James R. Damewood

Development and SAR of functionally selective allosteric modulators of GABAA receptors

Positive modulators at the benzodiazepine site of α2- and α3-containing GABA(A) receptors are believed to be anxiolytic. Through oocyte voltage clamp studies, we have discovered two series of compounds that are positive modulators at α2-/α3-containing GABA(A) receptors and that show no functional activity at α1-containing GABA(A) receptors. We report studies to improve this functional selectivity and ultimately deliver clinical candidates. The functional SAR of cinnolines and quinolines that are positive allosteric modulators of the α2- and α3-containing GABA(A) receptors, while simultaneously neutral antagonists at α1-containing GABA(A) receptors, is described. Such functionally selective modulators of GABA(A) receptors are expected to be useful in the treatment of anxiety and other psychiatric illnesses.

The discovery of non-basic atrial natriuretic peptide clearance receptor antagonists. Part 1

The cyclic peptide ANP 4-23 and the linear peptide analogue AP-811 have been shown to be selective ANP-CR antagonists. Via alanine scanning and truncation studies we sought to determine which residues in these molecules were important in their binding to the clearance receptor and the relationship between these two molecules. These studies show that several modifications to these compounds are possible which improve physical properties of these molecules while retaining high affinity for the ANP-CR.

NovoFLAP: A Ligand-Based De Novo Design Approach for the Generation of Medicinally Relevant Ideas

NovoFLAP is a computer-aided de novo design tool that generates medicinally relevant ideas for ligand-based projects. The approach combines an evolutionary algorithm (EA-Inventor) with a powerful ligand-based scoring function that uses both molecular shape and pharmacophore features in a multiconformational context (FLAP). We demonstrate that NovoFLAP can generate novel ideas that are not only appealing to design scientists but are also validated by comparison to compounds known to demonstrate activity at the desired biological target. NovoFLAP provides a novel computer-aided design technique that can be used to generate ideas that maintain desirable molecular attributes, such as activity at the primary biological target, while offering opportunities to surmount additional design challenges. Application to the design of the first nonbasic 5HT(1B) antagonist is presented.

De Novo Design of a Picomolar Nonbasic 5-HT1B Receptor Antagonist

We describe herein the discovery of novel, de novo designed, 5-HT(1B) receptor antagonists that lack a basic moiety and that provide improved hERG and in vitro phospholipidosis profiles. We used a known 5-HT(1B) antagonist template as our starting point and focused on replacing the piperazine moiety. Pyrazole-based ideas were designed and synthesized among a small library of piperazine replacements. To our knowledge, these are the first potent, nonbasic, functionally active antagonists of the 5-HT(1B) receptor.

Muse+TriposScore: a ligand-based de novo design approach

Successful drug discovery often requires optimization against a set of biological and physical properties. We describe our work on multi-parameter approaches to ligand-based de novo design and studies that demonstrate its ability to successfully generate lead hops or scaffold hops between known classes of ligands for some example receptors. We describe a multi-criteria scoring function incorporating molecular shape similarity, molecular fingerprint similarity, and a number of popular “Lipinski-like” molecular properties. Muse is based on an evolutionary algorithm that operates on an initial population of structures to invent new structures with improved scores. Muse is unique in that it has the ability to work with any user-defined scoring function that provides results in the form of a numerical evaluation of designed structures. Several retrospective studies on various targets demonstrate the ability of the above mentioned approach to generate novel ideas that are not only appealing to design scientists but are also validated by comparison to compounds known to demonstrate activity at the desired biological target. Specific examples where this approach has generated either significant modifications of existing molecular frameworks or structurally new molecular templates relative to design starting points (i.e., lead hopping) will be provided.