Challenges and Rewards in Medicinal Chemistry Targeting Cardiovascular and Metabolic Diseases.
Medicinal chemistry has been transformed by major technological and conceptual innovations over the last three decades: structural biology and bioinformatics, structure and property based molecular design, the concepts of multidimensional optimization (MDO), in silico and experimental high-throughput molecular property analysis. The novel technologies advanced gradually and in synergy with biology and Roche has been at the forefront. Applications in drug discovery programs towards new medicines in cardiovascular and metabolic diseases are highlighted to show impact and advancement: the early discovery of endothelin antagonists for endothelial dysfunction (Bosentan), 11-beta hydroxysteroid dehydrogenase (11β-HSD1) inhibitors for dysregulated cellular glucocorticoid tonus (type 2 diabetes and metabolic syndrome) and non-covalent hormone sensitive lipase (HSL) inhibitors to study the scope of direct inhibition of lipolysis in the conceptual frame of lipotoxicity and type 2 diabetes.
Roche Pharmaceutical Research and Early Development (pRED), Roche Innovation Center Basel, Medicinal Chemistry, 124 Grenzacherstrasse, B 92 / 4.92, CH-4070 Basel, Switzerland. werner.neidhart@roche.com.
Werner
W
Neidhart
Roche Pharmaceutical Research and Early Development (pRED), Roche Innovation Center Basel, Medicinal Chemistry, 124 Grenzacherstrasse, B 92 / 4.92, CH-4070 Basel, Switzerland.
Jean
J
Ackermann
Roche Pharmaceutical Research and Early Development (pRED), Roche Innovation Center Basel, Medicinal Chemistry, 124 Grenzacherstrasse, B 92 / 4.92, CH-4070 Basel, Switzerland.
Kurt
K
Amrein
Roche Pharmaceutical Research and Early Development (pRED), Roche Innovation Center Basel, Medicinal Chemistry, 124 Grenzacherstrasse, B 92 / 4.92, CH-4070 Basel, Switzerland.
Aurelia
A
Conte
Roche Pharmaceutical Research and Early Development (pRED), Roche Innovation Center Basel, Medicinal Chemistry, 124 Grenzacherstrasse, B 92 / 4.92, CH-4070 Basel, Switzerland.
Daniel
D
Hunziker
Roche Pharmaceutical Research and Early Development (pRED), Roche Innovation Center Basel, Medicinal Chemistry, 124 Grenzacherstrasse, B 92 / 4.92, CH-4070 Basel, Switzerland.
Bernd
B
Kuhn
Roche Pharmaceutical Research and Early Development (pRED), Roche Innovation Center Basel, Medicinal Chemistry, 124 Grenzacherstrasse, B 92 / 4.92, CH-4070 Basel, Switzerland.
Hans Peter
HP
Märki
Roche Pharmaceutical Research and Early Development (pRED), Roche Innovation Center Basel, Medicinal Chemistry, 124 Grenzacherstrasse, B 92 / 4.92, CH-4070 Basel, Switzerland.
Matthias
M
Nettekoven
Roche Pharmaceutical Research and Early Development (pRED), Roche Innovation Center Basel, Medicinal Chemistry, 124 Grenzacherstrasse, B 92 / 4.92, CH-4070 Basel, Switzerland.
Armin
A
Ruf
Roche Pharmaceutical Research and Early Development (pRED), Roche Innovation Center Basel, Medicinal Chemistry, 124 Grenzacherstrasse, B 92 / 4.92, CH-4070 Basel, Switzerland.
Tanja
T
Schulz-Gasch
Roche Pharmaceutical Research and Early Development (pRED), Roche Innovation Center Basel, Medicinal Chemistry, 124 Grenzacherstrasse, B 92 / 4.92, CH-4070 Basel, Switzerland.
Alexander V
AV
Mayweg
D000818:Animals; D002317:Cardiovascular Agents / Q000627:therapeutic use; D002318:Cardiovascular Diseases / Q000188:drug therapy*; D002626:Chemistry, Pharmaceutical / Q000639:trends*; D016503:Drug Delivery Systems; D015195:Drug Design; D006801:Humans; D008659:Metabolic Diseases / Q000188:drug therapy*
D002317:Cardiovascular Agents