(18)
Elizabeth E. Sugg
Lawrence Birkemo
Liang-Shang L. Gan
Timothy K. Tippin
1. Introduction	507	(1)
2. In Vivo Profile of GW7854	508	(2)
3. Pharmaceutical Studies with GW7854	510	(1)
3.1. Batch Variation	510	(1)
3.2. Dosing Vehicle	510	(1)
4. Pharmacology Studies	510	(1)
4.1. The Mouse Gallbladder Emptying Assay	510	(1)
4.2. Alternate Species	511	(1)
4.3. The Conditioned Feeder Rat Model	511	(1)
5. Pharmacokinetic Profile of GW7854	511	(1)
6. The Caco-2 Model for Intestinal Absorption	512	(4)
6.1. Correlation with Rat Intestinal Absorption	513	(1)
6.2. Structure-Transport Relationships	513	(3)
7. Bioavailability versus Bioactivity	516	(5)
8. Oral versus Intraduodenal Dosing	521	(1)
9. Discussion	521	(1)
10. Clinical Implications	522	(1)
References	522	(3)
Chapter 23 Orally Active Growth Hormone Secretagogues	525	(30)
Arthur A. Patchett
Roy G. Smith
Matthew J. Wyvratt
1. Introduction	525	(2)
2. Discovery of GHRP-6 Mimics: Benzolactam L-692, 429	527	(7)
2.1. Clinical Studies with L-692, 429	528	(1)
2.2. Structure-Activity-Bioavailability Relationships for the Benzolactams	529	(5)
3. New Structural Leads	534	(10)
3.1. Privileged Structure Screening	534	(2)
3.2. Discovery of MK-0677	536	(8)
4. Mechanism of Action of GH Secretagogues	544	(3)
4.1. Biochemistry	544	(1)
4.2. Characterization of the GH Secretagogue Receptor (GHS-R)	545	(1)
4.3. Cloning the GH Secretagogue Receptor	546	(1)
4.4. GH Secretagogue Receptor and GH Pulsatility	546	(1)
5. Conclusion	547	(2)
References	549	(6)
Chapter 24 Dorzolamide, a 40-Year Wait: From an Oral to a Topical Carbonic Anhydrase Inhibitor for the Treatment of Glaucoma	555	(20)
Gerald S. Ponticello
Michael F. Sugrue
Bernard Plazonnet
Genevieve Durand-Cavagna
1. Introduction	555	(2)
2. Benzothiazoles	557	(1)
3. Benzothiophenes	558	(1)
4. Thienothiopyrans	559	(1)
5. Dorzolamide	560	(3)
6. Pharmacology	563	(3)
6.1. In Vitro	563	(1)
6.2. In Vivo	564	(2)
7. Pharmaceutical Research and Development Studies	566	(1)
8. Safety Assessment Studies	567	(4)
9. Summary	571	(1)
References	572	(3)
Chapter 25 Discovery and Development of Novel Melanogenic Drugs: Melanotan-I and -II	575	(22)
Mac E. Hadley
Victor J. Hruby
James Blanchard
Robert T. Dorr
Norman Levine
Brenda V. Dawson
Fahad Al-Obeidi
Tomi K. Sawyer
1. Introduction	575	(1)
2. The Melanocortin Peptides and Receptors	576	(3)
2.1. Melanocortin Peptides	576	(1)
2.2. Melanocortin Receptors	577	(2)
3. Discovery of the MT-I and MT-II as MSH Superagonists	579	(4)
3.1. Structure-Activity Studies of Alpha-MSH	579	(1)
3.2. Design and Chemistry of MT-I and MT-II	580	(2)
3.3 In Vitro and in Vivo Pharmacology of MT-I and MT-II	582	(1)
4. Development of MT-I and MT-II as Novel Melanogenic Drugs	583	(7)
4.1. Stability, Pharmacokinetic, and Toxicological Studies	583	(2)
4.2. Drug Delivery and Clinical Studies	585	(5)
5. Summary and Future Directions	590	(1)
References	591	(6)
Index	597